Activity

Filter

Cancel
Date Panel Item Activity
3000 actions
Mendeliome v1.781 VWA8 Dean Phelan gene: VWA8 was added
gene: VWA8 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: VWA8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: VWA8 were set to PMID: 37012052
Phenotypes for gene: VWA8 were set to Retinitis pigmentosa (MONDO:0019200), VWA8-related
Review for gene: VWA8 was set to AMBER
Added comment: PMID: 37012052
- Single family with 11 affected patients, 9 - 87y, all presented initial symptoms of night blindness, visual field defects and reduced visual acuity later, macular changes, including macular degeneration and dystrophy. A heterozygous two-loci variant in VWA8 c.3070G>A;c.4558C>T (p.Gly1024Arg; p.Arg1520Ter) was identified and segregated with disease. Expression studies showed reduced protein expression. Zebrafish knockout model displayed an RP phenotype.
Sources: Literature
Mendeliome v1.781 MKL2 Dean Phelan gene: MKL2 was added
gene: MKL2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MKL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MKL2 were set to PMID: 37013900
Phenotypes for gene: MKL2 were set to Neurodevelopmental disorder (MONDO:0700092), MKL2-related
Mode of pathogenicity for gene: MKL2 was set to Other
Review for gene: MKL2 was set to AMBER
Added comment: PMID: 37013900
- de novo missense variants in MKL2 (now known as MRTFB) were identified in two patients with mild dysmorphic features, intellectual disability, global developmental delay, speech apraxia, and impulse control issues. Functional studies in a Drosophila model suggest a gain of function disease mechanism.
Sources: Literature
Mitochondrial disease v0.864 SLC25A36 Bryony Thompson Marked gene: SLC25A36 as ready
Mitochondrial disease v0.864 SLC25A36 Bryony Thompson Gene: slc25a36 has been classified as Green List (High Evidence).
Mitochondrial disease v0.864 SLC25A36 Bryony Thompson Classified gene: SLC25A36 as Green List (high evidence)
Mitochondrial disease v0.864 SLC25A36 Bryony Thompson Gene: slc25a36 has been classified as Green List (High Evidence).
Mitochondrial disease v0.863 PPCS Bryony Thompson Publications for gene: PPCS were set to 29754768
Mitochondrial disease v0.863 PPCS Bryony Thompson Classified gene: PPCS as Green List (high evidence)
Mitochondrial disease v0.863 PPCS Bryony Thompson Gene: ppcs has been classified as Green List (High Evidence).
Mitochondrial disease v0.862 ATP5E Bryony Thompson Publications for gene: ATP5E were set to 20566710; 27626380; 20026007
Mitochondrial disease v0.861 ATP5E Bryony Thompson Classified gene: ATP5E as Green List (high evidence)
Mitochondrial disease v0.861 ATP5E Bryony Thompson Gene: atp5e has been classified as Green List (High Evidence).
Vasculitis v0.74 LYN Seb Lunke changed review comment from: Three unrelated individuals from described with three distinct de novo variants in LYN, p.Y508*, p.Q507* and a missense variant, p.Y508F. The PTC variants do not cause NMD, and all three variants have been shown to result in constitutively active LYN kinase by preventing inhibitory phosphorylation of the Y508 regulatory tyrosine. Extensive functional data to confirm gain-of-function effect was presented.

Patient presented perinatally with immunological symptoms, including diffuse purpuric skin lesions, fever, and increased C-reactive protein (CRP). mild anemia, mild leukocytosis, moderate to severe thrombocytopenia. The patients with PTC were more severe, developing liver fibrosis and signs of cirrhosis.

All three patients responded to various degrees to treatment with src kinase inhibitors, dasatinib, etanercept and/or colchicine. Authors named the condition Lyn kinase-associated vasculopathy and liver fibrosis (LAVLI); to: Three unrelated individuals from described with three distinct de novo variants in LYN, p.Y508*, p.Q507* and a missense variant, p.Y508F. The PTC variants do not cause NMD, and all three variants have been shown to result in constitutively active LYN kinase by preventing inhibitory phosphorylation of the Y508 regulatory tyrosine. Extensive functional data to confirm gain-of-function effect was presented.

Patient presented perinatally with immunological symptoms, including diffuse purpuric skin lesions, fever, and increased C-reactive protein (CRP). mild anemia, mild leukocytosis, moderate to severe thrombocytopenia. The patients with PTC were more severe, developing liver fibrosis and signs of cirrhosis.

All three patients responded to various degrees to treatment with src kinase inhibitors, dasatinib, etanercept and/or colchicine. Authors named the condition Lyn kinase-associated vasculopathy and liver fibrosis (LAVLI).

A fourth patient with a Tyr508His has also been described and presented with since birth with recurrent fever, chronic urticaria, atopic dermatitis, arthralgia, increased inflammatory biomarkers, and elevated plasma cytokine levels. Other features not consistent with LYN disease were attributed to prematurity (following maternal HELLP syndrome) and potentially other genetic factors.
Vasculitis v0.74 LYN Seb Lunke edited their review of gene: LYN: Changed publications: 36932076, 36122175
Genetic Epilepsy v0.1838 RNH1 Seb Lunke Marked gene: RNH1 as ready
Genetic Epilepsy v0.1838 RNH1 Seb Lunke Gene: rnh1 has been classified as Red List (Low Evidence).
Regression v0.524 RNH1 Seb Lunke Marked gene: RNH1 as ready
Regression v0.524 RNH1 Seb Lunke Gene: rnh1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.5199 RNH1 Seb Lunke Marked gene: RNH1 as ready
Intellectual disability syndromic and non-syndromic v0.5199 RNH1 Seb Lunke Gene: rnh1 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.5199 RNH1 Seb Lunke Classified gene: RNH1 as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v0.5199 RNH1 Seb Lunke Gene: rnh1 has been classified as Red List (Low Evidence).
Genetic Epilepsy v0.1838 RNH1 Seb Lunke Classified gene: RNH1 as Red List (low evidence)
Genetic Epilepsy v0.1838 RNH1 Seb Lunke Gene: rnh1 has been classified as Red List (Low Evidence).
Regression v0.524 RNH1 Seb Lunke Classified gene: RNH1 as Red List (low evidence)
Regression v0.524 RNH1 Seb Lunke Gene: rnh1 has been classified as Red List (Low Evidence).
Mendeliome v1.781 RNH1 Seb Lunke Marked gene: RNH1 as ready
Mendeliome v1.781 RNH1 Seb Lunke Gene: rnh1 has been classified as Red List (Low Evidence).
Mendeliome v1.781 RNH1 Seb Lunke Classified gene: RNH1 as Red List (low evidence)
Mendeliome v1.781 RNH1 Seb Lunke Gene: rnh1 has been classified as Red List (Low Evidence).
Fetal anomalies v1.97 ESAM Seb Lunke Marked gene: ESAM as ready
Fetal anomalies v1.97 ESAM Seb Lunke Gene: esam has been classified as Green List (High Evidence).
Fetal anomalies v1.97 ESAM Seb Lunke Classified gene: ESAM as Green List (high evidence)
Fetal anomalies v1.97 ESAM Seb Lunke Gene: esam has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1837 ESAM Seb Lunke Marked gene: ESAM as ready
Genetic Epilepsy v0.1837 ESAM Seb Lunke Gene: esam has been classified as Green List (High Evidence).
Mendeliome v1.780 ESAM Seb Lunke Marked gene: ESAM as ready
Mendeliome v1.780 ESAM Seb Lunke Gene: esam has been classified as Green List (High Evidence).
Brain Calcification v1.51 ESAM Seb Lunke Marked gene: ESAM as ready
Brain Calcification v1.51 ESAM Seb Lunke Gene: esam has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1837 ESAM Seb Lunke Classified gene: ESAM as Green List (high evidence)
Genetic Epilepsy v0.1837 ESAM Seb Lunke Gene: esam has been classified as Green List (High Evidence).
Brain Calcification v1.51 ESAM Seb Lunke Classified gene: ESAM as Green List (high evidence)
Brain Calcification v1.51 ESAM Seb Lunke Gene: esam has been classified as Green List (High Evidence).
Mendeliome v1.780 ESAM Seb Lunke Classified gene: ESAM as Green List (high evidence)
Mendeliome v1.780 ESAM Seb Lunke Gene: esam has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5198 CRIPT Karina Sandoval commented on gene: CRIPT: PMID: 37013901 identified 6 individuals with Rothmund-Thomson syndrome characterised by poikiloderma, sparse hair, small stature, skeletal defects, cancer, cataracts, resembling features of premature aging. Two new variants identified and 4 were already published. 5 were hom, 1 was chet, all with different variants.
All CRIPT individuals fulfilled the diagnostic criteria for RTS, and additionally had neurodevelopmental delay and seizures.

CRIPT-deficient fibroblasts showed an unremarkable mitotic progression and unremarkable number of mitotic errors,

c.132del p.(Ala45Glyfs*82), hom
c.227G>A, p.(Cys76Tyr), hom
c.133_134insGG,p.(Ala45Glyfs*82),hom
c.141del p.(Phe47Leufs*84), hom
c.8G>A p.(Cys3Tyr), 1,331 bp del exon 1, chet
c.7_8del; p.(Cys3Argfs*4), hom
Intellectual disability syndromic and non-syndromic v0.5198 CRIPT Karina Sandoval gene: CRIPT was added
gene: CRIPT was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: CRIPT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CRIPT were set to PMID: 37013901
Phenotypes for gene: CRIPT were set to Short stature with microcephaly and distinctive facies (MIM#615789) : Rothmund-Thomson syndrome MONDO:0010002
Review for gene: CRIPT was set to GREEN
Added comment: Sources: Literature
Vasculitis v0.74 LYN Seb Lunke reviewed gene: LYN: Rating: GREEN; Mode of pathogenicity: Other; Publications: 36932076; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Growth failure v1.59 CRIPT Karina Sandoval reviewed gene: CRIPT: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37013901; Phenotypes: Short stature with microcephaly and distinctive facies (MIM#615789), Rothmund-Thomson syndrome MONDO:0010002; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5198 MKL2 Zornitza Stark Classified gene: MKL2 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.5198 MKL2 Zornitza Stark Gene: mkl2 has been classified as Amber List (Moderate Evidence).
Microcephalic Primordial Dwarfism and Slender bone dysplasias v0.24 CRIPT Karina Sandoval reviewed gene: CRIPT: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37013901; Phenotypes: Short stature with microcephaly and distinctive facies (MIM#615789), Rothmund-Thomson syndrome MONDO:0010002; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinitis pigmentosa_Autosomal Dominant v0.56 VWA8 Seb Lunke Marked gene: VWA8 as ready
Retinitis pigmentosa_Autosomal Dominant v0.56 VWA8 Seb Lunke Gene: vwa8 has been classified as Amber List (Moderate Evidence).
Retinitis pigmentosa_Autosomal Dominant v0.56 VWA8 Seb Lunke Classified gene: VWA8 as Amber List (moderate evidence)
Retinitis pigmentosa_Autosomal Dominant v0.56 VWA8 Seb Lunke Gene: vwa8 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.779 CRIPT Zornitza Stark Phenotypes for gene: CRIPT were changed from Short stature with microcephaly and distinctive facies (MIM#615789) to Short stature with microcephaly and distinctive facies (MIM#615789); Rothmund-Thomson syndrome MONDO:0010002
Mendeliome v1.778 CRIPT Zornitza Stark Classified gene: CRIPT as Green List (high evidence)
Mendeliome v1.778 CRIPT Zornitza Stark Gene: cript has been classified as Green List (High Evidence).
Fetal anomalies v1.96 CRIPT Zornitza Stark Phenotypes for gene: CRIPT were changed from Short stature with microcephaly and distinctive facies, 615789 to Short stature with microcephaly and distinctive facies (MIM#615789); Rothmund-Thomson syndrome MONDO:0010002
Fetal anomalies v1.95 CRIPT Zornitza Stark Publications for gene: CRIPT were set to 24389050; 27250922
Fetal anomalies v1.94 CRIPT Zornitza Stark Classified gene: CRIPT as Green List (high evidence)
Fetal anomalies v1.94 CRIPT Zornitza Stark Gene: cript has been classified as Green List (High Evidence).
Microcephaly v1.196 CRIPT Karina Sandoval reviewed gene: CRIPT: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37013901; Phenotypes: Short stature with microcephaly and distinctive facies (MIM#615789), Rothmund-Thomson syndrome MONDO:0010002; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinitis pigmentosa_Autosomal Recessive/X-linked v0.132 CEP162 Zornitza Stark Marked gene: CEP162 as ready
Retinitis pigmentosa_Autosomal Recessive/X-linked v0.132 CEP162 Zornitza Stark Gene: cep162 has been classified as Amber List (Moderate Evidence).
Retinitis pigmentosa_Autosomal Recessive/X-linked v0.132 CEP162 Zornitza Stark Marked gene: CEP162 as ready
Retinitis pigmentosa_Autosomal Recessive/X-linked v0.132 CEP162 Zornitza Stark Gene: cep162 has been classified as Amber List (Moderate Evidence).
Retinitis pigmentosa_Autosomal Recessive/X-linked v0.132 CEP162 Zornitza Stark Classified gene: CEP162 as Amber List (moderate evidence)
Retinitis pigmentosa_Autosomal Recessive/X-linked v0.132 CEP162 Zornitza Stark Gene: cep162 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.777 CEP162 Zornitza Stark Marked gene: CEP162 as ready
Mendeliome v1.777 CEP162 Zornitza Stark Gene: cep162 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.777 CEP162 Zornitza Stark Classified gene: CEP162 as Amber List (moderate evidence)
Mendeliome v1.777 CEP162 Zornitza Stark Gene: cep162 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.93 CRIPT Karina Sandoval reviewed gene: CRIPT: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37013901; Phenotypes: Short stature with microcephaly and distinctive facies (MIM#615789), Rothmund-Thomson syndrome MONDO:0010002; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.776 CRIPT Karina Sandoval changed review comment from: PMID: 37013901 identified 6 individuals with Rothmund-Thomson syndrome, two new identified and 4 were already published. 5 were hom, 1 was chet, all with different variants. Additionally all presented with neuro dev delay and seizures.

CRIPT-deficient fibroblasts showed an unremarkable mitotic progression and unremarkable number of mitotic errors,

c.132del p.(Ala45Glyfs*82), hom
c.227G>A, p.(Cys76Tyr), hom
c.133_134insGG,p.(Ala45Glyfs*82),hom
c.141del p.(Phe47Leufs*84), hom
c.8G>A p.(Cys3Tyr), 1,331 bp del exon 1, chet
c.7_8del; p.(Cys3Argfs*4), hom; to: PMID: 37013901 identified 6 individuals with Rothmund-Thomson syndrome characterised by poikiloderma, sparse hair, small stature, skeletal defects, cancer, cataracts, resembling features of premature aging. Two new variants identified and 4 were already published. 5 were hom, 1 was chet, all with different variants.
All CRIPT individuals fulfilled the diagnostic criteria for RTS, and additionally had neurodevelopmental delay and seizures.

CRIPT-deficient fibroblasts showed an unremarkable mitotic progression and unremarkable number of mitotic errors,

c.132del p.(Ala45Glyfs*82), hom
c.227G>A, p.(Cys76Tyr), hom
c.133_134insGG,p.(Ala45Glyfs*82),hom
c.141del p.(Phe47Leufs*84), hom
c.8G>A p.(Cys3Tyr), 1,331 bp del exon 1, chet
c.7_8del; p.(Cys3Argfs*4), hom
Fetal anomalies v1.93 ACTC1 Lilian Downie reviewed gene: ACTC1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36945405; Phenotypes: Atrial septal defect 5 MIM#612794, Cardiomyopathy, dilated, 1R MIM#613424, Cardiomyopathy, hypertrophic, 11 MIM#612098, ACTC1 related distal arthrogryposis MONDO:0019942; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.776 CEP162 Paul De Fazio gene: CEP162 was added
gene: CEP162 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CEP162 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP162 were set to 36862503
Phenotypes for gene: CEP162 were set to Retinitis pigmentosa MONDO:0019200, CEP162-related
Penetrance for gene: CEP162 were set to unknown
Review for gene: CEP162 was set to AMBER
gene: CEP162 was marked as current diagnostic
Added comment: 2 patients from reportedly unrelated consanguineous Moroccan families with the same homozygous frameshift variant reported with late-onset retinal degeneration. Patient 1 was diagnosed with RP at age 60, patient 2 at age 69. Both reported loss of visual acuity in the years prior.

Immunoblotting of cell lysates from patient fibroblasts showed that some mutant transcript escaped NMD. Functional testing showed that the truncated protein could bind microtubules but was unable to associate with centrioles or its interaction partner CEP290. Patient fibroblasts were shown to have delayed ciliation.

Mutant protein was unable to rescue loss of cilia in CEP162 knockdown mice supporting that the mutant protein does not retain any ciliary function, however additional data supported that the truncated protein was able to bind microtubules and function normally during neuroretinal development. The authors suggest this likely underlies the late-onset RP in both patients.

Rated Amber because only a single variant has been reported in patients who may or may not be related (same ethnic background).
Sources: Literature
Arthrogryposis v0.395 ACTC1 Zornitza Stark Marked gene: ACTC1 as ready
Arthrogryposis v0.395 ACTC1 Zornitza Stark Gene: actc1 has been classified as Green List (High Evidence).
Mendeliome v1.776 ACTC1 Lilian Downie gene: ACTC1 was added
gene: ACTC1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ACTC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ACTC1 were set to PMID: 36945405
Phenotypes for gene: ACTC1 were set to Atrial septal defect 5 MIM#612794; Cardiomyopathy, dilated, 1R MIM#613424; Cardiomyopathy, hypertrophic, 11 MIM#612098; ACTC1 related distal arthrogryposis MONDO:0019942
Review for gene: ACTC1 was set to GREEN
Added comment: ClinGen definitive association with HCM, moderate for DCM
5 new families (8 individuals) with a distral arthrogryposis phenotype (PMID: 36945405)
multiple congenital contractures, neck pterygia, scoliosis, and congenital heart defects/cardiomyopathy
facial features: microretrognathia, ptosis, downslanting palpebral fissures, low-set ears, and a long nasal bridge
All missense variants
Sources: Literature
Syndromic Retinopathy v0.197 CLCN2 Michelle Torres gene: CLCN2 was added
gene: CLCN2 was added to Syndromic Retinopathy. Sources: Literature
Mode of inheritance for gene: CLCN2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CLCN2 were set to 36964785
Phenotypes for gene: CLCN2 were set to Leukoencephalopathy with ataxia MIM# 615651
Review for gene: CLCN2 was set to GREEN
Added comment: The homozygous R753X was detected in a Chinese individual from a consanguineous family with leukodystrophy with ataxia (LKPAT) (described in a previous paper) as well as severe bilateral retinal degeneration with loss of photoreceptor and RPE.

Four additional patients with LKPAT (described elsewhere) have been reported with homozygous variants and ocular features (Table 1).

Transfection to HEK293T cells showed that R753X reduced channel activity compared to wild-type.

Additionally, patient iPSC-derived RPE cells carrying the R753X exhibited dysfunctional ClC-2 chloride channels and outer segment phagocytosis. These functions were rescued following the repair of the CLCN2 mutation using the CRISPR-Cas9 system. NB: No significant difference was observed in the R753X mRNA expression levels between the control and patient hiPSC-RPE cells (suggesting NMD escape).
Sources: Literature
Arthrogryposis v0.395 ACTC1 Zornitza Stark Classified gene: ACTC1 as Green List (high evidence)
Arthrogryposis v0.395 ACTC1 Zornitza Stark Gene: actc1 has been classified as Green List (High Evidence).
Vascular Malformations_Somatic v1.8 MAP3K3 Naomi Baker reviewed gene: MAP3K3: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33729480, 35355835, 33891857, 36995941; Phenotypes: Cerebral malformation, MONDO:0016054, MAP3K3-related; Mode of inheritance: Other
Retinitis pigmentosa_Autosomal Dominant v0.55 VWA8 Dean Phelan gene: VWA8 was added
gene: VWA8 was added to Retinitis pigmentosa_Autosomal Dominant. Sources: Literature
Mode of inheritance for gene: VWA8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: VWA8 were set to PMID: 37012052
Phenotypes for gene: VWA8 were set to Retinitis pigmentosa (MONDO:0019200), VWA8-related
Review for gene: VWA8 was set to AMBER
Added comment: PMID: 37012052
- Single family with 11 affected patients, 9 - 87y, all presented initial symptoms of night blindness, visual field defects and reduced visual acuity later, macular changes, including macular degeneration and dystrophy. A heterozygous two-loci variant in VWA8 c.3070G>A;c.4558C>T (p.Gly1024Arg; p.Arg1520Ter) was identified and segregated with disease. Expression studies showed reduced protein expression. Zebrafish knockout model displayed an RP phenotype.
Sources: Literature
Mendeliome v1.776 CRIPT Karina Sandoval reviewed gene: CRIPT: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 37013901; Phenotypes: Short stature with microcephaly and distinctive facies (MIM#615789), Rothmund-Thomson syndrome MONDO:0010002; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinitis pigmentosa_Autosomal Recessive/X-linked v0.131 CEP162 Paul De Fazio gene: CEP162 was added
gene: CEP162 was added to Retinitis pigmentosa_Autosomal Recessive/X-linked. Sources: Literature
Mode of inheritance for gene: CEP162 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP162 were set to 36862503
Phenotypes for gene: CEP162 were set to Retinitis pigmentosa MONDO:0019200, CEP162-related
Penetrance for gene: CEP162 were set to unknown
Review for gene: CEP162 was set to AMBER
gene: CEP162 was marked as current diagnostic
Added comment: 2 patients from reportedly unrelated consanguineous Moroccan families with the same homozygous frameshift variant reported with late-onset retinal degeneration. Patient 1 was diagnosed with RP at age 60, patient 2 at age 69. Both reported loss of visual acuity in the years prior.

Immunoblotting of cell lysates from patient fibroblasts showed that some mutant transcript escaped NMD. Functional testing showed that the truncated protein could bind microtubules but was unable to associate with centrioles or its interaction partner CEP290. Patient fibroblasts were shown to have delayed ciliation.

Mutant protein was unable to rescue loss of cilia in CEP162 knockdown mice supporting that the mutant protein does not retain any ciliary function, however additional data supported that the truncated protein was able to bind microtubules and function normally during neuroretinal development. The authors suggest this likely underlies the late-onset RP in both patients.

Rated Amber because only a single variant has been reported in patients who may or may not be related (same ethnic background).
Sources: Literature
Hereditary Spastic Paraplegia - paediatric v1.58 SNAPC4 Zornitza Stark Marked gene: SNAPC4 as ready
Hereditary Spastic Paraplegia - paediatric v1.58 SNAPC4 Zornitza Stark Gene: snapc4 has been classified as Green List (High Evidence).
Mendeliome v1.776 DOCK11 Seb Lunke Marked gene: DOCK11 as ready
Mendeliome v1.776 DOCK11 Seb Lunke Gene: dock11 has been classified as Green List (High Evidence).
Mendeliome v1.776 DOCK11 Seb Lunke Classified gene: DOCK11 as Green List (high evidence)
Mendeliome v1.776 DOCK11 Seb Lunke Gene: dock11 has been classified as Green List (High Evidence).
Hereditary Spastic Paraplegia - paediatric v1.58 SNAPC4 Zornitza Stark Classified gene: SNAPC4 as Green List (high evidence)
Hereditary Spastic Paraplegia - paediatric v1.58 SNAPC4 Zornitza Stark Gene: snapc4 has been classified as Green List (High Evidence).
Fetal anomalies v1.93 ESAM Chern Lim gene: ESAM was added
gene: ESAM was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: ESAM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ESAM were set to 36996813
Phenotypes for gene: ESAM were set to Neurodevelopmental disorder (MONDO#0700092), ESAM-related
Review for gene: ESAM was set to GREEN
gene: ESAM was marked as current diagnostic
Added comment: PMID 36996813
- Thirteen affected individuals, including four fetuses, from eight unrelated families, with homozygous loss-of-function-type variants in ESAM – 2 of the variants are frameshifts, 1x nonsense, 1x canonical splice.
- Affected individuals have profound global developmental delay/unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/cerebral calcifications, the latter being also observed in the fetuses.
- One of the frameshift variant c.115del (p.Arg39Glyfs*33), was detected in six individuals from four unrelated families from the same geographic region in Turkey (southeastern Anatolia), suggesting a founder effect.
- The c.451+1G>A variant was detected in three individuals from two independent families with the same ethnic origin (Arab Bedouin)
Sources: Literature
Mendeliome v1.775 POLR1A Lucy Spencer reviewed gene: POLR1A: Rating: AMBER; Mode of pathogenicity: None; Publications: 28051070, 36917474; Phenotypes: Leukodystrophy MONDO:0019046, POLR1A-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Brain Calcification v1.50 ESAM Chern Lim gene: ESAM was added
gene: ESAM was added to Brain Calcification. Sources: Literature
Mode of inheritance for gene: ESAM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ESAM were set to 36996813
Phenotypes for gene: ESAM were set to Neurodevelopmental disorder (MONDO#0700092), ESAM-related
Review for gene: ESAM was set to GREEN
gene: ESAM was marked as current diagnostic
Added comment: PMID 36996813
- Thirteen affected individuals, including four fetuses, from eight unrelated families, with homozygous loss-of-function-type variants in ESAM – 2 of the variants are frameshifts, 1x nonsense, 1x canonical splice.
- Affected individuals have profound global developmental delay/unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/cerebral calcifications, the latter being also observed in the fetuses.
- One of the frameshift variant c.115del (p.Arg39Glyfs*33), was detected in six individuals from four unrelated families from the same geographic region in Turkey (southeastern Anatolia), suggesting a founder effect.
- The c.451+1G>A variant was detected in three individuals from two independent families with the same ethnic origin (Arab Bedouin)
Sources: Literature
Disorders of immune dysregulation v0.168 DOCK11 Seb Lunke Marked gene: DOCK11 as ready
Disorders of immune dysregulation v0.168 DOCK11 Seb Lunke Gene: dock11 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5197 SNAPC4 Zornitza Stark Marked gene: SNAPC4 as ready
Intellectual disability syndromic and non-syndromic v0.5197 SNAPC4 Zornitza Stark Gene: snapc4 has been classified as Green List (High Evidence).
Disorders of immune dysregulation v0.168 DOCK11 Seb Lunke Classified gene: DOCK11 as Green List (high evidence)
Disorders of immune dysregulation v0.168 DOCK11 Seb Lunke Gene: dock11 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5197 SNAPC4 Zornitza Stark Classified gene: SNAPC4 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5197 SNAPC4 Zornitza Stark Gene: snapc4 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1836 ESAM Chern Lim gene: ESAM was added
gene: ESAM was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: ESAM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ESAM were set to 36996813
Phenotypes for gene: ESAM were set to Neurodevelopmental disorder (MONDO#0700092), ESAM-related
Review for gene: ESAM was set to GREEN
gene: ESAM was marked as current diagnostic
Added comment: PMID 36996813
- Thirteen affected individuals, including four fetuses, from eight unrelated families, with homozygous loss-of-function-type variants in ESAM – 2 of the variants are frameshifts, 1x nonsense, 1x canonical splice.
- Affected individuals have profound global developmental delay/unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/cerebral calcifications, the latter being also observed in the fetuses.
- One of the frameshift variant c.115del (p.Arg39Glyfs*33), was detected in six individuals from four unrelated families from the same geographic region in Turkey (southeastern Anatolia), suggesting a founder effect.
- The c.451+1G>A variant was detected in three individuals from two independent families with the same ethnic origin (Arab Bedouin)
Sources: Literature
Microcephaly v1.196 SNAPC4 Zornitza Stark Marked gene: SNAPC4 as ready
Microcephaly v1.196 SNAPC4 Zornitza Stark Gene: snapc4 has been classified as Green List (High Evidence).
Microcephaly v1.196 SNAPC4 Zornitza Stark Classified gene: SNAPC4 as Green List (high evidence)
Microcephaly v1.196 SNAPC4 Zornitza Stark Gene: snapc4 has been classified as Green List (High Evidence).
Mendeliome v1.775 ESAM Chern Lim gene: ESAM was added
gene: ESAM was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ESAM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ESAM were set to 36996813
Phenotypes for gene: ESAM were set to Neurodevelopmental disorder (MONDO#0700092), ESAM-related
Review for gene: ESAM was set to GREEN
gene: ESAM was marked as current diagnostic
Added comment: PMID 36996813
- Thirteen affected individuals, including four fetuses, from eight unrelated families, with homozygous loss-of-function-type variants in ESAM – 2 of the variants are frameshifts, 1x nonsense, 1x canonical splice.
- Affected individuals have profound global developmental delay/unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/cerebral calcifications, the latter being also observed in the fetuses.
- One of the frameshift variant c.115del (p.Arg39Glyfs*33), was detected in six individuals from four unrelated families from the same geographic region in Turkey (southeastern Anatolia), suggesting a founder effect.
- The c.451+1G>A variant was detected in three individuals from two independent families with the same ethnic origin (Arab Bedouin)
Sources: Literature
Mendeliome v1.775 SNAPC4 Zornitza Stark Marked gene: SNAPC4 as ready
Mendeliome v1.775 SNAPC4 Zornitza Stark Gene: snapc4 has been classified as Green List (High Evidence).
Mendeliome v1.775 SNAPC4 Zornitza Stark Classified gene: SNAPC4 as Green List (high evidence)
Mendeliome v1.775 SNAPC4 Zornitza Stark Gene: snapc4 has been classified as Green List (High Evidence).
Mendeliome v1.774 SNAPC4 Ee Ming Wong changed review comment from: - Ten individuals from eight families with neurodevelopmental disorder found to be compound heterozygous for variants in SNAPC4
- Identified variants included 6x missense, 1x nonsense, 1x frameshift and 6x splice
- Depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing, similarly observed in patient fibroblasts
Sources: Literature; to: - Ten individuals from eight families with neurodevelopmental disorder found to be biallelic for variants in SNAPC4
- Identified variants included 6x missense, 1x nonsense, 1x frameshift and 6x splice
- Depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing, similarly observed in patient fibroblasts
Sources: Literature
Hereditary Spastic Paraplegia - paediatric v1.57 SNAPC4 Ee Ming Wong changed review comment from: - Ten individuals from eight families with neurodevelopmental disorder found to be compound heterozygous for variants in SNAPC4
- Identified variants included 6x missense, 1x nonsense, 1x frameshift and 6x splice
- Depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing, similarly observed in patient fibroblasts
Sources: Literature; to: - Ten individuals from eight families with neurodevelopmental disorder found to be biallelic for variants in SNAPC4
- Identified variants included 6x missense, 1x nonsense, 1x frameshift and 6x splice
- Depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing, similarly observed in patient fibroblasts
Sources: Literature
Mendeliome v1.774 DOCK11 Lucy Spencer gene: DOCK11 was added
gene: DOCK11 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DOCK11 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: DOCK11 were set to 36952639
Phenotypes for gene: DOCK11 were set to autoimmune disease MONDO:0007179, DOCK11-related
Review for gene: DOCK11 was set to GREEN
Added comment: 8 male patients from 7 unrelated families all with hemizygous DOCK11 missense variants. 6 mothers were tested and found to carry the same missense. Early onset autoimmuniy with cytopenia, systemic lupus erythematosus, and skin and digestive manifestations. Patients platelets had abnormal morphology and spreading as well as impaired CDC42 activity. In vitro activated T cells and B lymphoblastoid cell lines (B-LCL) of patients exhibited aberrant protrusions and abnormal migration speed in confined channels concomitant with altered actin polymerization during migration. A DOCK11 knock-down recapitulated these abnormal cellular phenotypes in monocytes-derived dendritic cells (MDDC) and primary activated T cells from healthy controls.

6 of the variants are either absent or have only 1 het in gnomad v2, but one of them has 2 hemis and 1 het. The patient with this variant R1885C does seem to be more mild.
Sources: Literature
Microcephaly v1.195 SNAPC4 Ee Ming Wong changed review comment from: - Ten individuals from eight families with neurodevelopmental disorder found to be compound heterozygous for variants in SNAPC4
- Identified variants included 6x missense, 1x nonsense, 1x frameshift and 6x splice
- Depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing, similarly observed in patient fibroblasts
Sources: Literature; to: - Ten individuals from eight families with neurodevelopmental disorder found to be biallelic for variants in SNAPC4
- Identified variants included 6x missense, 1x nonsense, 1x frameshift and 6x splice
- Depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing, similarly observed in patient fibroblasts
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5196 SNAPC4 Ee Ming Wong changed review comment from: - Ten individuals from eight families with neurodevelopmental disorder found to be compound heterozygous for variants in SNAPC4
- Identified variants included 6x missense, 1x nonsense, 1x frameshift and 6x splice
- Depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing, similarly observed in patient fibroblasts
Sources: Literature; to: - Ten individuals from eight families with neurodevelopmental disorder found to be biallelic for variants in SNAPC4
- Identified variants included 6x missense, 1x nonsense, 1x frameshift and 6x splice
- Depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing, similarly observed in patient fibroblasts
Sources: Literature
Arthrogryposis v0.394 ACTC1 Lilian Downie gene: ACTC1 was added
gene: ACTC1 was added to Arthrogryposis. Sources: Literature
Mode of inheritance for gene: ACTC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ACTC1 were set to PMID: 36945405
Phenotypes for gene: ACTC1 were set to MONDO:0019942 ACTC1 related distal arthrogrypsis
Penetrance for gene: ACTC1 were set to Incomplete
Review for gene: ACTC1 was set to GREEN
Added comment: 5 new families (8 individuals) with a distral arthrogryposis phenotype:
multiple congenital contractures, neck pterygia, scoliosis, and congenital heart defects/cardiomyopathy, short stature
All missense variants
One variant p.Arg185Trp previously reported in patient with cardiac phenotype only
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5196 ESAM Seb Lunke Marked gene: ESAM as ready
Intellectual disability syndromic and non-syndromic v0.5196 ESAM Seb Lunke Gene: esam has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5196 ESAM Seb Lunke Classified gene: ESAM as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5196 ESAM Seb Lunke Gene: esam has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5195 RNH1 Krithika Murali edited their review of gene: RNH1: Changed rating: RED
Intellectual disability syndromic and non-syndromic v0.5195 SNAPC4 Ee Ming Wong gene: SNAPC4 was added
gene: SNAPC4 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: SNAPC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNAPC4 were set to 36965478
Phenotypes for gene: SNAPC4 were set to Neurodevelopmental disorder (MONDO#0700092), SNAPC4-related
Review for gene: SNAPC4 was set to GREEN
gene: SNAPC4 was marked as current diagnostic
Added comment: - Ten individuals from eight families with neurodevelopmental disorder found to be compound heterozygous for variants in SNAPC4
- Identified variants included 6x missense, 1x nonsense, 1x frameshift and 6x splice
- Depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing, similarly observed in patient fibroblasts
Sources: Literature
Regression v0.523 RNH1 Krithika Murali edited their review of gene: RNH1: Changed rating: RED
Genetic Epilepsy v0.1836 RNH1 Krithika Murali edited their review of gene: RNH1: Changed rating: RED
Arthrogryposis v0.394 FILIP1 Zornitza Stark Marked gene: FILIP1 as ready
Arthrogryposis v0.394 FILIP1 Zornitza Stark Gene: filip1 has been classified as Green List (High Evidence).
Disorders of immune dysregulation v0.167 DOCK11 Lucy Spencer gene: DOCK11 was added
gene: DOCK11 was added to Disorders of immune dysregulation. Sources: Literature
Mode of inheritance for gene: DOCK11 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: DOCK11 were set to 36952639
Phenotypes for gene: DOCK11 were set to autoimmune disease MONDO:0007179, DOCK11-related
Review for gene: DOCK11 was set to GREEN
Added comment: 8 male patients from 7 unrelated families all with hemizygous DOCK11 missense variants. 6 mothers were tested and found to carry the same missense. Early onset autoimmuniy with cytopenia, systemic lupus erythematosus, and skin and digestive manifestations. Patients platelets had abnormal morphology and spreading as well as impaired CDC42 activity. In vitro activated T cells and B lymphoblastoid cell lines (B-LCL) of patients exhibited aberrant protrusions and abnormal migration speed in confined channels concomitant with altered actin polymerization during migration. A DOCK11 knock-down recapitulated these abnormal cellular phenotypes in monocytes-derived dendritic cells (MDDC) and primary activated T cells from healthy controls.

6 of the variants are either absent or have only 1 het in gnomad v2, but one of them has 2 hemis and 1 het. The patient with this variant R1885C does seem to be more mild.
Sources: Literature
Cataract v0.351 RNH1 Seb Lunke Marked gene: RNH1 as ready
Cataract v0.351 RNH1 Seb Lunke Gene: rnh1 has been classified as Red List (Low Evidence).
Cataract v0.351 RNH1 Seb Lunke Classified gene: RNH1 as Red List (low evidence)
Cataract v0.351 RNH1 Seb Lunke Added comment: Comment on list classification: One consanguineous family only
Cataract v0.351 RNH1 Seb Lunke Gene: rnh1 has been classified as Red List (Low Evidence).
Mendeliome v1.774 RNH1 Krithika Murali edited their review of gene: RNH1: Changed rating: RED
Arthrogryposis v0.394 FILIP1 Zornitza Stark Phenotypes for gene: FILIP1 were changed from Arthrogryposis multiplex congenita MONDO:0015168, FILIP1 to Arthrogryposis multiplex congenita MONDO:0015168, FILIP1-related
Fetal anomalies v1.93 FILIP1 Paul De Fazio edited their review of gene: FILIP1: Changed phenotypes: Arthrogryposis multiplex congenita MONDO:0015168, FILIP1 related
Microcephaly v1.195 FILIP1 Paul De Fazio edited their review of gene: FILIP1: Changed phenotypes: Arthrogryposis multiplex congenita MONDO:0015168, FILIP1 related
Leukodystrophy - paediatric v0.285 POLR1A Zornitza Stark Marked gene: POLR1A as ready
Leukodystrophy - paediatric v0.285 POLR1A Zornitza Stark Gene: polr1a has been classified as Amber List (Moderate Evidence).
Mendeliome v1.774 FILIP1 Paul De Fazio edited their review of gene: FILIP1: Changed phenotypes: Arthrogryposis multiplex congenita MONDO:0015168, FILIP1 related
Arthrogryposis v0.394 FILIP1 Zornitza Stark Phenotypes for gene: FILIP1 were changed from Arthrogryposis multiplex congenita MONDO:0015168 to Arthrogryposis multiplex congenita MONDO:0015168, FILIP1
Intellectual disability syndromic and non-syndromic v0.5195 MKL2 Dean Phelan gene: MKL2 was added
gene: MKL2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: MKL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MKL2 were set to PMID: 37013900
Phenotypes for gene: MKL2 were set to Neurodevelopmental disorder (MONDO:0700092), MKL2-related
Mode of pathogenicity for gene: MKL2 was set to Other
Review for gene: MKL2 was set to AMBER
Added comment: PMID: 37013900
- de novo missense variants in MKL2 (now known as MRTFB) were identified in two patients with mild dysmorphic features, intellectual disability, global developmental delay, speech apraxia, and impulse control issues. Functional studies in a Drosophila model suggest a gain of function disease mechanism.
Sources: Literature
Microcephaly v1.195 SNAPC4 Ee Ming Wong gene: SNAPC4 was added
gene: SNAPC4 was added to Microcephaly. Sources: Literature
Mode of inheritance for gene: SNAPC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNAPC4 were set to 36965478
Phenotypes for gene: SNAPC4 were set to Neurodevelopmental disorder (MONDO#0700092), SNAPC4-related
Review for gene: SNAPC4 was set to GREEN
gene: SNAPC4 was marked as current diagnostic
Added comment: - Ten individuals from eight families with neurodevelopmental disorder found to be compound heterozygous for variants in SNAPC4
- Identified variants included 6x missense, 1x nonsense, 1x frameshift and 6x splice
- Depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing, similarly observed in patient fibroblasts
Sources: Literature
Fetal anomalies v1.93 FILIP1 Paul De Fazio gene: FILIP1 was added
gene: FILIP1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: FILIP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FILIP1 were set to 36943452
Phenotypes for gene: FILIP1 were set to Arthrogryposis multiplex congenita MONDO:0015168
Penetrance for gene: FILIP1 were set to unknown
Review for gene: FILIP1 was set to GREEN
gene: FILIP1 was marked as current diagnostic
Added comment: 3 families, all consanguineous, reported with 3 different homozygous loss of function variants (2x NMD-predicted nonsense, 1x intragenic deletion of exons 3-6 of 6). In one family, the variant segregated in 3 affected siblings.

Phenotypes consist of congenital contractures affecting shoulder, elbow, hand, hip, knee and foot as well as scoliosis, reduced palmar and plantar skin folds, microcephaly (-1.5 to -4 SD), and facial dysmorphism.
Sources: Literature
Leukodystrophy - paediatric v0.285 POLR1A Zornitza Stark Phenotypes for gene: POLR1A were changed from ataxia; psychomotor retardation; cerebellar and cerebral atrophy; leukodystrophy to Leukodystrophy MONDO:0019046, POLR1A related
Leukodystrophy - paediatric v0.284 POLR1A Zornitza Stark Publications for gene: POLR1A were set to 28051070
Leukodystrophy - paediatric v0.283 POLR1A Zornitza Stark Classified gene: POLR1A as Amber List (moderate evidence)
Leukodystrophy - paediatric v0.283 POLR1A Zornitza Stark Gene: polr1a has been classified as Amber List (Moderate Evidence).
Mendeliome v1.774 RNH1 Krithika Murali changed review comment from: PMID: 36935417 report two siblings from a consanguineous Somali family with homozygous RNH1 splice site variant (c.615-2A>C) with congenital cataracts, global developmental delay, hypotonia, seizures (focal and generalised) and regression in the context of infection. RT-PCR and RNASeq of skeletal muscle supported exon 7 skipping with an in-frame deletion involving 57 amino acids with reduced expression on Western blot analysis.
Sources: Literature; to: PMID: 36935417 report two siblings from a consanguineous Somali family with homozygous RNH1 splice site variant (c.615-2A>C) with congenital cataracts, global developmental delay, hypotonia, seizures (focal and generalised) and regression in the context of infection. RT-PCR and RNASeq of skeletal muscle supported exon 7 skipping with an in-frame deletion involving 57 amino acids with reduced expression on Western blot analysis. No antenatal features reported.
Sources: Literature
Hereditary Spastic Paraplegia - paediatric v1.57 SNAPC4 Ee Ming Wong gene: SNAPC4 was added
gene: SNAPC4 was added to Hereditary Spastic Paraplegia - paediatric. Sources: Literature
Mode of inheritance for gene: SNAPC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNAPC4 were set to 36965478
Phenotypes for gene: SNAPC4 were set to Neurodevelopmental disorder (MONDO#0700092), SNAPC4-related
Review for gene: SNAPC4 was set to GREEN
gene: SNAPC4 was marked as current diagnostic
Added comment: - Ten individuals from eight families with neurodevelopmental disorder found to be compound heterozygous for variants in SNAPC4
- Identified variants included 6x missense, 1x nonsense, 1x frameshift and 6x splice
- Depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing, similarly observed in patient fibroblasts
Sources: Literature
Arthrogryposis v0.393 FILIP1 Zornitza Stark Classified gene: FILIP1 as Green List (high evidence)
Arthrogryposis v0.393 FILIP1 Zornitza Stark Gene: filip1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.277 ACTC1 Lilian Downie reviewed gene: ACTC1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36945405; Phenotypes: Atrial septal defect 5 MIM#612794; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.774 SNAPC4 Ee Ming Wong gene: SNAPC4 was added
gene: SNAPC4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SNAPC4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNAPC4 were set to 36965478
Phenotypes for gene: SNAPC4 were set to Neurodevelopmental disorder (MONDO#0700092), SNAPC4-related
Review for gene: SNAPC4 was set to GREEN
gene: SNAPC4 was marked as current diagnostic
Added comment: - Ten individuals from eight families with neurodevelopmental disorder found to be compound heterozygous for variants in SNAPC4
- Identified variants included 6x missense, 1x nonsense, 1x frameshift and 6x splice
- Depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing, similarly observed in patient fibroblasts
Sources: Literature
Mendeliome v1.774 DAAM2 Zornitza Stark Phenotypes for gene: DAAM2 were changed from Nephrotic syndrome, type 24, MIM# 619263; steroid-resistant nephrotic syndrome (SRNS) to Nephrotic syndrome, type 24, MIM# 619263; steroid-resistant nephrotic syndrome (SRNS); Androgen insensitivity syndrome, MONDO:0019154, DAAM2-related
Mendeliome v1.773 RNH1 Krithika Murali gene: RNH1 was added
gene: RNH1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RNH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNH1 were set to PMID: 36935417
Phenotypes for gene: RNH1 were set to RNH1-related disorder
Review for gene: RNH1 was set to AMBER
Added comment: PMID: 36935417 report two siblings from a consanguineous Somali family with homozygous RNH1 splice site variant (c.615-2A>C) with congenital cataracts, global developmental delay, hypotonia, seizures (focal and generalised) and regression in the context of infection. RT-PCR and RNASeq of skeletal muscle supported exon 7 skipping with an in-frame deletion involving 57 amino acids with reduced expression on Western blot analysis.
Sources: Literature
Mendeliome v1.773 DAAM2 Zornitza Stark Publications for gene: DAAM2 were set to 33232676
Mendeliome v1.772 DAAM2 Zornitza Stark Mode of inheritance for gene: DAAM2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.771 DAAM2 Zornitza Stark edited their review of gene: DAAM2: Added comment: AIS: 6 unrelated individuals with extensive functional data.; Changed publications: 33232676, 36972684; Changed phenotypes: Nephrotic syndrome, type 24, MIM# 619263, Steroid-resistant nephrotic syndrome (SRNS), Androgen insensitivity syndrome, MONDO:0019154, DAAM2-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Differences of Sex Development v0.274 DAAM2 Zornitza Stark Marked gene: DAAM2 as ready
Differences of Sex Development v0.274 DAAM2 Zornitza Stark Gene: daam2 has been classified as Green List (High Evidence).
Differences of Sex Development v0.274 DAAM2 Zornitza Stark Classified gene: DAAM2 as Green List (high evidence)
Differences of Sex Development v0.274 DAAM2 Zornitza Stark Gene: daam2 has been classified as Green List (High Evidence).
Cataract v0.350 RNH1 Krithika Murali changed review comment from: PMID: 36935417 report two siblings from a consanguineous Somali family with homozygous RNH1 splice site variant (c.615-2A>C) with congenital cataracts, global developmental delay, hypotonia, regression in the context of infection and seizures. RT-PCR and RNASeq of skeletal muscle supported exon 7 skipping with an in-frame deletion involving 57 amino acids with reduced expression on Western blot analysis.
Sources: Literature; to: PMID: 36935417 report two siblings from a consanguineous Somali family with homozygous RNH1 splice site variant (c.615-2A>C) with congenital cataracts, global developmental delay, hypotonia, regression in the context of infection and seizures. RT-PCR and RNASeq of skeletal muscle supported exon 7 skipping with an in-frame deletion involving 57 amino acids with reduced expression on Western blot analysis.
Sources: Literature
Differences of Sex Development v0.273 DAAM2 Zornitza Stark gene: DAAM2 was added
gene: DAAM2 was added to Differences of Sex Development. Sources: Literature
Mode of inheritance for gene: DAAM2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DAAM2 were set to 36972684
Phenotypes for gene: DAAM2 were set to Androgen insensitivity syndrome, MONDO:0019154, DAAM2-related
Review for gene: DAAM2 was set to GREEN
Added comment: 6 unrelated individuals with extensive functional data.
Sources: Literature
Genetic Epilepsy v0.1836 RNH1 Krithika Murali gene: RNH1 was added
gene: RNH1 was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: RNH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNH1 were set to PMID: 36935417
Phenotypes for gene: RNH1 were set to RNH1-related disorder
Review for gene: RNH1 was set to AMBER
Added comment: PMID: 36935417 report two siblings from a consanguineous Somali family with homozygous RNH1 splice site variant (c.615-2A>C) with congenital cataracts, global developmental delay, hypotonia, seizures (focal and generalised) and regression in the context of infection. RT-PCR and RNASeq of skeletal muscle supported exon 7 skipping with an in-frame deletion involving 57 amino acids with reduced expression on Western blot analysis.
Sources: Literature
Mendeliome v1.771 MB Elena Savva Classified gene: MB as Green List (high evidence)
Mendeliome v1.771 MB Elena Savva Gene: mb has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5195 RNH1 Krithika Murali gene: RNH1 was added
gene: RNH1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: RNH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNH1 were set to PMID: 36935417
Phenotypes for gene: RNH1 were set to RNH1-related disorder
Review for gene: RNH1 was set to AMBER
Added comment: PMID: 36935417 report two siblings from a consanguineous Somali family with homozygous RNH1 splice site variant (c.615-2A>C) with congenital cataracts, global developmental delay, hypotonia, seizures (focal and generalised) and regression in the context of infection. RT-PCR and RNASeq of skeletal muscle supported exon 7 skipping with an in-frame deletion involving 57 amino acids with reduced expression on Western blot analysis.
Sources: Literature
Mendeliome v1.770 MB Elena Savva Classified gene: MB as Green List (high evidence)
Mendeliome v1.770 MB Elena Savva Gene: mb has been classified as Green List (High Evidence).
Mendeliome v1.769 MB Elena Savva Marked gene: MB as ready
Mendeliome v1.769 MB Elena Savva Gene: mb has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.5195 ESAM Chern Lim gene: ESAM was added
gene: ESAM was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ESAM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ESAM were set to 36996813
Phenotypes for gene: ESAM were set to Neurodevelopmental disorder (MONDO#0700092), ESAM-related
Review for gene: ESAM was set to GREEN
gene: ESAM was marked as current diagnostic
Added comment: PMID 36996813:
- Thirteen affected individuals, including four fetuses, from eight unrelated families, with homozygous loss-of-function-type variants in ESAM – 2 of the variants are frameshifts, 1x nonsense, 1x canonical splice.
- Affected individuals have profound global developmental delay/unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/cerebral calcifications, the latter being also observed in the fetuses.
- One of the frameshift variant c.115del (p.Arg39Glyfs*33), was detected in six individuals from four unrelated families from the same geographic region in Turkey (southeastern Anatolia), suggesting a founder effect.
- The c.451+1G>A variant was detected in three individuals from two independent families with the same ethnic origin (Arab Bedouin)
Sources: Literature
Regression v0.523 RNH1 Krithika Murali gene: RNH1 was added
gene: RNH1 was added to Regression. Sources: Literature
Mode of inheritance for gene: RNH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNH1 were set to PMID: 36935417
Phenotypes for gene: RNH1 were set to RNH1-related disorder
Review for gene: RNH1 was set to AMBER
Added comment: PMID: 36935417 report two siblings from a consanguineous Somali family with homozygous RNH1 splice site variant (c.615-2A>C) with congenital cataracts, global developmental delay, hypotonia, seizures (focal and generalised) and regression in the context of infection. RT-PCR and RNASeq of skeletal muscle supported exon 7 skipping with an in-frame deletion involving 57 amino acids with reduced expression on Western blot analysis.
Sources: Literature
Mendeliome v1.769 MB Elena Savva gene: MB was added
gene: MB was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MB were set to 35527200; 30918256
Phenotypes for gene: MB were set to Myopathy, sarcoplasmic body MIM#620286
Mode of pathogenicity for gene: MB was set to Other
Review for gene: MB was set to GREEN
Added comment: PMID: 30918256:
- Recurrent c.292C>T (p.His98Tyr) in fourteen members of six European families with AD progressive myopathy.
- Mutant myoglobin has altered O2 binding, exhibits a faster heme dissociation rate and has a lower reduction potential compared to wild-type myoglobin.
- GOF hypothesised
- 2/3 of myoglobin knockout mice die in utero, 1/3 live to adulthood with little sign of functional effects, likely due to multiple compensatory mechanisms.

PMID: 35527200:
- single adult patient with myoglobinopathy
- same recurring p.His98Tyr variant
Sources: Literature
Cataract v0.350 RNH1 Krithika Murali gene: RNH1 was added
gene: RNH1 was added to Cataract. Sources: Literature
Mode of inheritance for gene: RNH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNH1 were set to PMID: 36935417
Phenotypes for gene: RNH1 were set to RNH1-related disease
Review for gene: RNH1 was set to AMBER
Added comment: PMID: 36935417 report two siblings from a consanguineous Somali family with homozygous RNH1 splice site variant (c.615-2A>C) with congenital cataracts, global developmental delay, hypotonia, regression in the context of infection and seizures. RT-PCR and RNASeq of skeletal muscle supported exon 7 skipping with an in-frame deletion involving 57 amino acids with reduced expression on Western blot analysis.
Sources: Literature
Leukodystrophy - paediatric v0.282 POLR1A Lucy Spencer reviewed gene: POLR1A: Rating: AMBER; Mode of pathogenicity: None; Publications: 36917474; Phenotypes: Leukodystrophy MONDO:0019046, POLR1A related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.768 FILIP1 Paul De Fazio gene: FILIP1 was added
gene: FILIP1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: FILIP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FILIP1 were set to 36943452
Phenotypes for gene: FILIP1 were set to Arthrogryposis multiplex congenita MONDO:0015168
Penetrance for gene: FILIP1 were set to unknown
Review for gene: FILIP1 was set to GREEN
gene: FILIP1 was marked as current diagnostic
Added comment: 3 families, all consanguineous, reported with 3 different homozygous loss of function variants (2x NMD-predicted nonsense, 1x intragenic deletion of exons 3-6 of 6). In one family, the variant segregated in 3 affected siblings.

Phenotypes consist of congenital contractures affecting shoulder, elbow, hand, hip, knee and foot as well as scoliosis, reduced palmar and plantar skin folds, microcephaly (-1.5 to -4 SD), and facial dysmorphism.
Sources: Literature
Microcephaly v1.195 FILIP1 Paul De Fazio gene: FILIP1 was added
gene: FILIP1 was added to Microcephaly. Sources: Literature
Mode of inheritance for gene: FILIP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FILIP1 were set to 36943452
Phenotypes for gene: FILIP1 were set to Arthrogryposis multiplex congenita MONDO:0015168
Penetrance for gene: FILIP1 were set to unknown
Review for gene: FILIP1 was set to GREEN
gene: FILIP1 was marked as current diagnostic
Added comment: 3 families, all consanguineous, reported with 3 different homozygous loss of function variants (2x NMD-predicted nonsense, 1x intragenic deletion of exons 3-6 of 6). In one family, the variant segregated in 3 affected siblings.

Phenotypes consist of congenital contractures affecting shoulder, elbow, hand, hip, knee and foot as well as scoliosis, reduced palmar and plantar skin folds, microcephaly (-1.5 to -4 SD), and facial dysmorphism.
Sources: Literature
Skeletal dysplasia v0.232 PKDCC Zornitza Stark Phenotypes for gene: PKDCC were changed from Rhizomelia; dysmorphism to Rhizomelic limb shortening with dysmorphic features, MIM# 618821
Skeletal dysplasia v0.231 PKDCC Zornitza Stark Publications for gene: PKDCC were set to 30478137; 19097194
Skeletal dysplasia v0.230 PKDCC Zornitza Stark Classified gene: PKDCC as Green List (high evidence)
Skeletal dysplasia v0.230 PKDCC Zornitza Stark Gene: pkdcc has been classified as Green List (High Evidence).
Arthrogryposis v0.392 FILIP1 Paul De Fazio gene: FILIP1 was added
gene: FILIP1 was added to Arthrogryposis. Sources: Literature
Mode of inheritance for gene: FILIP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FILIP1 were set to 36943452
Phenotypes for gene: FILIP1 were set to Arthrogryposis multiplex congenita MONDO:0015168
Penetrance for gene: FILIP1 were set to unknown
Review for gene: FILIP1 was set to GREEN
gene: FILIP1 was marked as current diagnostic
Added comment: 3 families, all consanguineous, reported with 3 different homozygous loss of function variants (2x NMD-predicted nonsense, 1x intragenic deletion of exons 3-6 of 6). In one family, the variant segregated in 3 affected siblings.

Phenotypes consist of congenital contractures affecting shoulder, elbow, hand, hip, knee and foot as well as scoliosis, reduced palmar and plantar skin folds, microcephaly (-1.5 to -4 SD), and facial dysmorphism.
Sources: Literature
Skeletal dysplasia v0.229 PKDCC Zornitza Stark edited their review of gene: PKDCC: Changed rating: GREEN; Changed publications: 30478137, 19097194, 36896672; Changed phenotypes: Rhizomelic limb shortening with dysmorphic features, MIM# 618821
Mendeliome v1.768 PKDCC Zornitza Stark Phenotypes for gene: PKDCC were changed from Dysmorphism; shortening of extremities to Rhizomelic limb shortening with dysmorphic features, MIM# 618821
Mendeliome v1.767 PKDCC Zornitza Stark Publications for gene: PKDCC were set to PMID:30478137; 19097194
Mendeliome v1.766 PKDCC Zornitza Stark Classified gene: PKDCC as Green List (high evidence)
Mendeliome v1.766 PKDCC Zornitza Stark Gene: pkdcc has been classified as Green List (High Evidence).
Mendeliome v1.765 PKDCC Zornitza Stark reviewed gene: PKDCC: Rating: GREEN; Mode of pathogenicity: None; Publications: 36896672; Phenotypes: Rhizomelic limb shortening with dysmorphic features 618821; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.765 NPPA Chern Lim changed review comment from: PMID: 36303204:
- 1x Brugada patient with heterozygous R107X (NMD-predicted, 5 hets in gnomADv3), regarded as ACMG-LP.

PMID: 19646991:
- NPPA S64R missense in one fam with familial AF, heterozygous in two affected family members but was absent in unaffected family members and their controls. This variant has 195 hets in gnomADv3.

PMID: 23275345:
- Segregation of the homozygous p.R150Q mutation of the NPPA gene with the phenotype in the 6 families with autosomal recessive AD cardiomyopathy (ADCM). This variant has no homozygotes in gnomAD.

ClinGen gene curation: for autosomal recessive DCM - No Known Disease Relationship (09/04/2020).; to: PMID: 36303204:
- 1x Brugada patient with heterozygous R107X (NMD-predicted, 5 hets in gnomADv3), regarded as ACMG-LP.

PMID: 19646991:
- NPPA S64R missense in one fam with familial AF, heterozygous in two affected family members but was absent in unaffected family members and their controls. This variant has >200 hets in gnomADv3.

PMID: 23275345:
- Segregation of the homozygous p.R150Q mutation of the NPPA gene with the phenotype in the 6 families with autosomal recessive AD cardiomyopathy (ADCM). This variant has no homozygotes in gnomAD.

ClinGen gene curation: for autosomal recessive DCM - No Known Disease Relationship (09/04/2020).
Cardiomyopathy_Paediatric v0.157 PPCS Bryony Thompson Marked gene: PPCS as ready
Cardiomyopathy_Paediatric v0.157 PPCS Bryony Thompson Gene: ppcs has been classified as Green List (High Evidence).
Cardiomyopathy_Paediatric v0.157 PPCS Bryony Thompson reviewed gene: PPCS: Rating: GREEN; Mode of pathogenicity: None; Publications: 35616428, 29754768; Phenotypes: Cardiomyopathy, dilated, 2C, MIM# 618189; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.765 PPCS Bryony Thompson Publications for gene: PPCS were set to 29754768
Dilated Cardiomyopathy v1.16 PPCS Bryony Thompson Classified gene: PPCS as Red List (low evidence)
Dilated Cardiomyopathy v1.16 PPCS Bryony Thompson Added comment: Comment on list classification: This gene is associated with early-onset DCM and is not suitable for this panel which contains genes associated with adolescent and adult-onset DCM
Dilated Cardiomyopathy v1.16 PPCS Bryony Thompson Gene: ppcs has been classified as Red List (Low Evidence).
Mendeliome v1.764 PPCS Bryony Thompson Classified gene: PPCS as Green List (high evidence)
Mendeliome v1.764 PPCS Bryony Thompson Gene: ppcs has been classified as Green List (High Evidence).
Mendeliome v1.763 PPCS Bryony Thompson reviewed gene: PPCS: Rating: GREEN; Mode of pathogenicity: None; Publications: 35616428, 29754768; Phenotypes: Cardiomyopathy, dilated, 2C, MIM# 618189; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.763 PPCDC Bryony Thompson Marked gene: PPCDC as ready
Mendeliome v1.763 PPCDC Bryony Thompson Gene: ppcdc has been classified as Red List (Low Evidence).
Mendeliome v1.763 PPCDC Bryony Thompson gene: PPCDC was added
gene: PPCDC was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PPCDC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPCDC were set to 36564894
Phenotypes for gene: PPCDC were set to dilated cardiomyopathy MONDO:0005021
Review for gene: PPCDC was set to RED
Added comment: Single family reported with two siblings with a fatal cardiac phenotype including dilated cardiomyopathy with biallelic variants p.Thr53Pro and p.Ala95Val. Patient-derived fibroblasts showed an absence of PPCDC protein, and nearly 50% reductions in CoA levels. The cells showed clear energy deficiency problems, with defects in mitochondrial respiration, and mostly glycolytic ATP synthesis. Functional studies performed in yeast suggest these mutations to be functionally relevant.
Sources: Literature
Mendeliome v1.762 ELOC Bryony Thompson Marked gene: ELOC as ready
Mendeliome v1.762 ELOC Bryony Thompson Gene: eloc has been classified as Red List (Low Evidence).
Mendeliome v1.762 ELOC Bryony Thompson Classified gene: ELOC as Red List (low evidence)
Mendeliome v1.762 ELOC Bryony Thompson Gene: eloc has been classified as Red List (Low Evidence).
Mendeliome v1.761 EPHA10 Bryony Thompson Marked gene: EPHA10 as ready
Mendeliome v1.761 EPHA10 Bryony Thompson Gene: epha10 has been classified as Red List (Low Evidence).
Mendeliome v1.761 EPHA10 Bryony Thompson Classified gene: EPHA10 as Red List (low evidence)
Mendeliome v1.761 EPHA10 Bryony Thompson Gene: epha10 has been classified as Red List (Low Evidence).
Mendeliome v1.760 RNF212B Bryony Thompson Marked gene: RNF212B as ready
Mendeliome v1.760 RNF212B Bryony Thompson Gene: rnf212b has been classified as Amber List (Moderate Evidence).
Mendeliome v1.760 RNF212B Bryony Thompson Classified gene: RNF212B as Amber List (moderate evidence)
Mendeliome v1.760 RNF212B Bryony Thompson Gene: rnf212b has been classified as Amber List (Moderate Evidence).
Mendeliome v1.759 SLC25A36 Bryony Thompson Marked gene: SLC25A36 as ready
Mendeliome v1.759 SLC25A36 Bryony Thompson Gene: slc25a36 has been classified as Green List (High Evidence).
Mendeliome v1.759 SLC25A36 Bryony Thompson Classified gene: SLC25A36 as Green List (high evidence)
Mendeliome v1.759 SLC25A36 Bryony Thompson Gene: slc25a36 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5195 NCAPG2 Zornitza Stark Classified gene: NCAPG2 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.5195 NCAPG2 Zornitza Stark Gene: ncapg2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5195 NCAPG2 Zornitza Stark Classified gene: NCAPG2 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.5195 NCAPG2 Zornitza Stark Gene: ncapg2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5194 NCAPG2 Zornitza Stark reviewed gene: NCAPG2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Khan-Khan-Katsanis syndrome, MIM# 618460; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.758 NCAPG2 Zornitza Stark Classified gene: NCAPG2 as Amber List (moderate evidence)
Mendeliome v1.758 NCAPG2 Zornitza Stark Gene: ncapg2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.757 NCAPG2 Zornitza Stark changed review comment from: Two families and functional evidence (zebrafish model).
Sources: Literature; to: Two families and functional evidence (zebrafish model). Rated as LIMITED by ClinGen; one of the families had a homozygous missense variant. Internal case identified by VCGS but dual diagnosis.
Sources: Literature
Mendeliome v1.757 NCAPG2 Zornitza Stark edited their review of gene: NCAPG2: Changed rating: AMBER; Changed phenotypes: Khan-Khan-Katsanis syndrome, MIM# 618460
Mendeliome v1.757 NPPA Chern Lim reviewed gene: NPPA: Rating: AMBER; Mode of pathogenicity: None; Publications: 36303204, 19646991, 23275345; Phenotypes: Atrial fibrillation, familial, 6 (MIM#612201), AD, Atrial standstill 2 (MIM#615745), AR; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Atrial Fibrillation v1.1 NPPA Chern Lim reviewed gene: NPPA: Rating: AMBER; Mode of pathogenicity: None; Publications: 36303204, 19646991, 23275345; Phenotypes: Atrial fibrillation, familial, 6 (MIM#612201), AD, Atrial standstill 2 (MIM#615745), AR; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Incidentalome v0.229 UBQLN2 Sangavi Sivagnanasundram reviewed gene: UBQLN2: Rating: AMBER; Mode of pathogenicity: None; Publications: 21857683, 31319884, 26152284, 25388785; Phenotypes: Amyotrophic lateral sclerosis 15, with or without frontotemporal dementia (MONDO: 0010459, MIM#300857); Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Holoprosencephaly and septo-optic dysplasia v1.8 STIL Chirag Patel Classified gene: STIL as Green List (high evidence)
Holoprosencephaly and septo-optic dysplasia v1.8 STIL Chirag Patel Gene: stil has been classified as Green List (High Evidence).
Holoprosencephaly and septo-optic dysplasia v1.7 STIL Chirag Patel reviewed gene: STIL: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 25658757; Phenotypes: Holoprosencephaly and microcephaly; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Adult Cardiac SuperPanel v1.0 Bryony Thompson Added Panel Adult Cardiac SuperPanel
Set list of related panels to Cardiomyopathy; HP:0001638; Abnormality of the myocardium; HP:0001637; Arrhythmia; HP:0011675
Set child panels to: Dilated Cardiomyopathy; Short QT syndrome; Atrial Fibrillation; Sick sinus syndrome; Hypertrophic cardiomyopathy_HCM; Arrhythmogenic Cardiomyopathy; Long QT Syndrome; Brugada syndrome; Catecholaminergic Polymorphic Ventricular Tachycardia; Ventricular Fibrillation
Set panel types to: Royal Melbourne Hospital; Rare Disease
Incidentalome v0.229 TARDBP Sangavi Sivagnanasundram reviewed gene: TARDBP: Rating: GREEN; Mode of pathogenicity: Other; Publications: 18309045, 19609911; Phenotypes: Amyotrophic lateral sclerosis 10, with or without FTD, Frontotemporal lobar degeneration, TARDBP-related (MIM#612069, MONDO: 0012790); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.229 SORL1 Sangavi Sivagnanasundram reviewed gene: SORL1: Rating: RED; Mode of pathogenicity: Other; Publications: 17564960; Phenotypes: ; Mode of inheritance: Unknown
Incidentalome v0.229 SNCAIP Sangavi Sivagnanasundram reviewed gene: SNCAIP: Rating: RED; Mode of pathogenicity: None; Publications: 18366718; Phenotypes: ; Mode of inheritance: Unknown
Mosaic skin disorders v1.6 PORCN Sangavi Sivagnanasundram gene: PORCN was added
gene: PORCN was added to Mosaic skin disorders. Sources: NHS GMS
Mode of inheritance for gene: PORCN was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: PORCN were set to 17546030; 19309688
Phenotypes for gene: PORCN were set to Focal dermal hypoplasia (MONDO:0010592; MIM#305600)
Mode of pathogenicity for gene: PORCN was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: PORCN was set to GREEN
Added comment: Well established gene associated with Focal Dermal Hypoplasia (FDH). Predominantly reported in females (male lethality).

PMID: 19309688 - 24 unrelated patients (21 female and 3 male) with focal dermal hypoplasia (FDH) were studied. A variety of variants (nonsense, splice site and missense) were identified while 3 cases with skewed X inactivation had microdeletions eliminating PORCN. The 3 male cases were shown to be a result of postzygotic mosaicism which was also identified in 2 female cases.

PMID: 17546030 - 10 of 15 confirmed with FDH were analysed and heterozygous (missense, nonsense, indels) mutations causative of FDH was identified. In 9 cases, variants weren't detected in parental samples. A mildy affected father of 1 case showed somatic mosaicism for this variant while they identified de novo mosaic mutations in 3 male FDH cases but not in their parents.
Sources: NHS GMS
Mosaic skin disorders v1.6 BRAF Sangavi Sivagnanasundram gene: BRAF was added
gene: BRAF was added to Mosaic skin disorders. Sources: NHS GMS
Mode of inheritance for gene: BRAF was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: BRAF were set to 31111470
Phenotypes for gene: BRAF were set to Melanocytic naevus syndrome (MONDO:0044792; MIM#137550)
Mode of pathogenicity for gene: BRAF was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Added comment: More than 3 unrelated cases with tissue specific mosaic variants.

7 cases with congenital melanocytic naevi (CMN) identified a BRAF missense mutation (p.V600E) from naevus biopsies.
Sanger sequencing of mutant BRAF (p.V600E) naevus cultured cells showed confirmed heterozygosity with an increase in somatic load compared to those extracted directly from whole tissue from CMN.
Expression of the BRAF variant protein in all naevus cells was identified using immunohistochemistry.
Sources: NHS GMS
Mendeliome v1.757 RNF212B Sangavi Sivagnanasundram gene: RNF212B was added
gene: RNF212B was added to Mendeliome. Sources: Other
Mode of inheritance for gene: RNF212B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNF212B were set to https://doi.org/10.1016/j.xhgg.2023.100189
Phenotypes for gene: RNF212B were set to Infertility disorder, MONDO:0005047
Review for gene: RNF212B was set to AMBER
Added comment: Homozygous nonsense mutation (R150X) causative of oligoasthenotheratozoospermia (OAT) identified in three unrelated individuals (two of Jewish decent from the same consanguineous family).

Drosophila ZIP3/RNF212 related gene paralogs (vilya, narya, nenya) showed loss of function in the RNF212B protein and promoted formation of DNA double-stand breaks. The mutant was shown to result in a reduction in fertility in the Drosophila paralogs.

Note: RNF212B is reported to be exclusively expressed in the testes only compared to RNF212 which is reported in both the testes and ovaries.
Sources: Other
Mosaic skin disorders v1.6 CSPP1 Bryony Thompson Marked gene: CSPP1 as ready
Mosaic skin disorders v1.6 CSPP1 Bryony Thompson Gene: cspp1 has been classified as Red List (Low Evidence).
Mosaic skin disorders v1.6 GJA1 Bryony Thompson Marked gene: GJA1 as ready
Mosaic skin disorders v1.6 GJA1 Bryony Thompson Gene: gja1 has been classified as Red List (Low Evidence).
Mosaic skin disorders v1.6 GJA1 Bryony Thompson Classified gene: GJA1 as Red List (low evidence)
Mosaic skin disorders v1.6 GJA1 Bryony Thompson Gene: gja1 has been classified as Red List (Low Evidence).
Mosaic skin disorders v1.5 CSPP1 Bryony Thompson Classified gene: CSPP1 as Red List (low evidence)
Mosaic skin disorders v1.5 CSPP1 Bryony Thompson Gene: cspp1 has been classified as Red List (Low Evidence).
Mosaic skin disorders v1.4 CARD14 Bryony Thompson Publications for gene: CARD14 were set to
Mosaic skin disorders v1.3 CARD14 Bryony Thompson Mode of pathogenicity for gene: CARD14 was changed from to Other
Mosaic skin disorders v1.2 CARD14 Bryony Thompson Classified gene: CARD14 as Amber List (moderate evidence)
Mosaic skin disorders v1.2 CARD14 Bryony Thompson Added comment: Comment on list classification: Now published data, but only 2 cases
Mosaic skin disorders v1.2 CARD14 Bryony Thompson Gene: card14 has been classified as Amber List (Moderate Evidence).
Brain Calcification v1.50 FAM111A Zornitza Stark Marked gene: FAM111A as ready
Brain Calcification v1.50 FAM111A Zornitza Stark Gene: fam111a has been classified as Green List (High Evidence).
Brain Calcification v1.50 FAM111A Zornitza Stark Classified gene: FAM111A as Green List (high evidence)
Brain Calcification v1.50 FAM111A Zornitza Stark Gene: fam111a has been classified as Green List (High Evidence).
Brain Calcification v1.49 ERCC8 Zornitza Stark Publications for gene: ERCC8 were set to 26204423
Brain Calcification v1.48 ERCC6 Zornitza Stark Publications for gene: ERCC6 were set to
Brain Calcification v1.47 ERCC5 Zornitza Stark Marked gene: ERCC5 as ready
Brain Calcification v1.47 ERCC5 Zornitza Stark Gene: ercc5 has been classified as Red List (Low Evidence).
Brain Calcification v1.47 ERCC5 Zornitza Stark Classified gene: ERCC5 as Red List (low evidence)
Brain Calcification v1.47 ERCC5 Zornitza Stark Gene: ercc5 has been classified as Red List (Low Evidence).
Brain Calcification v1.46 ERCC3 Zornitza Stark Marked gene: ERCC3 as ready
Brain Calcification v1.46 ERCC3 Zornitza Stark Gene: ercc3 has been classified as Red List (Low Evidence).
Brain Calcification v1.46 ERCC3 Zornitza Stark Phenotypes for gene: ERCC3 were changed from to Xeroderma pigmentosum, group B, MIM# 610651
Brain Calcification v1.45 ECM1 Zornitza Stark Marked gene: ECM1 as ready
Brain Calcification v1.45 ECM1 Zornitza Stark Gene: ecm1 has been classified as Green List (High Evidence).
Brain Calcification v1.45 ERCC3 Zornitza Stark Classified gene: ERCC3 as Red List (low evidence)
Brain Calcification v1.45 ERCC3 Zornitza Stark Gene: ercc3 has been classified as Red List (Low Evidence).
Brain Calcification v1.44 ECM1 Zornitza Stark Classified gene: ECM1 as Green List (high evidence)
Brain Calcification v1.44 ECM1 Zornitza Stark Gene: ecm1 has been classified as Green List (High Evidence).
Brain Calcification v1.43 FAM111A Yetong Chen gene: FAM111A was added
gene: FAM111A was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: FAM111A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FAM111A were set to 32734340; 23996431; 35205306
Phenotypes for gene: FAM111A were set to Kenny-Caffey syndrome, type 2, MIM# 127000
Review for gene: FAM111A was set to GREEN
Added comment: PMID 32734340 reports 3 unrelated patients with FAM111A variants who developed calcification in the basal ganglia. Co-segregation is supported by pedigrees that contain parents and unaffected siblings.
PMID 35205306 reports a patient with a novel FAM111A variant who developed calcification in the basal ganglia and the thalamic region. The FAM111A variant caused Osteocraniostenosis (OCS, OMIM #602361), which is an allelic disorder sharing some common features with Kenny-Caffey syndrome.
Sources: Expert list
Brain Calcification v1.43 ERCC8 Yetong Chen reviewed gene: ERCC8: Rating: GREEN; Mode of pathogenicity: None; Publications: 17092472, 20522568; Phenotypes: Cockayne syndrome, type A, MIM# 216400; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Brain Calcification v1.43 ERCC6 Yetong Chen reviewed gene: ERCC6: Rating: GREEN; Mode of pathogenicity: None; Publications: 17092472, 20522568; Phenotypes: Cockayne syndrome, type B, MIM# 133540; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Brain Calcification v1.43 ERCC5 Yetong Chen gene: ERCC5 was added
gene: ERCC5 was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: ERCC5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERCC5 were set to 20301571; 26884178
Phenotypes for gene: ERCC5 were set to Xeroderma pigmentosum, group G; Cockayne syndrome, MIM# 278780
Review for gene: ERCC5 was set to RED
Added comment: PMID 26884178 reports 2 siblings with the same ERCC5 variant who developed bilateral globus pallidus and posterior periventricular white matter calcification.
Sources: Expert list
Heterotaxy v1.30 Bryony Thompson Panel types changed to Victorian Clinical Genetics Services; Royal Melbourne Hospital; Rare Disease
Brain Calcification v1.43 ERCC3 Yetong Chen edited their review of gene: ERCC3: Changed phenotypes: Xeroderma pigmentosum, group B, MIM# 610651
Brain Calcification v1.43 ERCC3 Yetong Chen gene: ERCC3 was added
gene: ERCC3 was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: ERCC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERCC3 were set to 16947863; 20301571
Review for gene: ERCC3 was set to RED
Added comment: PMID 20301571 reports 2 unrelated patients with ERCC3 variants who developed brain calcification.
Sources: Expert list
Brain Calcification v1.43 ECM1 Yetong Chen edited their review of gene: ECM1: Changed rating: GREEN
Brain Calcification v1.43 ECM1 Yetong Chen gene: ECM1 was added
gene: ECM1 was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: ECM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ECM1 were set to 27398129; 26336196; 12603844
Phenotypes for gene: ECM1 were set to Urbach-Wiethe disease, MIM# 247100
Review for gene: ECM1 was set to AMBER
Added comment: Although reported cases with ECM1 status are limited, Urbach-Wiethe disease is commonly associated with brain calcification.
PMID 27398129 reports a patient with calcifications in both the hippocampi and amygdala. The patient was confirmed to have Urbach-Wiethe syndrome by skin biopsy. However, the paper does not explicitly mention whether genetic testing of the ECM1 gene or genomics testing was done for the patient.

PMID 26336196 reports 2 siblings diagnosed to have Urbach-Wiethe syndrome who developed bilateral basal ganglia calcification. The method of diagnosis and patients' ECM1 status is not mentioned.

PMID 12603844 reports unrelated 3 patients with ECM1 variants who developed temporal lobe calcification.
Sources: Expert list
Mendeliome v1.757 RYR3 Chern Lim reviewed gene: RYR3: Rating: AMBER; Mode of pathogenicity: None; Publications: 25262651; Phenotypes: developmental and epileptic encephalopathy (MONDO:0100062); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Incidentalome v0.229 PSEN2 Sangavi Sivagnanasundram changed review comment from: Well established rare cause of Alzheimer Disease.

PMID: 10652366: In vitro functional assay shows that a mutation in the PSEN2 gene causes an effect to the endoproteolytic processing of the transmembrane protein thus a loss of function to the transmembrane protein.

PMID: 7638622: (Article refers to gene in previously terminology of STM2)
N141I founder mutation was identified in 20 individuals from 5 Volgan German families.
The point mutation is present in the conserved human and mouse homolog (S182).

PMID: 12925374: A spanish individual identified with a T430M mutation (a common variant reported in the Latino/Admixed American population but at a low frequency [PopMax AF 0.01%]).; to: Well established rare cause of Alzheimer Disease.

PMID: 10652366: In vitro functional assay shows that a mutation in the PSEN2 gene causes an effect to the endoproteolytic processing of the transmembrane protein thus a loss of function to the transmembrane protein.

PMID: 7638622: (Article refers to gene in previously terminology of STM2)
N141I founder mutation was identified in 20 individuals from 5 Volgan German families.
The point mutation is present in the conserved human and mouse homolog (S182).

PMID: 12925374: A spanish individual identified with a T430M mutation (a common variant reported in the Latino/Admixed American population but at a low frequency [PopMax AF 0.01%]).
Incidentalome v0.229 PSEN2 Sangavi Sivagnanasundram reviewed gene: PSEN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 10652366, 7638622, 7651536, 12925374; Phenotypes: Alzheimer Disease type 4 (MONDO:0011743, MIM#606889); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.229 PSEN1 Sangavi Sivagnanasundram reviewed gene: PSEN1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 20301340, 7596406, 16033913; Phenotypes: Alzheimer disease, type 3 (MONDO:0011913, MIM#607822); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Fetal anomalies v1.93 CRIPT Suliman Khan edited their review of gene: CRIPT: Changed rating: AMBER
Mosaic skin disorders v1.1 GJA1 Sangavi Sivagnanasundram gene: GJA1 was added
gene: GJA1 was added to Mosaic skin disorders. Sources: Other
Mode of inheritance for gene: GJA1 was set to Unknown
Publications for gene: GJA1 were set to 27890787
Phenotypes for gene: GJA1 were set to Inflammatory linear verrucous epidermal naevus (ILVEN)
Mode of pathogenicity for gene: GJA1 was set to Other
Review for gene: GJA1 was set to RED
Added comment: Only published in one article.
Somatic mutation p.A44V identified in one individual with ILVEN.
Sources: Other
Mosaic skin disorders v1.1 CARD14 Sangavi Sivagnanasundram reviewed gene: CARD14: Rating: AMBER; Mode of pathogenicity: Other; Publications: 34116062; Phenotypes: Inflammatory linear verrucous epidermal naevus (ILVEN); Mode of inheritance: None
Mosaic skin disorders v1.1 CSPP1 Sangavi Sivagnanasundram gene: CSPP1 was added
gene: CSPP1 was added to Mosaic skin disorders. Sources: Other
Mode of inheritance for gene: CSPP1 was set to Unknown
Publications for gene: CSPP1 were set to https://doi.org/10.1016/S2096-6911(21)00044-3
Phenotypes for gene: CSPP1 were set to Inflammatory linear verrucous epidermal naevus (ILVEN)
Mode of pathogenicity for gene: CSPP1 was set to Other
Review for gene: CSPP1 was set to RED
Added comment: Only one Chinese journal published relating to ILVEN - not on pubmed
1 somatic heterozygous mutation (R698X) was identified in a 10yr old individual.
Sources: Other
Regression v0.523 SLC31A1 Zornitza Stark Marked gene: SLC31A1 as ready
Regression v0.523 SLC31A1 Zornitza Stark Gene: slc31a1 has been classified as Amber List (Moderate Evidence).
Regression v0.523 SLC31A1 Zornitza Stark Classified gene: SLC31A1 as Amber List (moderate evidence)
Regression v0.523 SLC31A1 Zornitza Stark Gene: slc31a1 has been classified as Amber List (Moderate Evidence).
Regression v0.522 SLC31A1 Zornitza Stark gene: SLC31A1 was added
gene: SLC31A1 was added to Regression. Sources: Expert Review
Mode of inheritance for gene: SLC31A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC31A1 were set to 35913762; 36562171
Phenotypes for gene: SLC31A1 were set to Neurodegeneration and seizures due to copper transport defect, MIM# 620306
Review for gene: SLC31A1 was set to AMBER
Added comment: PMID:36562171
Homozygous c.236T>C; p.(Leu79Pro) identified in a newborn of consanguineous parents. Variant absent from gnomAD. Prenatal ultrasound showed a male fetus with short femoral bones, an apparently enlarged heart-to-thorax ratio, and a wide cisterna magna. The infant was born with pulmonary hypoplasia. At 2 weeks of age, multifocal brain hemorrhages were diagnosed and the infant developed seizures. The infant died at 1 month of age. The Mother had three healthy children while nine pregnancies had been extrauterine gravidities or ended in first or mid-trimester spontaneous abortions.

PMID: 35913762
SLC31A1 is also referred to as CTR1.
Monozygotic twins with hypotonia, global developmental delay, seizures, and rapid brain atrophy, consistent with profound central nervous system copper deficiency. Homozygous for a novel missense variant (p.(Arg95His)) in copper transporter CTR1, both parents heterozygous. A mouse knock-out model of CTR1 deficiency resulted in prenatal lethality.
Sources: Expert Review
Fetal anomalies v1.93 SLC31A1 Zornitza Stark Phenotypes for gene: SLC31A1 were changed from Neurodevelopmental disorder, SLC31A1-related (MONDO#0700092) to Neurodegeneration and seizures due to copper transport defect, MIM# 620306
Fetal anomalies v1.92 SLC31A1 Zornitza Stark reviewed gene: SLC31A1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodegeneration and seizures due to copper transport defect, MIM# 620306; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5194 SLC31A1 Zornitza Stark Phenotypes for gene: SLC31A1 were changed from Neurodevelopmental disorder, SLC31A1-related (MONDO#0700092) to Neurodegeneration and seizures due to copper transport defect, MIM# 620306
Intellectual disability syndromic and non-syndromic v0.5193 SLC31A1 Zornitza Stark edited their review of gene: SLC31A1: Changed phenotypes: Neurodegeneration and seizures due to copper transport defect, MIM# 620306
Genetic Epilepsy v0.1836 SLC31A1 Zornitza Stark Phenotypes for gene: SLC31A1 were changed from Neurodevelopmental disorder, SLC31A1-related (MONDO#0700092) to Neurodegeneration and seizures due to copper transport defect, MIM# 620306
Genetic Epilepsy v0.1835 SLC31A1 Zornitza Stark Publications for gene: SLC31A1 were set to PMID: 35913762
Genetic Epilepsy v0.1834 SLC31A1 Zornitza Stark reviewed gene: SLC31A1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodegeneration and seizures due to copper transport defect, MIM# 620306; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.757 SLC31A1 Zornitza Stark Phenotypes for gene: SLC31A1 were changed from Neurodevelopmental disorder, SLC31A1-related (MONDO#0700092) to Neurodegeneration and seizures due to copper transport defect, MIM# 620306
Mendeliome v1.756 SLC31A1 Zornitza Stark edited their review of gene: SLC31A1: Changed phenotypes: Neurodegeneration and seizures due to copper transport defect, MIM# 620306
Incidentalome v0.229 SCN1B Sangavi Sivagnanasundram reviewed gene: SCN1B: Rating: AMBER; Mode of pathogenicity: None; Publications: 9697698, 17020904, 12011299; Phenotypes: Generalized epilepsy with febrile seizures plus, type 1 (MONDO:0018214, MIM 604233); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability syndromic and non-syndromic v0.5193 SCN1B Sangavi Sivagnanasundram Deleted their review
Intellectual disability syndromic and non-syndromic v0.5193 SCN1B Sangavi Sivagnanasundram reviewed gene: SCN1B: Rating: AMBER; Mode of pathogenicity: None; Publications: 9697698, 17020904, 12011299; Phenotypes: Generalized epilepsy with febrile seizures plus, type 1 (MONDO:0018214, MIM 604233); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Incidentalome v0.229 RBM12 Sangavi Sivagnanasundram reviewed gene: RBM12: Rating: AMBER; Mode of pathogenicity: Other; Publications: 28628109, 36711667; Phenotypes: Schizophrenia 19 (MIM#617629); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.229 PCSK9 Zornitza Stark Marked gene: PCSK9 as ready
Incidentalome v0.229 PCSK9 Zornitza Stark Gene: pcsk9 has been classified as Green List (High Evidence).
Incidentalome v0.229 PCSK9 Zornitza Stark Phenotypes for gene: PCSK9 were changed from to Familial Hypercholesterolemia 3 (MONDO:0011369; MIM# 603776); Low-density lipoprotein cholesterol level quantitative trait locus-1 (LDLCQ1; MIM# 603776)
Incidentalome v0.228 PCSK9 Zornitza Stark Publications for gene: PCSK9 were set to
Incidentalome v0.227 PCSK9 Zornitza Stark Mode of inheritance for gene: PCSK9 was changed from Unknown to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Incidentalome v0.226 PCSK9 Zornitza Stark Tag treatable tag was added to gene: PCSK9.
BabyScreen+ newborn screening v0.2151 GPR161 Zornitza Stark Marked gene: GPR161 as ready
BabyScreen+ newborn screening v0.2151 GPR161 Zornitza Stark Gene: gpr161 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2151 GPR161 Zornitza Stark Classified gene: GPR161 as Red List (low evidence)
BabyScreen+ newborn screening v0.2151 GPR161 Zornitza Stark Gene: gpr161 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2150 GPR161 Zornitza Stark Tag cancer tag was added to gene: GPR161.
BabyScreen+ newborn screening v0.2150 CTR9 Zornitza Stark Tag cancer tag was added to gene: CTR9.
BabyScreen+ newborn screening v0.2150 CTR9 Zornitza Stark Marked gene: CTR9 as ready
BabyScreen+ newborn screening v0.2150 CTR9 Zornitza Stark Gene: ctr9 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2150 CTR9 Zornitza Stark Classified gene: CTR9 as Red List (low evidence)
BabyScreen+ newborn screening v0.2150 CTR9 Zornitza Stark Gene: ctr9 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2149 ALK Zornitza Stark Marked gene: ALK as ready
BabyScreen+ newborn screening v0.2149 ALK Zornitza Stark Gene: alk has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2149 ALK Zornitza Stark Tag cancer tag was added to gene: ALK.
BabyScreen+ newborn screening v0.2149 ALK Zornitza Stark Classified gene: ALK as Red List (low evidence)
BabyScreen+ newborn screening v0.2149 ALK Zornitza Stark Gene: alk has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2148 SUFU Lilian Downie gene: SUFU was added
gene: SUFU was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: SUFU was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SUFU were set to PMID: 29186568
Phenotypes for gene: SUFU were set to {Medulloblastoma} MIM#155255
Penetrance for gene: SUFU were set to Incomplete
Review for gene: SUFU was set to RED
Added comment: Medullobastoma 1st year of life
incomplete penetrance
worse outcomes
no determined screening protocol
Sources: Expert list
BabyScreen+ newborn screening v0.2148 PAX5 Lilian Downie gene: PAX5 was added
gene: PAX5 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: PAX5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PAX5 were set to PMID: 24013638
Phenotypes for gene: PAX5 were set to {Leukemia, acute lymphoblastic, susceptibility to, 3} MIM#615545
Penetrance for gene: PAX5 were set to Incomplete
Review for gene: PAX5 was set to RED
Added comment: Incomplete penetrance
Sources: Expert list
Incidentalome v0.226 PCSK9 Sangavi Sivagnanasundram reviewed gene: PCSK9: Rating: GREEN; Mode of pathogenicity: Other; Publications: 24404629, 18354137, 12730697, 15654334, 16909389; Phenotypes: Familial Hypercholesterolemia 3 (MONDO:0011369, MIM# 603776), Low-density lipoprotein cholesterol level quantitative trait locus-1 (LDLCQ1, MIM# 603776); Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.2148 GPR161 Lilian Downie gene: GPR161 was added
gene: GPR161 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: GPR161 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GPR161 were set to PMID: 31609649
Phenotypes for gene: GPR161 were set to Medulloblastoma predisposition syndrome MIM#155255
Penetrance for gene: GPR161 were set to Incomplete
Review for gene: GPR161 was set to RED
Added comment: Increased risk of medulloblastoma at <3yrs
Also identified in population and healthy parents
Sources: Expert list
BabyScreen+ newborn screening v0.2148 CTR9 Lilian Downie gene: CTR9 was added
gene: CTR9 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: CTR9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CTR9 were set to PMID: 32412586
Phenotypes for gene: CTR9 were set to Wilms tumour predisposition
Penetrance for gene: CTR9 were set to Incomplete
Review for gene: CTR9 was set to RED
Added comment: 9/14 germline variant developed Wilms (in 4 families)
Red due to reduced penetrance
Sources: Expert list
BabyScreen+ newborn screening v0.2148 ALK Lilian Downie gene: ALK was added
gene: ALK was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: ALK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ALK were set to PMID: 22071890
Phenotypes for gene: ALK were set to {Neuroblastoma, susceptibility to, 3} MIM#613014
Penetrance for gene: ALK were set to Incomplete
Review for gene: ALK was set to RED
Added comment: Reduced penetrance
Not clear guideline on management if detected
Sources: Expert list
Vasculitis v0.74 HCK Zornitza Stark Marked gene: HCK as ready
Vasculitis v0.74 HCK Zornitza Stark Gene: hck has been classified as Amber List (Moderate Evidence).
Vasculitis v0.74 HCK Zornitza Stark Classified gene: HCK as Amber List (moderate evidence)
Vasculitis v0.74 HCK Zornitza Stark Gene: hck has been classified as Amber List (Moderate Evidence).
Vasculitis v0.73 HCK Zornitza Stark gene: HCK was added
gene: HCK was added to Vasculitis. Sources: Expert Review
Mode of inheritance for gene: HCK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HCK were set to 34536415
Phenotypes for gene: HCK were set to Autoinflammation with pulmonary and cutaneous vasculitis, MIM#620296
Mode of pathogenicity for gene: HCK was set to Other
Review for gene: HCK was set to AMBER
Added comment: Single patient with supportive functional data. Gain of function demonstrated.
Sources: Expert Review
Mendeliome v1.756 HCK Zornitza Stark Phenotypes for gene: HCK were changed from Autoinflammatory syndrome, MONDO:0019751, HCK-related to Autoinflammation with pulmonary and cutaneous vasculitis, MIM#620296
Mendeliome v1.755 HCK Zornitza Stark edited their review of gene: HCK: Changed phenotypes: Autoinflammation with pulmonary and cutaneous vasculitis, MIM#620296
Autoinflammatory Disorders v1.4 HCK Zornitza Stark Phenotypes for gene: HCK were changed from Autoinflammatory syndrome, MONDO:0019751, HCK-related to Autoinflammation with pulmonary and cutaneous vasculitis, MIM#620296
Autoinflammatory Disorders v1.3 HCK Zornitza Stark reviewed gene: HCK: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Autoinflammation with pulmonary and cutaneous vasculitis, MIM#620296; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.226 PARK7 Sangavi Sivagnanasundram changed review comment from: Note that the gene was renamed from DJ1 to PARK7 (articles and OMIM reference our gene with previous name)

Variants in PARK7 (DJ1) gene are a rare cause of Parkinson Disease and is currently only reported in 3 individuals from 3 unrelated families.

PMID: 11462174; 11835383 – 2 individuals from 2 unrelated families with variants in DJ1 that were causative of Parkinson Disease.

PMID: 16240358 – 3 affected sibs from a consanguineous Italian family; to: Note that the gene was renamed from DJ1 to PARK7 (articles and OMIM reference our gene with previous name)

Variants in PARK7 (DJ1) gene are a rare cause of Parkinson Disease and is currently only reported in 3 individuals from 3 unrelated families.

PMID: 11462174; 11835383 – 2 individuals from 2 unrelated families with variants in DJ1 that were causative of Parkinson Disease.

PMID: 16240358 – 3 affected sibs from a consanguineous Italian family
Incidentalome v0.226 PARK7 Sangavi Sivagnanasundram reviewed gene: PARK7: Rating: AMBER; Mode of pathogenicity: None; Publications: 11462174, 11835383, 16240358, 20301402; Phenotypes: Parkinson Disease (MONDO:0005180, MIM: 606324); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Incidentalome v0.226 OPTN Sangavi Sivagnanasundram reviewed gene: OPTN: Rating: GREEN; Mode of pathogenicity: None; Publications: 20428114, 31838784, 27493188; Phenotypes: Amyotrophic lateral sclerosis 12 with or without frontotemporal dementia (MONDO: 0013264, MIM#613435); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Brain Calcification v1.43 DENND5A Zornitza Stark Marked gene: DENND5A as ready
Brain Calcification v1.43 DENND5A Zornitza Stark Gene: dennd5a has been classified as Red List (Low Evidence).
Brain Calcification v1.43 AP1S2 Yetong Chen edited their review of gene: AP1S2: Changed publications: 17617514
Brain Calcification v1.43 AP1S2 Yetong Chen changed review comment from: PMID 17617514 reports a linkage study of AP1S2 in 2 unrelated families with multiple generations affected by Fried syndrome. Cosegregation of the phenotype and AP1S2 variants is demonstrated. Two patients from the French family and 3 patients from the Scottish family developed brain calcification.
PMID 19161147 reports 8 individuals from 2 interrelated Omani families who developed brain calcification.; to: PMID 17617514 reports a linkage study of AP1S2 in 2 unrelated families with multiple generations affected by Fried syndrome. Cosegregation of the phenotype and AP1S2 variants is demonstrated. Two patients from the French family and 3 patients from the Scottish family developed brain calcification.
Brain Calcification v1.43 DENND5A Zornitza Stark Classified gene: DENND5A as Red List (low evidence)
Brain Calcification v1.43 DENND5A Zornitza Stark Gene: dennd5a has been classified as Red List (Low Evidence).
Brain Calcification v1.42 CYP2U1 Zornitza Stark Publications for gene: CYP2U1 were set to 23176821
Brain Calcification v1.41 COL4A2 Zornitza Stark Marked gene: COL4A2 as ready
Brain Calcification v1.41 COL4A2 Zornitza Stark Gene: col4a2 has been classified as Red List (Low Evidence).
Brain Calcification v1.41 CTC1 Zornitza Stark Publications for gene: CTC1 were set to 22267198; 22387016
Brain Calcification v1.40 COL4A2 Zornitza Stark Classified gene: COL4A2 as Red List (low evidence)
Brain Calcification v1.40 COL4A2 Zornitza Stark Gene: col4a2 has been classified as Red List (Low Evidence).
Brain Calcification v1.39 COL4A1 Zornitza Stark Publications for gene: COL4A1 were set to
Brain Calcification v1.38 DENND5A Yetong Chen gene: DENND5A was added
gene: DENND5A was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: DENND5A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DENND5A were set to 32734340; 27866705
Phenotypes for gene: DENND5A were set to Developmental and epileptic encephalopathy 49, MIM# 617281
Review for gene: DENND5A was set to RED
Added comment: Limited evidence supports a causal role of the DENND5A gene in brain calcification.
PMID 27866705 reports that 3 individuals with DENND5A variants, who were from 2 families, developed brain calcification. Co-segregation of the DENND5A variant and pathogenic phenotype is confirmed by sequencing their parents and unaffected sibs.
Sources: Expert list
Brain Calcification v1.38 COL4A2 Yetong Chen changed review comment from: There is no sufficient evidence supporting a causal role of the COL4A2 gene in brain calcification.
PMID 33247988 reports a patient with focal lesions with increased echogenicity in the right basal ganglia, which was suspected to result from either haemorrhage or calcification. However, the patient carries full duplications and deletions of COL4A1 and COL4A2, so it is likely that the brain calcification is not caused by COL4A2.
PMID 33577044 summarises that 4 patients with COL4A2 developed brain calcification, including 1 case from PMID 21357838, 2 cases from PMID 30315939 and 1 from the present paper. This paper does not mention brain calcification found in the 2 reported cases. (Interestingly, there is a calculation mistake for the total number of patients with COL4A2 who had brain calcification. The sum should be 4 instead of 5.)
None of the patients reported by PMID 21357838 carried COL4A2 variants nor developed brain calcification.
Although PMID 30315939 reports 2 patients with COL4A2 variants, they did not show any sign of calcification.
Sources: Expert list; to: There is no sufficient evidence supporting a causal role of the COL4A2 gene in brain calcification.
PMID 33247988 reports a patient with focal lesions with increased echogenicity in the right basal ganglia, which was suspected to result from either haemorrhage or calcification. However, the patient carries full duplications and deletions of COL4A1 and COL4A2, so it is likely that the brain calcification is not caused by COL4A2.
PMID 33577044 summarises that 4 patients with COL4A2 developed brain calcification, including 1 case from PMID 21357838, 2 cases from PMID 30315939 and 1 from the present paper. This paper does not mention brain calcification found in the 2 reported cases. (There is a calculation mistake for the total number of patients with COL4A2 who had brain calcification. The sum should be 4 instead of 5.)
None of the patients reported by PMID 21357838 carried COL4A2 variants nor developed brain calcification.
Although PMID 30315939 reports 2 patients with COL4A2 variants, they did not show any sign of calcification.
Sources: Expert list
Brain Calcification v1.38 CYP2U1 Yetong Chen reviewed gene: CYP2U1: Rating: ; Mode of pathogenicity: None; Publications: 30111349, 33107650, 23176821; Phenotypes: Spastic paraplegia 56, autosomal recessive, MIM# 615030; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Deafness_IsolatedAndComplex v1.156 ABHD12 Lilian Downie Deleted their review
BabyScreen+ newborn screening v0.2148 TUBB4B Lilian Downie gene: TUBB4B was added
gene: TUBB4B was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: TUBB4B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TUBB4B were set to PMID: 29198720, 35240325
Phenotypes for gene: TUBB4B were set to Leber congenital amaurosis with early-onset deafness MIM#617879
Review for gene: TUBB4B was set to RED
Added comment: The TUBB4B gene has been associated with autosomal dominant Leber congenital amaurosis with early-onset deafness
Not consistently hearing phenotype <5years therefore excluded
Sources: Expert list
BabyScreen+ newborn screening v0.2148 SLITRK6 Lilian Downie gene: SLITRK6 was added
gene: SLITRK6 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: SLITRK6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLITRK6 were set to PMID: 23543054, PMID: 25590127
Phenotypes for gene: SLITRK6 were set to Deafness and myopia MIM#221200
Review for gene: SLITRK6 was set to GREEN
Added comment: Congenital or prelingual deafness (SNHL or ANSD)
high myopia
Sources: Expert list
BabyScreen+ newborn screening v0.2148 MPZL2 Lilian Downie gene: MPZL2 was added
gene: MPZL2 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: MPZL2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MPZL2 were set to PMID: 29982980, 29961571, 35734045,33234333
Phenotypes for gene: MPZL2 were set to Deafness, autosomal recessive 111 MIM#618145
Review for gene: MPZL2 was set to RED
Added comment: Most cases are pre-lingual but 29961571, 35734045 report adult onset so I think should be excluded based on variability of age of onset
Sources: Expert list
Incidentalome v0.226 LRRK2 Sangavi Sivagnanasundram reviewed gene: LRRK2: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 20301387, 17200152, 15541308, 16172858; Phenotypes: Parkinson Disease type 8 (MONDO:0005180, MIM#607060); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Brain Calcification v1.38 CTC1 Yetong Chen changed review comment from: An additional case is found.
PMID 22532422 reports a patient with a CTC1 variant who developed right-sided thalamic calcification.

PMID 22899577 reports 4 patients with CTC1 variants who developed intracranial cysts or calcification; however, the exact number of patients who developed intracranial calcification is not specified.; to: An additional case is found.
PMID 22532422 reports a patient with a CTC1 variant who developed right-sided thalamic calcification.

PMID 22899577 reports 4 patients with CTC1 variants from 3 families who developed intracranial cysts or calcification; however, the exact number of patients who developed intracranial calcification is not specified.
BabyScreen+ newborn screening v0.2148 CRYM Zornitza Stark Marked gene: CRYM as ready
BabyScreen+ newborn screening v0.2148 CRYM Zornitza Stark Gene: crym has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2148 CRYM Zornitza Stark Classified gene: CRYM as Red List (low evidence)
BabyScreen+ newborn screening v0.2148 CRYM Zornitza Stark Gene: crym has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2147 COL4A6 Zornitza Stark Marked gene: COL4A6 as ready
BabyScreen+ newborn screening v0.2147 COL4A6 Zornitza Stark Added comment: Comment when marking as ready: Agree, report in males only.
BabyScreen+ newborn screening v0.2147 COL4A6 Zornitza Stark Gene: col4a6 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2147 COL4A6 Zornitza Stark Classified gene: COL4A6 as Green List (high evidence)
BabyScreen+ newborn screening v0.2147 COL4A6 Zornitza Stark Gene: col4a6 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2146 CLDN9 Zornitza Stark Marked gene: CLDN9 as ready
BabyScreen+ newborn screening v0.2146 CLDN9 Zornitza Stark Gene: cldn9 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2146 CLDN9 Zornitza Stark Classified gene: CLDN9 as Red List (low evidence)
BabyScreen+ newborn screening v0.2146 CLDN9 Zornitza Stark Gene: cldn9 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2145 CEP250 Zornitza Stark Marked gene: CEP250 as ready
BabyScreen+ newborn screening v0.2145 CEP250 Zornitza Stark Gene: cep250 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2145 CEP250 Zornitza Stark Classified gene: CEP250 as Red List (low evidence)
BabyScreen+ newborn screening v0.2145 CEP250 Zornitza Stark Gene: cep250 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2144 ABHD12 Zornitza Stark Marked gene: ABHD12 as ready
BabyScreen+ newborn screening v0.2144 ABHD12 Zornitza Stark Gene: abhd12 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2144 ABHD12 Zornitza Stark Classified gene: ABHD12 as Red List (low evidence)
BabyScreen+ newborn screening v0.2144 ABHD12 Zornitza Stark Gene: abhd12 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2143 CD164 Zornitza Stark Marked gene: CD164 as ready
BabyScreen+ newborn screening v0.2143 CD164 Zornitza Stark Gene: cd164 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2143 CD164 Zornitza Stark Classified gene: CD164 as Red List (low evidence)
BabyScreen+ newborn screening v0.2143 CD164 Zornitza Stark Gene: cd164 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2142 AP1B1 Zornitza Stark Marked gene: AP1B1 as ready
BabyScreen+ newborn screening v0.2142 AP1B1 Zornitza Stark Gene: ap1b1 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.2142 AP1B1 Zornitza Stark Classified gene: AP1B1 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.2142 AP1B1 Zornitza Stark Gene: ap1b1 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.2141 AP1B1 Zornitza Stark reviewed gene: AP1B1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Keratitis-ichthyosis-deafness syndrome, autosomal recessive MIM#242150; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Incidentalome v0.226 FA2H Zornitza Stark Marked gene: FA2H as ready
Incidentalome v0.226 FA2H Zornitza Stark Gene: fa2h has been classified as Green List (High Evidence).
Incidentalome v0.226 FA2H Zornitza Stark Phenotypes for gene: FA2H were changed from to Spastic Paraplegia (MIM#612319)
Incidentalome v0.225 FA2H Zornitza Stark Publications for gene: FA2H were set to
Incidentalome v0.224 FA2H Zornitza Stark Mode of inheritance for gene: FA2H was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Incidentalome v0.223 FA2H Zornitza Stark Tag neurological tag was added to gene: FA2H.
BabyScreen+ newborn screening v0.2141 LMX1A Lilian Downie gene: LMX1A was added
gene: LMX1A was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: LMX1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LMX1A were set to PMID: 29754270
Phenotypes for gene: LMX1A were set to Deafness, autosomal dominant 7 MIM#601412
Review for gene: LMX1A was set to RED
Added comment: Age of onset too variable
Sources: Expert list
BabyScreen+ newborn screening v0.2141 GREB1L Lilian Downie gene: GREB1L was added
gene: GREB1L was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: GREB1L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GREB1L were set to PMID: 29955957, 32585897
Phenotypes for gene: GREB1L were set to Deafness, autosomal dominant 80 MIM#619274
Review for gene: GREB1L was set to GREEN
Added comment: Congenital hearing impairment with cochlear abnormalities
This gene also causes Renal hypodysplasia/aplasia 3 MIM#617805 with no clear difference in mutation spectrum
Sources: Expert list
BabyScreen+ newborn screening v0.2141 CRYM Lilian Downie gene: CRYM was added
gene: CRYM was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: CRYM was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CRYM were set to PMID: 12471561, 32742378
Phenotypes for gene: CRYM were set to Deafness, autosomal dominant 40 MIM#616357
Review for gene: CRYM was set to RED
Added comment: Dominant hearing loss
One paper infant onset, the other all adult onset
Sources: Expert list
BabyScreen+ newborn screening v0.2141 COL4A6 Lilian Downie gene: COL4A6 was added
gene: COL4A6 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: COL4A6 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: COL4A6 were set to PMID: 33840813, PMID: 23714752
Phenotypes for gene: COL4A6 were set to Deafness, X-linked 6 MIM#300914
Review for gene: COL4A6 was set to GREEN
Added comment: Pre-lingual or congenital deafness in males
consider not reporting in females (may have adult onset hearing impairment)
Sources: Expert list
Brain Calcification v1.38 CTC1 Yetong Chen reviewed gene: CTC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22267198, 22532422, 22899577, 22387016, 24372060; Phenotypes: Cerebroretinal microangiopathy with calcifications and cysts, MIM# 612199; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.2141 CLDN9 Lilian Downie gene: CLDN9 was added
gene: CLDN9 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: CLDN9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CLDN9 were set to PMID: 34265170
Phenotypes for gene: CLDN9 were set to Deafness, autosomal recessive 116 MIM#619093
Review for gene: CLDN9 was set to RED
Added comment: Age of onset not consistently <5
Sources: Expert list
BabyScreen+ newborn screening v0.2141 CEP250 Lilian Downie gene: CEP250 was added
gene: CEP250 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: CEP250 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CEP250 were set to PMID: 34223797, PMID: 29718797, PMID: 30459346, PMID: 28005958
Phenotypes for gene: CEP250 were set to Cone-rod dystrophy and hearing loss 2 MIM#618358
Review for gene: CEP250 was set to RED
Added comment: Hearing loss and RP
Atypical Usher phenotype
Age of onset and penetrance of hearing loss component is variable and seeing as this is the treatable component have excluded from list
Sources: Expert list
BabyScreen+ newborn screening v0.2141 ABHD12 Lilian Downie gene: ABHD12 was added
gene: ABHD12 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: ABHD12 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ABHD12 were set to Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract MIM#612674
Review for gene: ABHD12 was set to RED
Added comment: Age of onset not consistently under 5 for treatable elements such as hearing loss.
Sources: Expert list
Deafness_IsolatedAndComplex v1.156 ABHD12 Lilian Downie Deleted their comment
Deafness_IsolatedAndComplex v1.156 ABHD12 Lilian Downie reviewed gene: ABHD12: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract MIM#612674; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.2141 CD164 Lilian Downie gene: CD164 was added
gene: CD164 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: CD164 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: CD164 were set to Deafness, autosomal dominant 66 MIM#616969
Review for gene: CD164 was set to RED
Added comment: Green in our mendeliome/deafness but limited evidence by clingen
variable age of onset from newborn to 20's reason for exclusion
Sources: Expert list
BabyScreen+ newborn screening v0.2141 AP1B1 Lilian Downie gene: AP1B1 was added
gene: AP1B1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: AP1B1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP1B1 were set to PMID:31630791, 31630788, 33452671
Phenotypes for gene: AP1B1 were set to Keratitis-ichthyosis-deafness syndrome, autosomal recessive MIM#242150
Review for gene: AP1B1 was set to GREEN
Added comment: Icthyosis
progressive hearing loss (childhood) often detected newborn screening
photophobia
corneal scarring/keratitis
variable dev delay
part of copper metabolism pathway but no proven treatment
Sources: Expert list
Brain Calcification v1.38 COL4A2 Yetong Chen gene: COL4A2 was added
gene: COL4A2 was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: COL4A2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: COL4A2 were set to 33577044; 33247988
Phenotypes for gene: COL4A2 were set to Brain small vessel disease 2, MIM# 614483
Review for gene: COL4A2 was set to RED
Added comment: There is no sufficient evidence supporting a causal role of the COL4A2 gene in brain calcification.
PMID 33247988 reports a patient with focal lesions with increased echogenicity in the right basal ganglia, which was suspected to result from either haemorrhage or calcification. However, the patient carries full duplications and deletions of COL4A1 and COL4A2, so it is likely that the brain calcification is not caused by COL4A2.
PMID 33577044 summarises that 4 patients with COL4A2 developed brain calcification, including 1 case from PMID 21357838, 2 cases from PMID 30315939 and 1 from the present paper. This paper does not mention brain calcification found in the 2 reported cases. (Interestingly, there is a calculation mistake for the total number of patients with COL4A2 who had brain calcification. The sum should be 4 instead of 5.)
None of the patients reported by PMID 21357838 carried COL4A2 variants nor developed brain calcification.
Although PMID 30315939 reports 2 patients with COL4A2 variants, they did not show any sign of calcification.
Sources: Expert list
Incidentalome v0.223 FIG4 Sangavi Sivagnanasundram reviewed gene: FIG4: Rating: GREEN; Mode of pathogenicity: None; Publications: 19118816, 20301623; Phenotypes: Amyotrophic Lateral Sclerosis Type 11 (MONDO: 0012945, MIM#612577); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Susceptibility to Viral Infections v0.109 STAT2 Peter McNaughton changed review comment from: Susceptibility to virus including disseminated vaccine strain measles.; to: Susceptibility to virus including disseminated vaccine strain measles.

Additional publication
PMID: 36976641
Brain Calcification v1.38 COL4A1 Yetong Chen Deleted their comment
Susceptibility to Viral Infections v0.109 STAT2 Peter McNaughton changed review comment from: Susceptibility to virus including disseminated vaccine strain measles.; to: Susceptibility to virus including disseminated vaccine strain measles.
Brain Calcification v1.38 COL4A1 Yetong Chen edited their review of gene: COL4A1: Added comment: In total, 20 patients with COL4A1 variants who developed brain calcification were reported.
PMID 22134833 reports 5 patients with different COL4A1 variants who developed brain calcification.
PMID 24372060 mentions a patient who has been reported by PMID 22134833 (case 3).
PMID 25719457 reports 2 unrelated patients with different COL4A1 variants who developed brain calcification.
PMID 23225343 reports 7 patients with different COL4A1 variants who developed brain calcification.
PMID 22932948 reports 3 patients with COL4A1 variants who developed brain calcification, and mentions 5 patients who have been reported by PMID 22134833.; Changed publications: 24372060, 22134833, 25719457, 23225343, 22932948
Brain Calcification v1.38 COL4A1 Yetong Chen reviewed gene: COL4A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24372060, 22134833; Phenotypes: Brain small vessel disease with or without ocular anomalies, MIM#175780; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.223 VPS13A Sangavi Sivagnanasundram reviewed gene: VPS13A: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301561, 12404112, 15824261, 12404112; Phenotypes: Chorea-acanthocytosis (MONDO: 0008695, MIM#200150); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Incidentalome v0.223 VPS13A Sangavi Sivagnanasundram Deleted their review
Incidentalome v0.223 VPS13A Sangavi Sivagnanasundram reviewed gene: VPS13A: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301561, 12404112, 15824261, 12404112; Phenotypes: Chorea-acanthocytosis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Incidentalome v0.223 XK Sangavi Sivagnanasundram reviewed gene: XK: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301528, 17133513; Phenotypes: McLeod Syndrome with or without chronic granulomatous disease (MIM#300842); Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Incidentalome v0.223 CLU Sangavi Sivagnanasundram reviewed gene: CLU: Rating: RED; Mode of pathogenicity: Other; Publications: 19734903, 20301340; Phenotypes: Alzheimer's Disease (MIM#104300); Mode of inheritance: Unknown
Incidentalome v0.223 FA2H Sangavi Sivagnanasundram reviewed gene: FA2H: Rating: GREEN; Mode of pathogenicity: Other; Publications: 31135052, 29395073, 18463364, 19068277, 20104589; Phenotypes: Spastic Paraplegia (MIM#612319); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.2141 LAMP2 Zornitza Stark Classified gene: LAMP2 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.2141 LAMP2 Zornitza Stark Gene: lamp2 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.2140 LAMP2 Zornitza Stark edited their review of gene: LAMP2: Added comment: Treatment is currently symptomatic.

On watch list with regards to specific treatment/clinical trials.; Changed rating: AMBER
BabyScreen+ newborn screening v0.2140 NKX2-5 Zornitza Stark Tag treatable tag was added to gene: NKX2-5.
BabyScreen+ newborn screening v0.2140 MYH7 Zornitza Stark Phenotypes for gene: MYH7 were changed from Laing early-onset distal myopathy, MONDO:0008050; Cardiomyopathy, hypertrophic, 1, OMIM:192600; Dilated cardiomyopathy 1S, MONDO:0013262; Hypertrophic cardiomyopathy 1, MONDO:0008647; Laing distal myopathy, OMIM:160500; Left ventricular noncompaction 5, OMIM:613426; Cardiomyopathy, dilated, 1S, OMIM:613426 to Cardiomyopathy, hypertrophic, 1, MIM# 192600
BabyScreen+ newborn screening v0.2139 MYH7 Zornitza Stark Mode of inheritance for gene: MYH7 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.2138 MYH7 Zornitza Stark Classified gene: MYH7 as Green List (high evidence)
BabyScreen+ newborn screening v0.2138 MYH7 Zornitza Stark Gene: myh7 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2137 MYH7 Zornitza Stark Tag cardiac tag was added to gene: MYH7.
Tag treatable tag was added to gene: MYH7.
BabyScreen+ newborn screening v0.2137 MYH7 Zornitza Stark edited their review of gene: MYH7: Added comment: Discussed with paedric cardiologist: include bi-allelic cardiac variants as can present in the neonatal period with an aggressive cardiomyopathy and associated arrhythmias.; Changed rating: GREEN; Changed phenotypes: Cardiomyopathy, hypertrophic, 1, MIM# 192600; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.2137 KCNJ2 Zornitza Stark Phenotypes for gene: KCNJ2 were changed from Andersen syndrome MIM#170390; Atrial fibrillation, familial, 9 MIM#613980; Short QT syndrome 3 MIM#609622 to Andersen syndrome MIM#170390
Incidentalome v0.223 CALHM1 Sangavi Sivagnanasundram changed review comment from: PMID:19472444 – Study to identify whether mutation sin CALHM1 had any correlation to Alzheimers Disease. Study showed no association between CALHM1 and Alzheimers Disease; to: PMID:19472444 – Study to identify whether mutations in CALHM1 had any correlation to Alzheimers Disease. Study showed no association between CALHM1 and Alzheimers Disease (AD)

No evidence showing correlation between CALHM1 mutations and AD
Incidentalome v0.223 CALHM1 Sangavi Sivagnanasundram reviewed gene: CALHM1: Rating: RED; Mode of pathogenicity: Other; Publications: 19472444; Phenotypes: ; Mode of inheritance: Unknown
BabyScreen+ newborn screening v0.2136 KCNJ2 Zornitza Stark Classified gene: KCNJ2 as Green List (high evidence)
BabyScreen+ newborn screening v0.2136 KCNJ2 Zornitza Stark Gene: kcnj2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2135 KCNJ2 Zornitza Stark edited their review of gene: KCNJ2: Added comment: Include for Andersen syndrome and Long QT-associated variants only. Onset in infancy.; Changed rating: GREEN; Changed phenotypes: Andersen syndrome MIM#170390
BabyScreen+ newborn screening v0.2135 TRDN Zornitza Stark Classified gene: TRDN as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.2135 TRDN Zornitza Stark Gene: trdn has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.2134 TRDN Zornitza Stark changed review comment from: Rated as 'strong actionability' for paediatric patients by ClinGen.

The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease.

Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events.

In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended.

Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years.

For review: age of onset and penetrance.; to: Rated as 'strong actionability' for paediatric patients by ClinGen.

The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease.

Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events.

In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended.

Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years.

Reviewed with paediatric cardiologist: variable penetrance and age of onset, does not fulfil criteria for gNBS.
BabyScreen+ newborn screening v0.2134 TRDN Zornitza Stark edited their review of gene: TRDN: Changed rating: AMBER
BabyScreen+ newborn screening v0.2134 TECRL Zornitza Stark Classified gene: TECRL as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.2134 TECRL Zornitza Stark Gene: tecrl has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.2133 TECRL Zornitza Stark changed review comment from: Rated as 'strong actionability' for paediatric patients by ClinGen.

The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease.

Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events.

In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended.

Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years.

For review: age of onset and penetrance.
Sources: ClinGen; to: Rated as 'strong actionability' for paediatric patients by ClinGen.

The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease.

Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events.

In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended.

Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years.

Reviewed with a paediatric cardiologist: variable penetrance and age of onset, does not fulfil criteria for gNBS.
BabyScreen+ newborn screening v0.2133 TECRL Zornitza Stark edited their review of gene: TECRL: Changed rating: AMBER; Changed phenotypes: Ventricular tachycardia, catecholaminergic polymorphic, 3, MIM# 614021
BabyScreen+ newborn screening v0.2133 SCN5A Zornitza Stark Classified gene: SCN5A as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.2133 SCN5A Zornitza Stark Gene: scn5a has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.2132 SCN5A Zornitza Stark changed review comment from: These two associations have been rated as 'strong actionability' in paediatric patients by ClinGen.

Note LongQT generally has symptom onset in adolescence and Brugada typically presents in adulthood.

For review: age of onset and penetrance.; to: These two associations have been rated as 'strong actionability' in paediatric patients by ClinGen.

Note LongQT generally has symptom onset in adolescence and Brugada typically presents in adulthood.

Reviewed with paediatric cardiologist: generally later age of onset, does not fulfil criteria for gNBS.
BabyScreen+ newborn screening v0.2132 SCN5A Zornitza Stark edited their review of gene: SCN5A: Changed rating: AMBER
BabyScreen+ newborn screening v0.2132 PRKG1 Zornitza Stark Classified gene: PRKG1 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.2132 PRKG1 Zornitza Stark Gene: prkg1 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.2131 PRKG1 Zornitza Stark changed review comment from: Assessed as 'strong actionability' in paediatric patients by ClinGen.

FTAAD is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection, or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch, or descending aorta).

Variable age of clinical presentation.

Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with pathogenic variants in MYH11, SMAD3, and ACTA2 and at 4.0-4.5 cm for patients with pathogenic variants in TGFBR1 or TGFBR2.

Beta adrenergic-blocking agents are recommended to reduce aortic dilation. Losartan was added as an alternative to beta adrenergic-blocking agents in FTAAD after studies showed its efficacy in children and young adults with MFS who were randomly assigned to losartan or atenolol.

Penetrance: A study of 31 individuals with PRKG1 pathogenic variants indicated that 63% presented with an aortic dissection and 37% had aortic root enlargement. The cumulative risk of an aortic dissection or repair of an aortic aneurysm by age 55 has been estimated as 86% (95% CI: 70-95%).
Sources: ClinGen; to: Assessed as 'strong actionability' in paediatric patients by ClinGen.

FTAAD is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection, or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch, or descending aorta).

Variable age of clinical presentation.

Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with pathogenic variants in MYH11, SMAD3, and ACTA2 and at 4.0-4.5 cm for patients with pathogenic variants in TGFBR1 or TGFBR2.

Beta adrenergic-blocking agents are recommended to reduce aortic dilation. Losartan was added as an alternative to beta adrenergic-blocking agents in FTAAD after studies showed its efficacy in children and young adults with MFS who were randomly assigned to losartan or atenolol.

Penetrance: A study of 31 individuals with PRKG1 pathogenic variants indicated that 63% presented with an aortic dissection and 37% had aortic root enlargement. The cumulative risk of an aortic dissection or repair of an aortic aneurysm by age 55 has been estimated as 86% (95% CI: 70-95%).

Discussed with a paediatric cardiologist: variable penetrance and age of onset, does not fulfil criteria for gNBS.
Sources: ClinGen
BabyScreen+ newborn screening v0.2131 PRKG1 Zornitza Stark edited their review of gene: PRKG1: Changed rating: AMBER
BabyScreen+ newborn screening v0.2131 MYH11 Zornitza Stark Classified gene: MYH11 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.2131 MYH11 Zornitza Stark Gene: myh11 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.2130 MYH11 Zornitza Stark changed review comment from: Assessed as 'strong actionability' in paediatric patients by ClinGen.

FTAAD is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection, or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch, or descending aorta).

Variable age of clinical presentation.

Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with pathogenic variants in MYH11, SMAD3, and ACTA2 and at 4.0-4.5 cm for patients with pathogenic variants in TGFBR1 or TGFBR2.

Beta adrenergic-blocking agents are recommended to reduce aortic dilation. Losartan was added as an alternative to beta adrenergic-blocking agents in FTAAD after studies showed its efficacy in children and young adults with MFS who were randomly assigned to losartan or atenolol.

Penetrance: A study of 12 individuals with MYH11 pathogenic variants indicated that 34% had an aortic dissection and one individual (8%) underwent prophylactic aortic aneurysm repair.; to: Assessed as 'strong actionability' in paediatric patients by ClinGen.

FTAAD is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection, or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch, or descending aorta).

Variable age of clinical presentation.

Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with pathogenic variants in MYH11, SMAD3, and ACTA2 and at 4.0-4.5 cm for patients with pathogenic variants in TGFBR1 or TGFBR2.

Beta adrenergic-blocking agents are recommended to reduce aortic dilation. Losartan was added as an alternative to beta adrenergic-blocking agents in FTAAD after studies showed its efficacy in children and young adults with MFS who were randomly assigned to losartan or atenolol.

Penetrance: A study of 12 individuals with MYH11 pathogenic variants indicated that 34% had an aortic dissection and one individual (8%) underwent prophylactic aortic aneurysm repair.

Reviewed with a paediatric cardiologist: variable penetrance and age of onset, does not meet criteria for gNBS.
BabyScreen+ newborn screening v0.2130 MYH11 Zornitza Stark edited their review of gene: MYH11: Changed rating: AMBER
BabyScreen+ newborn screening v0.2130 LOX Zornitza Stark Classified gene: LOX as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.2130 LOX Zornitza Stark Gene: lox has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.2129 LOX Zornitza Stark changed review comment from: Assessed as 'strong actionability' in paediatric patients by ClinGen.

FTAAD is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection, or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch, or descending aorta).

Variable age of clinical presentation.

Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with pathogenic variants in MYH11, SMAD3, and ACTA2 and at 4.0-4.5 cm for patients with pathogenic variants in TGFBR1 or TGFBR2.

Beta adrenergic-blocking agents are recommended to reduce aortic dilation. Losartan was added as an alternative to beta adrenergic-blocking agents in FTAAD after studies showed its efficacy in children and young adults with MFS who were randomly assigned to losartan or atenolol.

Penetrance: A study of 15 individuals with LOX pathogenic variants indicated that 73% had aortic aneurysms and 1 individual (7%) had an aortic dissection.
Sources: ClinGen; to: Assessed as 'strong actionability' in paediatric patients by ClinGen.

FTAAD is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection, or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch, or descending aorta).

Variable age of clinical presentation.

Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with pathogenic variants in MYH11, SMAD3, and ACTA2 and at 4.0-4.5 cm for patients with pathogenic variants in TGFBR1 or TGFBR2.

Beta adrenergic-blocking agents are recommended to reduce aortic dilation. Losartan was added as an alternative to beta adrenergic-blocking agents in FTAAD after studies showed its efficacy in children and young adults with MFS who were randomly assigned to losartan or atenolol.

Penetrance: A study of 15 individuals with LOX pathogenic variants indicated that 73% had aortic aneurysms and 1 individual (7%) had an aortic dissection.

Discussed with paediatric cardiologist: variable penetrance and age of onset, does not fit with criteria for gNBS.
Sources: ClinGen
BabyScreen+ newborn screening v0.2129 LOX Zornitza Stark edited their review of gene: LOX: Changed rating: AMBER
BabyScreen+ newborn screening v0.2129 JUP Zornitza Stark Classified gene: JUP as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.2129 JUP Zornitza Stark Gene: jup has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.2128 JUP Zornitza Stark changed review comment from: Screen for bi-allelic disease as can be earlier onset, more severe.; to: Discussed potentially just screening for bi-allelic disease as can be earlier onset, more severe.

Discussed further with a paediatric cardiologist: variable age of onset and penetrance, therefore does not meet criteria.
BabyScreen+ newborn screening v0.2128 JUP Zornitza Stark edited their review of gene: JUP: Changed rating: AMBER
BabyScreen+ newborn screening v0.2128 DSP Zornitza Stark Classified gene: DSP as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.2128 DSP Zornitza Stark Gene: dsp has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.2127 DSP Zornitza Stark changed review comment from: Screen for bi-allelic disease as can be more severe, earlier onset.; to: Discussed screening for bi-allelic disease as can be more severe, earlier onset.

Also discussed with paediatric cardiologist: variable age of onset and penetrance, exclude.
BabyScreen+ newborn screening v0.2127 DSP Zornitza Stark edited their review of gene: DSP: Changed rating: AMBER
Bone Marrow Failure v1.32 SRP54 Raja Vasireddy reviewed gene: SRP54: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29914977; Phenotypes: Neutropenia, promyelocytic maturation arrest, neurodevelopmental delay, exocrine pancreatic insuffciency.; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
BabyScreen+ newborn screening v0.2127 CASQ2 Zornitza Stark Classified gene: CASQ2 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.2127 CASQ2 Zornitza Stark Gene: casq2 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.2126 CASQ2 Zornitza Stark changed review comment from: Well established gene-disease association.

ClinGen: 'strong actionability' both for adult and paediatric patients. Treatment: beta blockers first line; ICD. There are also numerous known arrhythmia triggers which can be avoided.

The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease.

; to: Well established gene-disease association.

ClinGen: 'strong actionability' both for adult and paediatric patients. Treatment: beta blockers first line; ICD. There are also numerous known arrhythmia triggers which can be avoided.

The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease.

Reviewed with paediatric cardiologist: variable penetrance and age of onset.
BabyScreen+ newborn screening v0.2126 CASQ2 Zornitza Stark edited their review of gene: CASQ2: Changed rating: AMBER
Incidentalome v0.223 APP Sangavi Sivagnanasundram changed review comment from: PubMed: 17121991: transgenic mouse study identified that hypoxia increase BACE1 activity which resulted in a significant increase in the production of beta-amyloid in AD-related APP mutations. The study showed that hypoxia up-regulated Bace1 mRNA and increased deposition of beta proteins.

PMID: 1520398 – V717I variant identified in multiple members in a Canadian family of European decent with a dominant inheritance of Alzheimers disease
PMID: 15365148 – 1 family with 6 affected individuals over 3 generations with heterozygous mutations in APP gene – phenotypic features of Alzheimers. Individuals had MRI conducted showing multiple white matter infarcts along the long penetrating arteries
PubMed: 15668448 – two siblings in an African American family with distinctive features of early-onset AD with APP mutations
PMID: 1671712 - V717I mutation identified in 2 unrelated UK families with Alzheimers disease via a genetic linkage study
PMID: 1678058 – 2 individuals from 2 unrelated Japanese families with early onset Alzheimers disease via a genetic linkage study; to: PubMed: 17121991: transgenic mouse study identified that hypoxia increase BACE1 activity which resulted in a significant increase in the production of beta-amyloid in AD-related APP mutations. The study showed that hypoxia up-regulated Bace1 mRNA leading to an increased deposition of beta proteins.

PMID: 1520398 – V717I variant identified in multiple members in a Canadian family of European decent with a dominant inheritance of Alzheimers disease
PMID: 15365148 – 1 family with 6 affected individuals over 3 generations with heterozygous mutations in APP gene – phenotypic features of Alzheimers. Individuals had MRI conducted showing multiple white matter infarcts along the long penetrating arteries
PubMed: 15668448 – two siblings in an African American family with distinctive features of early-onset AD with APP mutations
PMID: 1671712 - V717I mutation identified in 2 unrelated UK families with Alzheimers disease via a genetic linkage study
PMID: 1678058 – 2 individuals from 2 unrelated Japanese families with early onset Alzheimers disease via a genetic linkage study
Incidentalome v0.223 APP Sangavi Sivagnanasundram reviewed gene: APP: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 17121991, 1520398, 15365148, 15668448, 1671712, 1678058; Phenotypes: Alzheimer's Disease (MIM#104300); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
BabyScreen+ newborn screening v0.2126 CALM1 Zornitza Stark Classified gene: CALM1 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.2126 CALM1 Zornitza Stark Gene: calm1 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.2125 CALM3 Zornitza Stark Phenotypes for gene: CALM3 were changed from Ventricular tachycardia, catecholaminergic polymorphic 6 , MIM# 618782; Long QT syndrome 16, MIM#618782 to Long QT syndrome 16, MIM#618782
BabyScreen+ newborn screening v0.2124 CALM3 Zornitza Stark changed review comment from: Rated as 'strong actionability' for paediatric patients by ClinGen.

The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Instances of sudden infant death syndrome (SIDS) have been associated with pathogenic variants in RYR2.

Individuals with pathogenic variants in CALM1, CALM2 or CALM3 can have a severe phenotype, with earlier onset, QT prolongation, and a high predilection for cardiac arrest and sudden death.

Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events.

In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended.

Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years.

For review: age of onset and penetrance.
Sources: ClinGen; to: Rated as 'strong actionability' for paediatric patients by ClinGen.

The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Instances of sudden infant death syndrome (SIDS) have been associated with pathogenic variants in RYR2.

Individuals with pathogenic variants in CALM1, CALM2 or CALM3 can have a severe phenotype, with earlier onset, QT prolongation, and a high predilection for cardiac arrest and sudden death.

Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events.

In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended.

Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years.

Exclude for CPVT: association has moderate evidence, there are issues with penetrance, and treatment is generally only recommended in symptomatic individuals.
Sources: ClinGen
BabyScreen+ newborn screening v0.2124 CALM3 Zornitza Stark edited their review of gene: CALM3: Changed phenotypes: Long QT syndrome 16, MIM#618782
BabyScreen+ newborn screening v0.2124 CALM3 Zornitza Stark edited their review of gene: CALM3: Changed rating: GREEN
BabyScreen+ newborn screening v0.2124 CALM3 Zornitza Stark edited their review of gene: CALM3: Changed rating: AMBER
BabyScreen+ newborn screening v0.2124 CALM2 Zornitza Stark Classified gene: CALM2 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.2124 CALM2 Zornitza Stark Gene: calm2 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.2123 CALM2 Zornitza Stark changed review comment from: Rated as 'strong actionability' for paediatric patients by ClinGen.

The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Instances of sudden infant death syndrome (SIDS) have been associated with pathogenic variants in RYR2.

Individuals with pathogenic variants in CALM1, CALM2 or CALM3 can have a severe phenotype, with earlier onset, QT prolongation, and a high predilection for cardiac arrest and sudden death.

Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events.

In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended.

Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years.

For review: age of onset and penetrance.
Sources: ClinGen; to: Rated as 'strong actionability' for paediatric patients by ClinGen.

The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Instances of sudden infant death syndrome (SIDS) have been associated with pathogenic variants in RYR2.

Individuals with pathogenic variants in CALM1, CALM2 or CALM3 can have a severe phenotype, with earlier onset, QT prolongation, and a high predilection for cardiac arrest and sudden death.

Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events.

In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended.

Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years.

Reviewed with paediatric cardiologist: not for inclusion due to issues with penetrance, plus guidelines only generally recommend treatment is symptomatic individuals.
BabyScreen+ newborn screening v0.2123 CALM2 Zornitza Stark edited their review of gene: CALM2: Changed rating: AMBER
BabyScreen+ newborn screening v0.2123 CALM1 Zornitza Stark changed review comment from: Rated as 'strong actionability' for paediatric patients by ClinGen.

The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Instances of sudden infant death syndrome (SIDS) have been associated with pathogenic variants in RYR2.

Individuals with pathogenic variants in CALM1, CALM2 or CALM3 can have a severe phenotype, with earlier onset, QT prolongation, and a high predilection for cardiac arrest and sudden death.

Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events.

In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended.

Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years.

For review: age of onset and penetrance.
Sources: ClinGen; to: Rated as 'strong actionability' for paediatric patients by ClinGen.

The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Instances of sudden infant death syndrome (SIDS) have been associated with pathogenic variants in RYR2.

Individuals with pathogenic variants in CALM1, CALM2 or CALM3 can have a severe phenotype, with earlier onset, QT prolongation, and a high predilection for cardiac arrest and sudden death.

Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events.

In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended.

Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years.

Reviewed with paediatric cardiologist: not for inclusion due to issues with penetrance, plus guidelines only generally recommend treatment is symptomatic individuals.
BabyScreen+ newborn screening v0.2123 CALM1 Zornitza Stark edited their review of gene: CALM1: Changed rating: AMBER
Incidentalome v0.223 ANG Sangavi Sivagnanasundram reviewed gene: ANG: Rating: GREEN; Mode of pathogenicity: None; Publications: 17886298, 16501576, 18087731, 20301623; Phenotypes: Amyotrophic Lateral Sclerosis (MONDO: 0012753, MIM#611895); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Incidentalome v0.223 ATP7B Sangavi Sivagnanasundram reviewed gene: ATP7B: Rating: GREEN; Mode of pathogenicity: None; Publications: 8298639, 9554743, 10790207, 7626145, 16133174; Phenotypes: Wilson Disease (MONDO:0010200, MIM #277900); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Incidentalome v0.223 ATP7B Sangavi Sivagnanasundram Deleted their review
Incidentalome v0.223 ATP7B Sangavi Sivagnanasundram changed review comment from: Well established gene known to be causative of Wilson Disease (Gene Reviews: NBK1512); Loss of function is a well established mechanism - functional study showed impaired production of copper transport and abberant cellular localization of mutant ATP7B proteins – PMID: 16133174; to: Well established gene known to be causative of Wilson Disease (Gene Reviews: NBK1512); Loss of function is a well established mechanism - functional study showed impaired production of copper transport and abberant cellular localization of mutant ATP7B proteins – PMID: 16133174
Incidentalome v0.223 ATP7B Sangavi Sivagnanasundram reviewed gene: ATP7B: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 8298639, 9554743, 10790207, 7626145, 16133174; Phenotypes: Wilson Disease (MIM#277900); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Osteogenesis Imperfecta and Osteoporosis v0.106 Bryony Thompson Panel name changed from Osteogenesis Imperfecta to Osteogenesis Imperfecta and Osteoporosis
Brain Calcification v1.38 COASY Zornitza Stark Marked gene: COASY as ready
Brain Calcification v1.38 COASY Zornitza Stark Gene: coasy has been classified as Red List (Low Evidence).
Brain Calcification v1.38 COASY Zornitza Stark Phenotypes for gene: COASY were changed from Neurodegeneration with brain iron accumulation 6 (COPAN); NBIA6 to Neurodegeneration with brain iron accumulation 6, MIM# 615643
Brain Calcification v1.37 COASY Zornitza Stark Classified gene: COASY as Red List (low evidence)
Brain Calcification v1.37 COASY Zornitza Stark Gene: coasy has been classified as Red List (Low Evidence).
Brain Calcification v1.36 CA2 Zornitza Stark Phenotypes for gene: CA2 were changed from Osteopetrosis, autosomal recessive 3, with renal tubular acidosis, MIM# 259730 to Osteopetrosis, autosomal recessive 3, with renal tubular acidosis, MIM# 259730
Brain Calcification v1.35 CASR Zornitza Stark Marked gene: CASR as ready
Brain Calcification v1.35 CASR Zornitza Stark Gene: casr has been classified as Green List (High Evidence).
Brain Calcification v1.35 CASR Zornitza Stark Phenotypes for gene: CASR were changed from Hypocalcemia, autosomal dominant; HYPOC1; Hypercalciuric Hypocalcemia; Hypocalcemia, familial to Hypocalcemia, autosomal dominant, MIM# 601198
Brain Calcification v1.34 CASR Zornitza Stark Publications for gene: CASR were set to 32775520; 35402765
Brain Calcification v1.33 CA2 Zornitza Stark Phenotypes for gene: CA2 were changed from Osteopetrosis, autosomal recessive 3, with renal tubular acidosis; OPTB3 to Osteopetrosis, autosomal recessive 3, with renal tubular acidosis, MIM# 259730
Brain Calcification v1.33 CASR Zornitza Stark Classified gene: CASR as Green List (high evidence)
Brain Calcification v1.33 CASR Zornitza Stark Gene: casr has been classified as Green List (High Evidence).
Brain Calcification v1.32 CA2 Zornitza Stark Marked gene: CA2 as ready
Brain Calcification v1.32 CA2 Zornitza Stark Gene: ca2 has been classified as Green List (High Evidence).
Brain Calcification v1.32 CASR Zornitza Stark reviewed gene: CASR: Rating: GREEN; Mode of pathogenicity: None; Publications: 8733126, 8813042; Phenotypes: Hypocalcemia, autosomal dominant, MIM# 601198; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Brain Calcification v1.32 C1QB Zornitza Stark Phenotypes for gene: C1QB were changed from C1q deficiency; C1QD to C1q deficiency, MIM# 613652
Brain Calcification v1.32 ATN1 Zornitza Stark Marked gene: ATN1 as ready
Brain Calcification v1.32 ATN1 Zornitza Stark Gene: atn1 has been classified as Red List (Low Evidence).
Brain Calcification v1.32 CA2 Zornitza Stark Classified gene: CA2 as Green List (high evidence)
Brain Calcification v1.32 CA2 Zornitza Stark Gene: ca2 has been classified as Green List (High Evidence).
Brain Calcification v1.31 CA2 Zornitza Stark reviewed gene: CA2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Osteopetrosis, autosomal recessive 3, with renal tubular acidosis, MIM# 259730; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Brain Calcification v1.31 C1QB Zornitza Stark Classified gene: C1QB as Red List (low evidence)
Brain Calcification v1.31 C1QB Zornitza Stark Gene: c1qb has been classified as Red List (Low Evidence).
Brain Calcification v1.30 BTD Zornitza Stark Marked gene: BTD as ready
Brain Calcification v1.30 BTD Zornitza Stark Gene: btd has been classified as Red List (Low Evidence).
Brain Calcification v1.30 C1QB Zornitza Stark reviewed gene: C1QB: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: C1q deficiency, MIM# 613652; Mode of inheritance: None
Brain Calcification v1.30 BTD Zornitza Stark Phenotypes for gene: BTD were changed from Biotinidase Deficiency to Biotinidase deficiency, MIM# 253260
Brain Calcification v1.29 ATN1 Zornitza Stark Phenotypes for gene: ATN1 were changed from Dentatorubral-pallidoluysian atrophy; DRPLA to Dentatorubral-pallidoluysian atrophy, MIM# 125370
Brain Calcification v1.28 BTD Zornitza Stark Classified gene: BTD as Red List (low evidence)
Brain Calcification v1.28 BTD Zornitza Stark Gene: btd has been classified as Red List (Low Evidence).
Brain Calcification v1.27 BTD Zornitza Stark reviewed gene: BTD: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Biotinidase deficiency, MIM# 253260; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Brain Calcification v1.27 ATN1 Zornitza Stark Classified gene: ATN1 as Red List (low evidence)
Brain Calcification v1.27 ATN1 Zornitza Stark Gene: atn1 has been classified as Red List (Low Evidence).
Brain Calcification v1.26 ATN1 Zornitza Stark Tag STR tag was added to gene: ATN1.
Brain Calcification v1.26 AP1S2 Zornitza Stark Publications for gene: AP1S2 were set to
Brain Calcification v1.25 ACVR1 Zornitza Stark Marked gene: ACVR1 as ready
Brain Calcification v1.25 ACVR1 Zornitza Stark Gene: acvr1 has been classified as Green List (High Evidence).
Brain Calcification v1.25 ACVR1 Zornitza Stark Phenotypes for gene: ACVR1 were changed from Fibrodysplasia ossificans progressiva; FOP to Fibrodysplasia ossificans progressiva, MIM# 135100
Brain Calcification v1.25 ADAR Zornitza Stark Publications for gene: ADAR were set to 23001123; 24262145
Brain Calcification v1.24 ACVR1 Zornitza Stark Classified gene: ACVR1 as Green List (high evidence)
Brain Calcification v1.24 ACVR1 Zornitza Stark Gene: acvr1 has been classified as Green List (High Evidence).
Brain Calcification v1.23 ACVR1 Zornitza Stark reviewed gene: ACVR1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Fibrodysplasia ossificans progressiva, MIM# 135100; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Brain Calcification v1.23 ACP5 Zornitza Stark Phenotypes for gene: ACP5 were changed from Spondyloenchondrodysplasia with immune dysregulation, MIM# 607944 to Spondyloenchondrodysplasia with immune dysregulation, MIM# 607944
Brain Calcification v1.23 ACP5 Zornitza Stark Phenotypes for gene: ACP5 were changed from Spondyloenchondrodysplasia, short stature, SLE, intracranial calcification, spasticity, chilblains, autoimmune haemolytic anaemia to Spondyloenchondrodysplasia with immune dysregulation, MIM# 607944
Brain Calcification v1.22 ACP5 Zornitza Stark edited their review of gene: ACP5: Changed phenotypes: Spondyloenchondrodysplasia with immune dysregulation, MIM# 607944
Brain Calcification v1.22 AP1S2 Yetong Chen changed review comment from: PMID 17617514 reports a linkage study of AP1S2 in 2 unrelated families with multiple generations affected by Fried syndrome. Cosegregation of the phenotype and AP1S2 variants is demonstrated. Two patients from the French family and 3 patients from the Scottish family developed brain calcification.; to: PMID 17617514 reports a linkage study of AP1S2 in 2 unrelated families with multiple generations affected by Fried syndrome. Cosegregation of the phenotype and AP1S2 variants is demonstrated. Two patients from the French family and 3 patients from the Scottish family developed brain calcification.
PMID 19161147 reports 8 individuals from 2 interrelated Omani families who developed brain calcification.
Brain Calcification v1.22 COASY Yetong Chen gene: COASY was added
gene: COASY was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: COASY was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COASY were set to 27487380; 24360804
Phenotypes for gene: COASY were set to Neurodegeneration with brain iron accumulation 6 (COPAN); NBIA6
Review for gene: COASY was set to RED
Added comment: There is limited evidence to support a causal role for the COASY gene in brain calcification.
PMID 24360804 demonstrates variants in COASY as a cause of brain iron accumulation, which includes brain calcification, by using segregation analysis. Brain calcification was found in one patient with a homozygous variant of COASY.
Sources: Expert list
Brain Calcification v1.22 CASR Yetong Chen gene: CASR was added
gene: CASR was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: CASR was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CASR were set to 32775520; 35402765
Phenotypes for gene: CASR were set to Hypocalcemia, autosomal dominant; HYPOC1; Hypercalciuric Hypocalcemia; Hypocalcemia, familial
Review for gene: CASR was set to RED
Added comment: PMID 32775520 reports co-segregation of a CASR variant and intracranial calcification found in 2 patients from the same family.
PMID 35402765 reports a patient with a CASR variant who developed multiple intracerebral calcifications. A pedigree including the patient and her parents can be found in the paper, but CASR genetic testing was not done on the proband's parents so it could not confirm whether the variant is de novo.
Sources: Expert list
Brain Calcification v1.22 CA2 Yetong Chen gene: CA2 was added
gene: CA2 was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: CA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CA2 were set to 25674028
Phenotypes for gene: CA2 were set to Osteopetrosis, autosomal recessive 3, with renal tubular acidosis; OPTB3
Review for gene: CA2 was set to GREEN
Added comment: PMID 25674028 reports a female patient with a homozygous variant in the CA2 gene who developed extensive symmetric intracranial calcification.
PMID 22120147 reports brain calcification in 18 individuals, who carry a CA2 variant, from 10 unrelated families. Pedigrees show co-segregation of genotype (homozygous mutant allele) and phenotype.
Sources: Expert list
Fetal anomalies v1.92 PLXND1 Zornitza Stark Phenotypes for gene: PLXND1 were changed from Congenital heart disease, MONDO:0005453, PLXND1-related to Congenital heart defects, multiple types, 9, MIM# 620294
Fetal anomalies v1.91 PLXND1 Zornitza Stark edited their review of gene: PLXND1: Changed phenotypes: Congenital heart defects, multiple types, 9, MIM# 620294
Mendeliome v1.755 PLXND1 Zornitza Stark Phenotypes for gene: PLXND1 were changed from Möbius syndrome, MONDO:0008006; Congenital heart disease, MONDO:0005453, PLXND1-related to Möbius syndrome, MONDO:0008006; Congenital heart defects, multiple types, 9, MIM# 620294
Mendeliome v1.754 PLXND1 Zornitza Stark edited their review of gene: PLXND1: Changed phenotypes: Möbius syndrome, Congenital heart defects, multiple types, 9, MIM# 620294
Congenital Heart Defect v0.277 PLXND1 Zornitza Stark Phenotypes for gene: PLXND1 were changed from Congenital heart disease, MONDO:0005453, PLXND1-related to Congenital heart defects, multiple types, 9, MIM# 620294
Congenital Heart Defect v0.276 PLXND1 Zornitza Stark edited their review of gene: PLXND1: Changed phenotypes: Congenital heart defects, multiple types, 9, MIM# 620294
Intellectual disability syndromic and non-syndromic v0.5193 AGO1 Zornitza Stark Phenotypes for gene: AGO1 were changed from Intellectual disability; autism to Neurodevelopmental disorder with language delay and behavioral abnormalities, with or without seizures, MIM# 620292
Intellectual disability syndromic and non-syndromic v0.5192 AGO1 Zornitza Stark edited their review of gene: AGO1: Changed phenotypes: Neurodevelopmental disorder with language delay and behavioral abnormalities, with or without seizures, MIM# 620292
Genetic Epilepsy v0.1834 AGO1 Zornitza Stark Phenotypes for gene: AGO1 were changed from Neurodevelopmental disorder MONDO:0700092, AGO1-related; non-syndromic ID and seizures to Neurodevelopmental disorder with language delay and behavioral abnormalities, with or without seizures, MIM# 620292
Genetic Epilepsy v0.1833 AGO1 Zornitza Stark edited their review of gene: AGO1: Changed phenotypes: Neurodevelopmental disorder with language delay and behavioral abnormalities, with or without seizures, MIM# 620292
Mendeliome v1.754 AGO1 Zornitza Stark Phenotypes for gene: AGO1 were changed from Neurodevelopmental disorder MONDO:0700092, AGO1-related; non-syndromic ID and seizures to Neurodevelopmental disorder with language delay and behavioral abnormalities, with or without seizures, MIM# 620292
Mendeliome v1.753 AGO1 Zornitza Stark edited their review of gene: AGO1: Changed phenotypes: Neurodevelopmental disorder with language delay and behavioral abnormalities, with or without seizures, MIM# 620292
Mendeliome v1.753 PRDM10 Zornitza Stark Marked gene: PRDM10 as ready
Mendeliome v1.753 PRDM10 Zornitza Stark Gene: prdm10 has been classified as Red List (Low Evidence).
Mendeliome v1.753 PRDM10 Zornitza Stark Classified gene: PRDM10 as Red List (low evidence)
Mendeliome v1.753 PRDM10 Zornitza Stark Gene: prdm10 has been classified as Red List (Low Evidence).
Brain Calcification v1.22 C1QB Yetong Chen gene: C1QB was added
gene: C1QB was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: C1QB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C1QB were set to 23651859
Phenotypes for gene: C1QB were set to C1q deficiency; C1QD
Review for gene: C1QB was set to RED
Added comment: Limited evidence supports a casual role of the C1QB gene in brain calcification.
PMID 23651859 reports a patient with a novel homozygous variant in C1QB who developed bilateral frontal infarcts and basal ganglia calcification.
Sources: Expert list
Brain Calcification v1.22 BTD Yetong Chen gene: BTD was added
gene: BTD was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: BTD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BTD were set to 32734340; 3399084
Phenotypes for gene: BTD were set to Biotinidase Deficiency
Review for gene: BTD was set to RED
Added comment: PMID 3399084 reports one case of Biotinidase Deficiency with basal ganglia calcification. However, no strong or moderate evidence suggests that variants in the BTN gene can cause brain calcification.
Sources: Expert list
Brain Calcification v1.22 ATN1 Yetong Chen gene: ATN1 was added
gene: ATN1 was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: ATN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATN1 were set to 2742549
Phenotypes for gene: ATN1 were set to Dentatorubral-pallidoluysian atrophy; DRPLA
Review for gene: ATN1 was set to RED
Added comment: PMID 2742549 reports the calcification of the globus pallidus in 4 out of the 10 assessed patients with Haw River Syndrome. Although both Haw River Syndrome and DRPLA are caused by the same expanded CAG repeat in the ATN1 gene, no genetic testing was done on the patients to confirm whether they carried ATN1 variants.
Sources: Expert list
Brain Calcification v1.22 AP1S2 Yetong Chen reviewed gene: AP1S2: Rating: GREEN; Mode of pathogenicity: None; Publications: 19161147, 17617514; Phenotypes: Pettigrew syndrome, Fried syndrome, PG5; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Brain Calcification v1.22 ADAR Yetong Chen reviewed gene: ADAR: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301648, 23001123, 24262145, 30692772; Phenotypes: Aicardi-Goutieres syndrome 6, AGS6; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.752 PRDM10 Achchuthan Shanmugasundram gene: PRDM10 was added
gene: PRDM10 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PRDM10 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PRDM10 were set to 36440963
Phenotypes for gene: PRDM10 were set to Fibrofolliculoma, HP:0030436; lipomatosis, MONDO:0006574; renal cell carcinoma, MONDO:0005086
Review for gene: PRDM10 was set to RED
Added comment: PMID:36440963 reported a family presenting with skin and mucosal lesions, extensive lipomatosis and renal cell carcinomas. The proband was initially diagnosed with Birt-Hogg-Dubé syndrome (BHD, MIM #135150) based on the presence of fibrofolliculomas, but no pathogenic germline variant was detected in FLCN, the gene associated with BHD. A heterozygous missense variant (p.Cys677Tyr) was identified, which co-segregated with the phenotype in the family.

Functional studies show that Cys677Tyr loses affinity for a regulatory binding motif in the FLCN promoter, abrogating cellular FLCN mRNA and protein levels. Overexpressing inducible PRDM10Cys677Tyr in renal epithelial cells altered the transcription of multiple genes, showing overlap but also differences with the effects of knocking out FLCN.

This gene has not yet been associated with phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Brain Calcification v1.22 ACVR1 Yetong Chen gene: ACVR1 was added
gene: ACVR1 was added to Brain Calcification. Sources: Expert list
Mode of inheritance for gene: ACVR1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ACVR1 were set to 27565519
Phenotypes for gene: ACVR1 were set to Fibrodysplasia ossificans progressiva; FOP
Review for gene: ACVR1 was set to GREEN
Added comment: PMID 27565519 reports that 4 individuals with an ACVR1 variant developed T2-hyperintensity with calcifications, while 2 individuals developed isolated calcification in the dentate nuclei. In addition, 7 individuals with an ACVR1 variant developed striatal calcifications in the basal ganglia. (However, the relationship between the reported individuals and their clinical presentations is not clear, and the online supplementary Table S3, which contains the clinico-genetic characteristics of patients, cannot be found.)
Sources: Expert list
Brain Calcification v1.22 ACP5 Yetong Chen changed review comment from: PMID 21217755 reports 4 unrelated individuals with ACP5 variants who developed intracranial calcification.
PMID 21217752 reports 4 individuals with ACP5 variants who developed brain calcification.; to: PMID 21217755 reports 4 unrelated individuals with ACP5 variants who developed intracranial calcification.
PMID 21217752 reports 4 individuals with ACP5 variants who developed brain calcification.
Brain Calcification v1.22 ACP5 Yetong Chen reviewed gene: ACP5: Rating: GREEN; Mode of pathogenicity: None; Publications: 24372060, 21217755; Phenotypes: Spondyloenchondrodysplasia with immune dysregulation, SPENCDI; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.752 COL12A1 Elena Savva commented on gene: COL12A1
Muscular dystrophy and myopathy_Paediatric v0.128 COL12A1 Elena Savva changed review comment from: Additional infant proband but with limited clinical information, had chet canonical splice with a PTC.

VCGS patient: homozygous for a canonical splice variant with a severe neonatal presentation of arthrogryposis and muscular hypotonia.

Total: three reports, upgraded to green; to: Additional infant proband but with limited clinical information, had chet canonical splice with a PTC.

VCGS patient: homozygous for a canonical splice variant with a severe neonatal presentation of arthrogryposis and muscular hypotonia.

Total: three reports, upgraded to green
Muscular dystrophy and myopathy_Paediatric v0.128 COL12A1 Elena Savva changed review comment from: Additional infant proband but with limited clinical information, had chet canonical splice with a PTC; to: Additional infant proband but with limited clinical information, had chet canonical splice with a PTC.

VCGS patient: homozygous for a canonical splice variant with a severe neonatal presentation of arthrogryposis and muscular hypotonia.

Total: three reports, upgraded to green
Muscular dystrophy and myopathy_Paediatric v0.128 COL12A1 Elena Savva Classified gene: COL12A1 as Green List (high evidence)
Muscular dystrophy and myopathy_Paediatric v0.128 COL12A1 Elena Savva Gene: col12a1 has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v0.127 COL12A1 Elena Savva Publications for gene: COL12A1 were set to 24334604
Muscular dystrophy and myopathy_Paediatric v0.127 COL12A1 Elena Savva Classified gene: COL12A1 as Green List (high evidence)
Muscular dystrophy and myopathy_Paediatric v0.127 COL12A1 Elena Savva Gene: col12a1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2123 VAMP1 Zornitza Stark Marked gene: VAMP1 as ready
BabyScreen+ newborn screening v0.2123 VAMP1 Zornitza Stark Gene: vamp1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2123 VAMP1 Zornitza Stark Phenotypes for gene: VAMP1 were changed from Spastic ataxia; Myasthenic syndrome, congenital, 25, MIM# 618323 to Myasthenic syndrome, congenital, 25, MIM# 618323
BabyScreen+ newborn screening v0.2122 VAMP1 Zornitza Stark Publications for gene: VAMP1 were set to
BabyScreen+ newborn screening v0.2121 VAMP1 Zornitza Stark Mode of inheritance for gene: VAMP1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.2120 VAMP1 Zornitza Stark Classified gene: VAMP1 as Green List (high evidence)
BabyScreen+ newborn screening v0.2120 VAMP1 Zornitza Stark Gene: vamp1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2119 VAMP1 Zornitza Stark Tag treatable tag was added to gene: VAMP1.
Tag neurological tag was added to gene: VAMP1.
BabyScreen+ newborn screening v0.2119 VAMP1 Zornitza Stark reviewed gene: VAMP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28168212, 28253535, 28600779, 17102983; Phenotypes: Myasthenic syndrome, congenital, 25, MIM# 618323; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.2119 TUBB1 Zornitza Stark Marked gene: TUBB1 as ready
BabyScreen+ newborn screening v0.2119 TUBB1 Zornitza Stark Gene: tubb1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2119 TUBB1 Zornitza Stark Classified gene: TUBB1 as Green List (high evidence)
BabyScreen+ newborn screening v0.2119 TUBB1 Zornitza Stark Gene: tubb1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2118 TUBB1 Zornitza Stark Tag treatable tag was added to gene: TUBB1.
Tag endocrine tag was added to gene: TUBB1.
BabyScreen+ newborn screening v0.2118 TUBB1 Zornitza Stark gene: TUBB1 was added
gene: TUBB1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: TUBB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TUBB1 were set to 30446499
Phenotypes for gene: TUBB1 were set to Congenital hypothyroidism, MONDO:0018612, TUBB1-related; Macrothrombocytopenia, autosomal dominant, TUBB1-related, OMIM # 613112
Review for gene: TUBB1 was set to GREEN
Added comment: At least 3 families reported with congenital hypothyroidism associated with TUBB1 variants. Platelet abnormalities reported.

Treatment: thyroxine.

Non-genetic confirmatory testing: TFTs, blood film.
Sources: Expert list
Congenital hypothyroidism v0.43 TUBB1 Zornitza Stark changed review comment from: Comment when marking as ready: Green for mono allelic variants, limited evidence for bi-allelic variants.; to: Comment when marking as ready: Green for mono allelic variants, limited evidence for bi-allelic variants.

Congenital hypothyroidism in some.
Mendeliome v1.752 SLC26A7 Zornitza Stark Marked gene: SLC26A7 as ready
Mendeliome v1.752 SLC26A7 Zornitza Stark Gene: slc26a7 has been classified as Green List (High Evidence).
Mendeliome v1.752 SLC26A7 Zornitza Stark Classified gene: SLC26A7 as Green List (high evidence)
Mendeliome v1.752 SLC26A7 Zornitza Stark Gene: slc26a7 has been classified as Green List (High Evidence).
Mendeliome v1.751 SLC26A7 Zornitza Stark gene: SLC26A7 was added
gene: SLC26A7 was added to Mendeliome. Sources: Expert list
Mode of inheritance for gene: SLC26A7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC26A7 were set to 34780050; 32486989; 31372509; 30333321
Phenotypes for gene: SLC26A7 were set to Congenital hypothyroidism, MONDO:0018612, SLC26A7-related
Review for gene: SLC26A7 was set to GREEN
Added comment: More than 10 unrelated families reported.
Sources: Expert list
BabyScreen+ newborn screening v0.2117 SLC26A7 Zornitza Stark Marked gene: SLC26A7 as ready
BabyScreen+ newborn screening v0.2117 SLC26A7 Zornitza Stark Gene: slc26a7 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2117 SLC26A7 Zornitza Stark Classified gene: SLC26A7 as Green List (high evidence)
BabyScreen+ newborn screening v0.2117 SLC26A7 Zornitza Stark Gene: slc26a7 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2116 SLC26A7 Zornitza Stark gene: SLC26A7 was added
gene: SLC26A7 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, endocrine tags were added to gene: SLC26A7.
Mode of inheritance for gene: SLC26A7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC26A7 were set to 34780050; 32486989; 31372509; 30333321
Phenotypes for gene: SLC26A7 were set to Congenital hypothyroidism, MONDO:0018612, SLC26A7-related
Review for gene: SLC26A7 was set to GREEN
Added comment: More than 10 unrelated families reported.

Congenital hypothyroidism.

Treatment: thyroxine.

Should be detected through standard NBS.
Sources: Expert list
Congenital hypothyroidism v0.43 SLC26A7 Zornitza Stark Marked gene: SLC26A7 as ready
Congenital hypothyroidism v0.43 SLC26A7 Zornitza Stark Gene: slc26a7 has been classified as Green List (High Evidence).
Congenital hypothyroidism v0.43 SLC26A7 Zornitza Stark Phenotypes for gene: SLC26A7 were changed from Primary congenital hypothyroidism (dyshormonogenesis) to Congenital hypothyroidism, MONDO:0018612, SLC26A7-related
Congenital hypothyroidism v0.42 SLC26A7 Zornitza Stark Publications for gene: SLC26A7 were set to 30333321; 29546359
Congenital hypothyroidism v0.41 SLC26A7 Zornitza Stark reviewed gene: SLC26A7: Rating: GREEN; Mode of pathogenicity: None; Publications: 34780050, 32486989, 31372509, 30333321; Phenotypes: Congenital hypothyroidism, MONDO:0018612, SLC26A7-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.2115 OTX2 Zornitza Stark Marked gene: OTX2 as ready
BabyScreen+ newborn screening v0.2115 OTX2 Zornitza Stark Gene: otx2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2115 OTX2 Zornitza Stark Classified gene: OTX2 as Green List (high evidence)
BabyScreen+ newborn screening v0.2115 OTX2 Zornitza Stark Gene: otx2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2114 OTX2 Zornitza Stark gene: OTX2 was added
gene: OTX2 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, endocrine tags were added to gene: OTX2.
Mode of inheritance for gene: OTX2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: OTX2 were set to 18728160; 35320640; 33950863
Phenotypes for gene: OTX2 were set to Pituitary hormone deficiency, combined, 6, MIM# 613986
Review for gene: OTX2 was set to GREEN
Added comment: Variants in this gene have been associated with pituitary hormone deficiency with or without microphthalmia, including of TSH.

Congenital onset.

Microphthalmia would present clinically in the newborn period. Infants with TSH deficiency should be detected by standard NBS.

Treatment: thyroxine and other hormone replacements.
Sources: Expert list
Congenital hypothyroidism v0.41 OTX2 Zornitza Stark Marked gene: OTX2 as ready
Congenital hypothyroidism v0.41 OTX2 Zornitza Stark Gene: otx2 has been classified as Green List (High Evidence).
Congenital hypothyroidism v0.41 OTX2 Zornitza Stark Phenotypes for gene: OTX2 were changed from GH, TSH, ACTH, LH, FSH deficiency; ectopic posterior pituitary; Anophthalmia Retinal dystrophy; normal or hypoplastic anterior pituitary; Pituitary hormone deficiency, combined, 6, 613986 to Pituitary hormone deficiency, combined, 6, MIM# 613986
Congenital hypothyroidism v0.40 OTX2 Zornitza Stark Publications for gene: OTX2 were set to 18628516; 26416826 (2015 review)
Congenital hypothyroidism v0.39 OTX2 Zornitza Stark reviewed gene: OTX2: Rating: GREEN; Mode of pathogenicity: None; Publications: 18728160, 35320640, 33950863; Phenotypes: Pituitary hormone deficiency, combined, 6, MIM# 613986; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
BabyScreen+ newborn screening v0.2113 HESX1 Zornitza Stark Marked gene: HESX1 as ready
BabyScreen+ newborn screening v0.2113 HESX1 Zornitza Stark Gene: hesx1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2113 HESX1 Zornitza Stark Phenotypes for gene: HESX1 were changed from Septooptic dysplasia, MIM# 182230; Pituitary hypoplasia to Pituitary hormone deficiency, combined, 5, MIM# 182230
BabyScreen+ newborn screening v0.2112 HESX1 Zornitza Stark Mode of inheritance for gene: HESX1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.2111 HESX1 Zornitza Stark Classified gene: HESX1 as Green List (high evidence)
BabyScreen+ newborn screening v0.2111 HESX1 Zornitza Stark Gene: hesx1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2110 HESX1 Zornitza Stark Tag treatable tag was added to gene: HESX1.
Tag endocrine tag was added to gene: HESX1.
BabyScreen+ newborn screening v0.2110 HESX1 Zornitza Stark reviewed gene: HESX1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Pituitary hormone deficiency, combined, 5, MIM# 182230; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Congenital hypothyroidism v0.39 CDCA8 Zornitza Stark Phenotypes for gene: CDCA8 were changed from Congenital hypothyroidism; No OMIM number; thyroid dysgenesis to Congenital hypothyroidism, MONDO:0018612, CDCA8-related
BabyScreen+ newborn screening v0.2110 CDCA8 Zornitza Stark Marked gene: CDCA8 as ready
BabyScreen+ newborn screening v0.2110 CDCA8 Zornitza Stark Gene: cdca8 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2110 CDCA8 Zornitza Stark Classified gene: CDCA8 as Green List (high evidence)
BabyScreen+ newborn screening v0.2110 CDCA8 Zornitza Stark Gene: cdca8 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2109 CDCA8 Zornitza Stark gene: CDCA8 was added
gene: CDCA8 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, endocrine tags were added to gene: CDCA8.
Mode of inheritance for gene: CDCA8 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: CDCA8 were set to 28025328; 29546359
Phenotypes for gene: CDCA8 were set to Congenital hypothyroidism, MONDO:0018612, CDCA8-related
Review for gene: CDCA8 was set to GREEN
Added comment: 4 families (1 with bilallelic variants [parent affected as HTZ], 3 with monoallelic variants) with functional evidence of variants.

Treatment: thyroxine

Likely to be detected on standard NBS.
Sources: Expert list
Severe Combined Immunodeficiency (absent T absent B cells) v1.5 LCP2 Zornitza Stark Classified gene: LCP2 as Amber List (moderate evidence)
Severe Combined Immunodeficiency (absent T absent B cells) v1.5 LCP2 Zornitza Stark Gene: lcp2 has been classified as Amber List (Moderate Evidence).
Severe Combined Immunodeficiency (absent T absent B cells) v1.4 LCP2 Zornitza Stark edited their review of gene: LCP2: Added comment: PMID 36474126: 3-year-old child who was born to first-cousins parents and presented with recurrent infections, failure to thrive, and severe EBV-related infection and lymphoproliferation. Functional testing linking gene with impaired t cell signalling.; Changed rating: AMBER; Changed publications: 33231617, 36474126
Mendeliome v1.750 LCP2 Zornitza Stark Publications for gene: LCP2 were set to 33231617
Mendeliome v1.749 LCP2 Zornitza Stark Classified gene: LCP2 as Green List (high evidence)
Mendeliome v1.749 LCP2 Zornitza Stark Gene: lcp2 has been classified as Green List (High Evidence).
Mendeliome v1.748 LCP2 Zornitza Stark edited their review of gene: LCP2: Added comment: PMID 36474126: second individual reported. Functional data.; Changed rating: GREEN; Changed publications: 33231617, 36474126
Combined Immunodeficiency v1.34 LCP2 Zornitza Stark Marked gene: LCP2 as ready
Combined Immunodeficiency v1.34 LCP2 Zornitza Stark Gene: lcp2 has been classified as Green List (High Evidence).
Combined Immunodeficiency v1.34 LCP2 Zornitza Stark Phenotypes for gene: LCP2 were changed from to Immunodeficiency 81, MIM# 619374
Combined Immunodeficiency v1.33 LCP2 Zornitza Stark reviewed gene: LCP2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Immunodeficiency 81, MIM# 619374; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Combined Immunodeficiency v1.33 LCP2 Zornitza Stark Classified gene: LCP2 as Green List (high evidence)
Combined Immunodeficiency v1.33 LCP2 Zornitza Stark Gene: lcp2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2108 FOXN1 Zornitza Stark Marked gene: FOXN1 as ready
BabyScreen+ newborn screening v0.2108 FOXN1 Zornitza Stark Gene: foxn1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2108 FOXN1 Zornitza Stark Phenotypes for gene: FOXN1 were changed from Congenital alopecia with T-cell immunodeficiency; T-cell immunodeficiency, congenital alopecia, and nail dystrophy , MIM#601705; T-cell lymphopenia, infantile, with or without nail dystrophy, autosomal dominant, MIM# 618806 to T-cell immunodeficiency, congenital alopecia, and nail dystrophy, autosomal recessive MIM# 601705; T-cell lymphopenia, infantile, with or without nail dystrophy, autosomal dominant, MIM#t 618806
BabyScreen+ newborn screening v0.2107 FOXN1 Zornitza Stark Publications for gene: FOXN1 were set to
BabyScreen+ newborn screening v0.2106 FOXN1 Zornitza Stark Mode of inheritance for gene: FOXN1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.2105 FOXN1 Zornitza Stark Classified gene: FOXN1 as Green List (high evidence)
BabyScreen+ newborn screening v0.2105 FOXN1 Zornitza Stark Gene: foxn1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2104 FOXN1 Zornitza Stark Tag treatable tag was added to gene: FOXN1.
Tag immunological tag was added to gene: FOXN1.
BabyScreen+ newborn screening v0.2104 FOXN1 Zornitza Stark reviewed gene: FOXN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31447097, 18339010, 10206641; Phenotypes: T-cell immunodeficiency, congenital alopecia, and nail dystrophy, autosomal recessive MIM# 601705, T-cell lymphopenia, infantile, with or without nail dystrophy, autosomal dominant, MIM#t 618806; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Muscular dystrophy and myopathy_Paediatric v0.126 COL12A1 Elena Savva reviewed gene: COL12A1: Rating: AMBER; Mode of pathogenicity: None; Publications: 28973083, 24334604; Phenotypes: ?Ullrich congenital muscular dystrophy 2 MIM#616470; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Osteogenesis Imperfecta and Osteoporosis v0.105 TRPV6 Zornitza Stark Marked gene: TRPV6 as ready
Osteogenesis Imperfecta and Osteoporosis v0.105 TRPV6 Zornitza Stark Gene: trpv6 has been classified as Green List (High Evidence).
Osteogenesis Imperfecta and Osteoporosis v0.105 TRPV6 Zornitza Stark Phenotypes for gene: TRPV6 were changed from to Hyperparathyroidism, transient neonatal, MIM# 618188
Osteogenesis Imperfecta and Osteoporosis v0.104 TRPV6 Zornitza Stark Publications for gene: TRPV6 were set to
Osteogenesis Imperfecta and Osteoporosis v0.103 TRPV6 Zornitza Stark Mode of inheritance for gene: TRPV6 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Osteogenesis Imperfecta and Osteoporosis v0.102 TRPV6 Zornitza Stark reviewed gene: TRPV6: Rating: GREEN; Mode of pathogenicity: None; Publications: 29861107; Phenotypes: Hyperparathyroidism, transient neonatal, MIM# 618188; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.2104 TMEM38B Zornitza Stark Marked gene: TMEM38B as ready
BabyScreen+ newborn screening v0.2104 TMEM38B Zornitza Stark Gene: tmem38b has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2104 TMEM38B Zornitza Stark Classified gene: TMEM38B as Green List (high evidence)
BabyScreen+ newborn screening v0.2104 TMEM38B Zornitza Stark Gene: tmem38b has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2103 TMEM38B Zornitza Stark Tag treatable tag was added to gene: TMEM38B.
Tag skeletal tag was added to gene: TMEM38B.
BabyScreen+ newborn screening v0.2103 TMEM38B Zornitza Stark gene: TMEM38B was added
gene: TMEM38B was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: TMEM38B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM38B were set to 23054245; 28323974
Phenotypes for gene: TMEM38B were set to Osteogenesis imperfecta, type XIV , MIM#615066
Review for gene: TMEM38B was set to GREEN
Added comment: More than 10 families reported.

Variable severity, onset of fractures generally in infancy.

Treatment: bisphosphanates; improvement in BMD reported.

Non-genetic confirmatory testing: skeletal survey.
Sources: Expert list
Osteogenesis Imperfecta and Osteoporosis v0.102 TMEM38B Zornitza Stark Marked gene: TMEM38B as ready
Osteogenesis Imperfecta and Osteoporosis v0.102 TMEM38B Zornitza Stark Gene: tmem38b has been classified as Green List (High Evidence).
Osteogenesis Imperfecta and Osteoporosis v0.102 TMEM38B Zornitza Stark Phenotypes for gene: TMEM38B were changed from to Osteogenesis imperfecta, type XIV , MIM#615066
Osteogenesis Imperfecta and Osteoporosis v0.101 TMEM38B Zornitza Stark Publications for gene: TMEM38B were set to
Osteogenesis Imperfecta and Osteoporosis v0.100 TMEM38B Zornitza Stark Mode of inheritance for gene: TMEM38B was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Osteogenesis Imperfecta and Osteoporosis v0.99 TMEM38B Zornitza Stark reviewed gene: TMEM38B: Rating: GREEN; Mode of pathogenicity: None; Publications: 23054245, 28323974; Phenotypes: Osteogenesis imperfecta, type XIV , MIM#615066; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Osteogenesis Imperfecta and Osteoporosis v0.99 SPARC Zornitza Stark Marked gene: SPARC as ready
Osteogenesis Imperfecta and Osteoporosis v0.99 SPARC Zornitza Stark Gene: sparc has been classified as Green List (High Evidence).
Inflammatory bowel disease v0.99 C17orf62 Aimee Huynh gene: C17orf62 was added
gene: C17orf62 was added to Inflammatory bowel disease. Sources: Expert Review
Mode of inheritance for gene: C17orf62 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C17orf62 were set to 28600779, 30361506
Phenotypes for gene: C17orf62 were set to Chronic granulomatous disease
Penetrance for gene: C17orf62 were set to unknown
Review for gene: C17orf62 was set to AMBER
gene: C17orf62 was marked as current diagnostic
Added comment: Homozygous LOF mutation leading to CYBC1 deficiency causes CGD in pair of Icelandic brothers and 6 other individuals - colitis an early feature. Brothers diagnosed with Crohn's at ages 7 and 9 years. 3 out of 6 other individuals also had colitis.
Sources: Expert Review
Osteogenesis Imperfecta and Osteoporosis v0.99 SPARC Zornitza Stark Phenotypes for gene: SPARC were changed from to Osteogenesis imperfecta, type XVII, MIM# 616507
BabyScreen+ newborn screening v0.2102 SPARC Zornitza Stark Marked gene: SPARC as ready
BabyScreen+ newborn screening v0.2102 SPARC Zornitza Stark Gene: sparc has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2102 SPARC Zornitza Stark gene: SPARC was added
gene: SPARC was added to Baby Screen+ newborn screening. Sources: Expert list
skeletal tags were added to gene: SPARC.
Mode of inheritance for gene: SPARC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPARC were set to 26027498; 34462290
Phenotypes for gene: SPARC were set to Osteogenesis imperfecta, type XVII, MIM# 616507
Review for gene: SPARC was set to RED
Added comment: Established gene-disease association, 5 families reported.

Onset of fractures in infancy.

Prominent neuromuscular features, MRI brain changes; some with ID.

Treatment: bisphosphanates are generally used in OI but the case reports where these have been used do not seem terribly convincing in terms of response/improvement.

Exclude for now.
Sources: Expert list
Osteogenesis Imperfecta and Osteoporosis v0.98 SPARC Zornitza Stark Publications for gene: SPARC were set to
Osteogenesis Imperfecta and Osteoporosis v0.97 SPARC Zornitza Stark Mode of inheritance for gene: SPARC was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Osteogenesis Imperfecta and Osteoporosis v0.96 SPARC Zornitza Stark edited their review of gene: SPARC: Changed rating: GREEN
Osteogenesis Imperfecta and Osteoporosis v0.96 SPARC Zornitza Stark reviewed gene: SPARC: Rating: ; Mode of pathogenicity: None; Publications: 26027498, 34462290; Phenotypes: Osteogenesis imperfecta, type XVII, MIM# 616507; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.2101 SP7 Zornitza Stark Marked gene: SP7 as ready
BabyScreen+ newborn screening v0.2101 SP7 Zornitza Stark Gene: sp7 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.2101 SP7 Zornitza Stark Phenotypes for gene: SP7 were changed from Osteogenesis imperfecta, type XII to Osteogenesis imperfecta, type XII, MIM# 613849
BabyScreen+ newborn screening v0.2100 SP7 Zornitza Stark Publications for gene: SP7 were set to
BabyScreen+ newborn screening v0.2099 SP7 Zornitza Stark Mode of inheritance for gene: SP7 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.2098 SP7 Zornitza Stark Classified gene: SP7 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.2098 SP7 Zornitza Stark Gene: sp7 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.2097 SP7 Zornitza Stark Tag skeletal tag was added to gene: SP7.
BabyScreen+ newborn screening v0.2097 SP7 Zornitza Stark reviewed gene: SP7: Rating: AMBER; Mode of pathogenicity: None; Publications: 36881265; Phenotypes: Osteogenesis imperfecta, type XII, MIM# 613849; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.2097 SERPINH1 Zornitza Stark Marked gene: SERPINH1 as ready
BabyScreen+ newborn screening v0.2097 SERPINH1 Zornitza Stark Gene: serpinh1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2097 SERPINH1 Zornitza Stark Classified gene: SERPINH1 as Green List (high evidence)
BabyScreen+ newborn screening v0.2097 SERPINH1 Zornitza Stark Gene: serpinh1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2096 SERPINH1 Zornitza Stark gene: SERPINH1 was added
gene: SERPINH1 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, skeletal tags were added to gene: SERPINH1.
Mode of inheritance for gene: SERPINH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SERPINH1 were set to 29520608; 25510505; 33524049
Phenotypes for gene: SERPINH1 were set to Osteogenesis imperfecta, type X, MIM# 613848
Review for gene: SERPINH1 was set to GREEN
Added comment: Established gene-disease association.

Onset of fractures is in infancy.

Treatment: bisphosphanates.

Non-genetic confirmatory testing: skeletal survey.
Sources: Expert list
Osteogenesis Imperfecta and Osteoporosis v0.96 SERPINF1 Zornitza Stark Marked gene: SERPINF1 as ready
Osteogenesis Imperfecta and Osteoporosis v0.96 SERPINF1 Zornitza Stark Gene: serpinf1 has been classified as Green List (High Evidence).
Osteogenesis Imperfecta and Osteoporosis v0.96 SERPINF1 Zornitza Stark Phenotypes for gene: SERPINF1 were changed from to Osteogenesis imperfecta, type VI, MIM# 613982
Osteogenesis Imperfecta and Osteoporosis v0.95 SERPINF1 Zornitza Stark Publications for gene: SERPINF1 were set to
Osteogenesis Imperfecta and Osteoporosis v0.94 SERPINF1 Zornitza Stark Mode of inheritance for gene: SERPINF1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.2095 SERPINF1 Zornitza Stark Marked gene: SERPINF1 as ready
BabyScreen+ newborn screening v0.2095 SERPINF1 Zornitza Stark Gene: serpinf1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2095 SERPINF1 Zornitza Stark Classified gene: SERPINF1 as Green List (high evidence)
BabyScreen+ newborn screening v0.2095 SERPINF1 Zornitza Stark Gene: serpinf1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2094 SERPINF1 Zornitza Stark gene: SERPINF1 was added
gene: SERPINF1 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, skeletal tags were added to gene: SERPINF1.
Mode of inheritance for gene: SERPINF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SERPINF1 were set to 28689307
Phenotypes for gene: SERPINF1 were set to Osteogenesis imperfecta, type VI, MIM# 613982
Review for gene: SERPINF1 was set to GREEN
Added comment: Established gene-disease association.

Onset of fractures is in infancy.

Treatment: bisphosphanates.

Non-genetic confirmatory testing: skeletal survey.
Sources: Expert list
Osteogenesis Imperfecta and Osteoporosis v0.93 SERPINF1 Zornitza Stark reviewed gene: SERPINF1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28689307; Phenotypes: Osteogenesis imperfecta, type VI, MIM# 613982; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.2093 PPIB Zornitza Stark Marked gene: PPIB as ready
BabyScreen+ newborn screening v0.2093 PPIB Zornitza Stark Gene: ppib has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2093 PPIB Zornitza Stark gene: PPIB was added
gene: PPIB was added to Baby Screen+ newborn screening. Sources: Expert list
skeletal tags were added to gene: PPIB.
Mode of inheritance for gene: PPIB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPIB were set to 19781681; 32392875
Phenotypes for gene: PPIB were set to Osteogenesis imperfecta, type IX, MIM# 259440
Review for gene: PPIB was set to RED
Added comment: Established gene-diseases association.

Most reported families have had severe OI, presenting perinatally, therefore exclude.
Sources: Expert list
BabyScreen+ newborn screening v0.2092 PLOD2 Zornitza Stark Marked gene: PLOD2 as ready
BabyScreen+ newborn screening v0.2092 PLOD2 Zornitza Stark Gene: plod2 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2092 PLOD2 Zornitza Stark Phenotypes for gene: PLOD2 were changed from Bruck syndrome to Bruck syndrome 2, MIM# 609220
BabyScreen+ newborn screening v0.2091 PLOD2 Zornitza Stark reviewed gene: PLOD2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Bruck syndrome 2, MIM# 609220; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Osteogenesis Imperfecta and Osteoporosis v0.93 PLOD2 Zornitza Stark Marked gene: PLOD2 as ready
Osteogenesis Imperfecta and Osteoporosis v0.93 PLOD2 Zornitza Stark Gene: plod2 has been classified as Green List (High Evidence).
Osteogenesis Imperfecta and Osteoporosis v0.93 PLOD2 Zornitza Stark Phenotypes for gene: PLOD2 were changed from to Bruck syndrome 2, MIM# 609220
Osteogenesis Imperfecta and Osteoporosis v0.92 PLOD2 Zornitza Stark Publications for gene: PLOD2 were set to
Osteogenesis Imperfecta and Osteoporosis v0.91 PLOD2 Zornitza Stark Mode of inheritance for gene: PLOD2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Osteogenesis Imperfecta and Osteoporosis v0.90 PLOD2 Zornitza Stark reviewed gene: PLOD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 12881513, 15523624, 22689593; Phenotypes: Bruck syndrome 2, MIM# 609220; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Osteogenesis Imperfecta and Osteoporosis v0.90 P4HB Zornitza Stark changed review comment from: Four unrelated individuals reported with same recurrent de novo missense variant, p.Tyr393Cys, and an additional individual with de novo intragenic deletion of exons 5-8. Hydrocephalus is part of the phenotype.; to: Four unrelated individuals reported with same recurrent de novo missense variant, p.Tyr393Cys, and an additional individual with de novo intragenic deletion of exons 5-8. Bone fragility is part of the phenotype.
BabyScreen+ newborn screening v0.2091 P3H1 Zornitza Stark Marked gene: P3H1 as ready
BabyScreen+ newborn screening v0.2091 P3H1 Zornitza Stark Gene: p3h1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2091 P3H1 Zornitza Stark Classified gene: P3H1 as Green List (high evidence)
BabyScreen+ newborn screening v0.2091 P3H1 Zornitza Stark Gene: p3h1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2090 P3H1 Zornitza Stark gene: P3H1 was added
gene: P3H1 was added to Baby Screen+ newborn screening. Sources: Expert Review
treatable, skeletal tags were added to gene: P3H1.
Mode of inheritance for gene: P3H1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: P3H1 were set to 17277775; 18566967
Phenotypes for gene: P3H1 were set to Osteogenesis imperfecta, type VIII, (MIM# 610915)
Review for gene: P3H1 was set to GREEN
Added comment: More than 15 families reported.

Congenital onset.

Treatment: bisphosphanates.

Non-genetic confirmatory testing: skeletal survey.
Sources: Expert Review
BabyScreen+ newborn screening v0.2089 MESD Zornitza Stark Marked gene: MESD as ready
BabyScreen+ newborn screening v0.2089 MESD Zornitza Stark Gene: mesd has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2089 MESD Zornitza Stark Classified gene: MESD as Green List (high evidence)
BabyScreen+ newborn screening v0.2089 MESD Zornitza Stark Gene: mesd has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2088 MESD Zornitza Stark gene: MESD was added
gene: MESD was added to Baby Screen+ newborn screening. Sources: Expert Review
treatable, skeletal tags were added to gene: MESD.
Mode of inheritance for gene: MESD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MESD were set to 31564437; 35092157; 33596325; 31564437
Phenotypes for gene: MESD were set to Osteogenesis imperfecta, type XX, MIM# 618644
Review for gene: MESD was set to GREEN
Added comment: More than 5 families reported.

Severe form of OI, some perinatal lethal.

Treatment: bisphosphanates.

Non-genetic confirmatory testing: skeletal survey.
Sources: Expert Review
BabyScreen+ newborn screening v0.2087 KDELR2 Zornitza Stark Marked gene: KDELR2 as ready
BabyScreen+ newborn screening v0.2087 KDELR2 Zornitza Stark Gene: kdelr2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2087 KDELR2 Zornitza Stark Classified gene: KDELR2 as Green List (high evidence)
BabyScreen+ newborn screening v0.2087 KDELR2 Zornitza Stark Gene: kdelr2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2086 KDELR2 Zornitza Stark gene: KDELR2 was added
gene: KDELR2 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, skeletal tags were added to gene: KDELR2.
Mode of inheritance for gene: KDELR2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: KDELR2 were set to Osteogenesis imperfecta 21, MIM# 619131
Review for gene: KDELR2 was set to GREEN
Added comment: 4 families with osteogenesis imperfecta reported with functional studies.

Onset in infancy.

Improvement reported with bisphosphanates, similar to other OI.

Non-genetic confirmatory testing: skeletal survey.
Sources: Expert list
BabyScreen+ newborn screening v0.2085 FKBP10 Zornitza Stark Marked gene: FKBP10 as ready
BabyScreen+ newborn screening v0.2085 FKBP10 Zornitza Stark Gene: fkbp10 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2085 FKBP10 Zornitza Stark Classified gene: FKBP10 as Green List (high evidence)
BabyScreen+ newborn screening v0.2085 FKBP10 Zornitza Stark Gene: fkbp10 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2084 FKBP10 Zornitza Stark Tag treatable tag was added to gene: FKBP10.
Tag skeletal tag was added to gene: FKBP10.
BabyScreen+ newborn screening v0.2084 FKBP10 Zornitza Stark gene: FKBP10 was added
gene: FKBP10 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: FKBP10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FKBP10 were set to 34173012
Phenotypes for gene: FKBP10 were set to Osteogenesis imperfecta, type XI, OMIM:610968
Review for gene: FKBP10 was set to GREEN
Added comment: Well established gene-disease association.

Early-onset bone fractures and progressive skeletal deformities.

Treatment: bisphosphanates.

Non-genetic confirmatory testing: skeletal survey.
Sources: Expert list
BabyScreen+ newborn screening v0.2083 BMP1 Zornitza Stark Marked gene: BMP1 as ready
BabyScreen+ newborn screening v0.2083 BMP1 Zornitza Stark Gene: bmp1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2083 BMP1 Zornitza Stark Classified gene: BMP1 as Green List (high evidence)
BabyScreen+ newborn screening v0.2083 BMP1 Zornitza Stark Gene: bmp1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2082 BMP1 Zornitza Stark gene: BMP1 was added
gene: BMP1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: BMP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BMP1 were set to 33818922
Phenotypes for gene: BMP1 were set to Osteogenesis imperfecta, type XIII , MIM#614856
Review for gene: BMP1 was set to GREEN
Added comment: Rare cause of OI. 20 families reported.

Treatment: bisphosphanates.
Sources: Expert list
BabyScreen+ newborn screening v0.2081 PTH1R Zornitza Stark changed review comment from: Variants in this gene are associated with a range of skeletal disorder.

Wide variability in severity, with BOCD manifesting antenatally.

No specific treatment.; to: Variants in this gene are associated with a range of skeletal disorders.

Wide variability in severity, with BOCD manifesting antenatally.

No specific treatment.
Inflammatory bowel disease v0.99 IL2RB Zornitza Stark Marked gene: IL2RB as ready
Inflammatory bowel disease v0.99 IL2RB Zornitza Stark Gene: il2rb has been classified as Green List (High Evidence).
Inflammatory bowel disease v0.99 IL2RB Zornitza Stark Phenotypes for gene: IL2RB were changed from immunodeficiency; autoimmune enteropathy to Immunodeficiency 63 with lymphoproliferation and autoimmunity, MIM# 618495
Inflammatory bowel disease v0.98 IL2RB Zornitza Stark Classified gene: IL2RB as Green List (high evidence)
Inflammatory bowel disease v0.98 IL2RB Zornitza Stark Gene: il2rb has been classified as Green List (High Evidence).
Inflammatory bowel disease v0.97 IL2RB Zornitza Stark reviewed gene: IL2RB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Immunodeficiency 63 with lymphoproliferation and autoimmunity, MIM# 618495; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inflammatory bowel disease v0.97 IL21 Zornitza Stark Marked gene: IL21 as ready
Inflammatory bowel disease v0.97 IL21 Zornitza Stark Gene: il21 has been classified as Amber List (Moderate Evidence).
Inflammatory bowel disease v0.97 IL21 Zornitza Stark Phenotypes for gene: IL21 were changed from immunodeficiency; inflammatory bowel disease to Immunodeficiency, common variable, 11, MIM# 615767
Inflammatory bowel disease v0.96 IL21 Zornitza Stark Classified gene: IL21 as Amber List (moderate evidence)
Inflammatory bowel disease v0.96 IL21 Zornitza Stark Gene: il21 has been classified as Amber List (Moderate Evidence).
Inflammatory bowel disease v0.95 IL21 Zornitza Stark reviewed gene: IL21: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Immunodeficiency, common variable, 11, MIM# 615767; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inflammatory bowel disease v0.95 DKC1 Zornitza Stark Marked gene: DKC1 as ready
Inflammatory bowel disease v0.95 DKC1 Zornitza Stark Gene: dkc1 has been classified as Amber List (Moderate Evidence).
Inflammatory bowel disease v0.95 DKC1 Zornitza Stark Phenotypes for gene: DKC1 were changed from Dyskeratosis congenita to Dyskeratosis congenita, X-linked, MIM# 305000
Inflammatory bowel disease v0.94 DKC1 Zornitza Stark Classified gene: DKC1 as Amber List (moderate evidence)
Inflammatory bowel disease v0.94 DKC1 Zornitza Stark Gene: dkc1 has been classified as Amber List (Moderate Evidence).
Inflammatory bowel disease v0.93 DKC1 Zornitza Stark reviewed gene: DKC1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Dyskeratosis congenita, X-linked, MIM# 305000; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Stickler Syndrome v1.6 SLC29A3 Zornitza Stark Marked gene: SLC29A3 as ready
Stickler Syndrome v1.6 SLC29A3 Zornitza Stark Gene: slc29a3 has been classified as Amber List (Moderate Evidence).
Stickler Syndrome v1.6 SLC29A3 Zornitza Stark Classified gene: SLC29A3 as Amber List (moderate evidence)
Stickler Syndrome v1.6 SLC29A3 Zornitza Stark Gene: slc29a3 has been classified as Amber List (Moderate Evidence).
Stickler Syndrome v1.5 SLC29A3 Zornitza Stark reviewed gene: SLC29A3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Histiocytosis-lymphadenopathy plus syndrome - MIM#602782; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Deafness_Isolated v1.42 STX4 Zornitza Stark Marked gene: STX4 as ready
Deafness_Isolated v1.42 STX4 Zornitza Stark Gene: stx4 has been classified as Amber List (Moderate Evidence).
Deafness_Isolated v1.42 STX4 Zornitza Stark Classified gene: STX4 as Amber List (moderate evidence)
Deafness_Isolated v1.42 STX4 Zornitza Stark Gene: stx4 has been classified as Amber List (Moderate Evidence).
Deafness_Isolated v1.41 STX4 Zornitza Stark gene: STX4 was added
gene: STX4 was added to Deafness_Isolated. Sources: Literature
Mode of inheritance for gene: STX4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: STX4 were set to 36355422
Phenotypes for gene: STX4 were set to Non-syndromic genetic hearing loss, MONDO:0019497, STX4-related
Review for gene: STX4 was set to AMBER
Added comment: PMID:36355422 reported a large consanguineous Pakistani family with eight affected individuals showing bilateral severe-to-profound hearing impairment. A homozygous splice region variant was identified in STX4 (c.232 + 6T>C), which causes exon skipping and a frameshift, that segregated with hearing impairment in this family. In silico analysis showed that murine Stx4a is highly and widespread expressed in the developing and adult inner ear. Knockdown of stx4 in zebrafish showed an abnormal startle response, morphological and developmental defects, and a disrupted mechanotransduction function in neuromast hair cells.
Sources: Literature
Mendeliome v1.748 STX4 Zornitza Stark Phenotypes for gene: STX4 were changed from to Non-syndromic genetic hearing loss, MONDO:0019497, STX4-related.
Mendeliome v1.747 STX4 Zornitza Stark Publications for gene: STX4 were set to
Mendeliome v1.746 STX4 Zornitza Stark Mode of inheritance for gene: STX4 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.745 STX4 Zornitza Stark Classified gene: STX4 as Amber List (moderate evidence)
Mendeliome v1.745 STX4 Zornitza Stark Gene: stx4 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.744 ARF1 Zornitza Stark Publications for gene: ARF1 were set to 28868155; 34353862
BabyScreen+ newborn screening v0.2081 SARS Zornitza Stark Marked gene: SARS as ready
BabyScreen+ newborn screening v0.2081 SARS Zornitza Stark Gene: sars has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2081 SARS Zornitza Stark Classified gene: SARS as Red List (low evidence)
BabyScreen+ newborn screening v0.2081 SARS Zornitza Stark Gene: sars has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2080 SCARB2 Zornitza Stark Marked gene: SCARB2 as ready
BabyScreen+ newborn screening v0.2080 SCARB2 Zornitza Stark Gene: scarb2 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2080 SCARB2 Zornitza Stark Classified gene: SCARB2 as Red List (low evidence)
BabyScreen+ newborn screening v0.2080 SCARB2 Zornitza Stark Gene: scarb2 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2079 SERPING1 Zornitza Stark Marked gene: SERPING1 as ready
BabyScreen+ newborn screening v0.2079 SERPING1 Zornitza Stark Gene: serping1 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2079 SERPING1 Zornitza Stark Classified gene: SERPING1 as Red List (low evidence)
BabyScreen+ newborn screening v0.2079 SERPING1 Zornitza Stark Gene: serping1 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2078 SERPING1 Zornitza Stark Tag treatable tag was added to gene: SERPING1.
Tag immunological tag was added to gene: SERPING1.
BabyScreen+ newborn screening v0.2078 SGPL1 Zornitza Stark Marked gene: SGPL1 as ready
BabyScreen+ newborn screening v0.2078 SGPL1 Zornitza Stark Gene: sgpl1 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2078 SGPL1 Zornitza Stark Classified gene: SGPL1 as Red List (low evidence)
BabyScreen+ newborn screening v0.2078 SGPL1 Zornitza Stark Gene: sgpl1 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2077 SGPL1 Zornitza Stark Tag renal tag was added to gene: SGPL1.
BabyScreen+ newborn screening v0.2077 SLC1A3 Zornitza Stark Marked gene: SLC1A3 as ready
BabyScreen+ newborn screening v0.2077 SLC1A3 Zornitza Stark Gene: slc1a3 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2077 SLC1A3 Zornitza Stark Classified gene: SLC1A3 as Red List (low evidence)
BabyScreen+ newborn screening v0.2077 SLC1A3 Zornitza Stark Gene: slc1a3 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2076 SLC1A3 Zornitza Stark Tag neurological tag was added to gene: SLC1A3.
BabyScreen+ newborn screening v0.2076 SMARCD2 Zornitza Stark Marked gene: SMARCD2 as ready
BabyScreen+ newborn screening v0.2076 SMARCD2 Zornitza Stark Gene: smarcd2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2076 SMARCD2 Zornitza Stark Classified gene: SMARCD2 as Green List (high evidence)
BabyScreen+ newborn screening v0.2076 SMARCD2 Zornitza Stark Gene: smarcd2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2075 SMARCD2 Zornitza Stark Tag treatable tag was added to gene: SMARCD2.
Tag immunological tag was added to gene: SMARCD2.
BabyScreen+ newborn screening v0.2075 SMARCD2 Zornitza Stark reviewed gene: SMARCD2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Specific granule deficiency 2 MIM#617475; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.2075 SNX10 Zornitza Stark Marked gene: SNX10 as ready
BabyScreen+ newborn screening v0.2075 SNX10 Zornitza Stark Gene: snx10 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2075 SNX10 Zornitza Stark Classified gene: SNX10 as Green List (high evidence)
BabyScreen+ newborn screening v0.2075 SNX10 Zornitza Stark Gene: snx10 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2074 SNX10 Zornitza Stark Tag treatable tag was added to gene: SNX10.
Tag skeletal tag was added to gene: SNX10.
BabyScreen+ newborn screening v0.2074 SORD Zornitza Stark Marked gene: SORD as ready
BabyScreen+ newborn screening v0.2074 SORD Zornitza Stark Gene: sord has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2074 SORD Zornitza Stark Classified gene: SORD as Red List (low evidence)
BabyScreen+ newborn screening v0.2074 SORD Zornitza Stark Gene: sord has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2073 SORD Zornitza Stark Tag treatable tag was added to gene: SORD.
Tag metabolic tag was added to gene: SORD.
BabyScreen+ newborn screening v0.2073 SOX3 Zornitza Stark Marked gene: SOX3 as ready
BabyScreen+ newborn screening v0.2073 SOX3 Zornitza Stark Gene: sox3 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.2073 SOX3 Zornitza Stark Classified gene: SOX3 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.2073 SOX3 Zornitza Stark Gene: sox3 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.2072 SOX3 Zornitza Stark Tag for review tag was added to gene: SOX3.
Tag treatable tag was added to gene: SOX3.
Tag endocrine tag was added to gene: SOX3.
BabyScreen+ newborn screening v0.2072 SOX3 Zornitza Stark reviewed gene: SOX3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Panhypopituitarism, X-linked MIM#312000; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Pituitary hormone deficiency v0.32 SOX3 Zornitza Stark Marked gene: SOX3 as ready
Pituitary hormone deficiency v0.32 SOX3 Zornitza Stark Gene: sox3 has been classified as Amber List (Moderate Evidence).
Pituitary hormone deficiency v0.32 SOX3 Zornitza Stark Classified gene: SOX3 as Amber List (moderate evidence)
Pituitary hormone deficiency v0.32 SOX3 Zornitza Stark Gene: sox3 has been classified as Amber List (Moderate Evidence).
Pituitary hormone deficiency v0.31 SOX3 Zornitza Stark Tag SV/CNV tag was added to gene: SOX3.
Pituitary hormone deficiency v0.31 SOX3 Zornitza Stark reviewed gene: SOX3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Panhypopituitarism, X-linked, MIM# 312000; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
BabyScreen+ newborn screening v0.2072 STAT1 Zornitza Stark Marked gene: STAT1 as ready
BabyScreen+ newborn screening v0.2072 STAT1 Zornitza Stark Gene: stat1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2072 STAT1 Zornitza Stark Mode of inheritance for gene: STAT1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.2071 STAT1 Zornitza Stark Classified gene: STAT1 as Green List (high evidence)
BabyScreen+ newborn screening v0.2071 STAT1 Zornitza Stark Gene: stat1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2070 STAT1 Zornitza Stark Tag treatable tag was added to gene: STAT1.
Tag immunological tag was added to gene: STAT1.
BabyScreen+ newborn screening v0.2070 STAT1 Zornitza Stark reviewed gene: STAT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Immunodeficiency 31B, mycobacterial and viral infections, autosomal recessive, MIM# 613796; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.2070 STIM1 Zornitza Stark Marked gene: STIM1 as ready
BabyScreen+ newborn screening v0.2070 STIM1 Zornitza Stark Gene: stim1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2070 STIM1 Zornitza Stark Classified gene: STIM1 as Green List (high evidence)
BabyScreen+ newborn screening v0.2070 STIM1 Zornitza Stark Gene: stim1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2069 STIM1 Zornitza Stark Tag treatable tag was added to gene: STIM1.
Tag immunological tag was added to gene: STIM1.
BabyScreen+ newborn screening v0.2069 STIM1 Zornitza Stark reviewed gene: STIM1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Immunodeficiency 10 MIM612783; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.2069 STK4 Zornitza Stark Marked gene: STK4 as ready
BabyScreen+ newborn screening v0.2069 STK4 Zornitza Stark Gene: stk4 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2069 STK4 Zornitza Stark Classified gene: STK4 as Green List (high evidence)
BabyScreen+ newborn screening v0.2069 STK4 Zornitza Stark Gene: stk4 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2068 STK4 Zornitza Stark Tag treatable tag was added to gene: STK4.
Tag immunological tag was added to gene: STK4.
BabyScreen+ newborn screening v0.2068 STK4 Zornitza Stark reviewed gene: STK4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: T-cell immunodeficiency, recurrent infections, autoimmunity, and cardiac malformations MIM#614868; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inflammatory bowel disease v0.93 IL2RB Aimee Huynh gene: IL2RB was added
gene: IL2RB was added to Inflammatory bowel disease. Sources: Expert Review
Mode of inheritance for gene: IL2RB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IL2RB were set to 31040184, 31040185
Phenotypes for gene: IL2RB were set to immunodeficiency; autoimmune enteropathy
Penetrance for gene: IL2RB were set to unknown
Review for gene: IL2RB was set to AMBER
gene: IL2RB was marked as current diagnostic
Added comment: 3 homozygous mutations in the IL2RB gene of 8 individuals from 4 consanguineous families that cause disease by distinct mechanisms. Nearly all patients presented with autoantibodies, hypergammaglobulinemia, bowel inflammation, dermatological abnormalities, lymphadenopathy, and CMV disease. 4/5 children had severe diarrhea and infectious/autoimmune enteropathy. Endoscopy of patient B1 showed villous atrophy, and gastrointestinal biopsies revealed chronic inflammatory infiltration of the duodenum and rectum.
Sources: Expert Review
BabyScreen+ newborn screening v0.2068 STX16 Zornitza Stark Marked gene: STX16 as ready
BabyScreen+ newborn screening v0.2068 STX16 Zornitza Stark Gene: stx16 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2068 STX16 Zornitza Stark Classified gene: STX16 as Green List (high evidence)
BabyScreen+ newborn screening v0.2068 STX16 Zornitza Stark Gene: stx16 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2067 STX16 Zornitza Stark Tag treatable tag was added to gene: STX16.
Tag endocrine tag was added to gene: STX16.
BabyScreen+ newborn screening v0.2067 SYT2 Zornitza Stark Marked gene: SYT2 as ready
BabyScreen+ newborn screening v0.2067 SYT2 Zornitza Stark Gene: syt2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2067 SYT2 Zornitza Stark Mode of inheritance for gene: SYT2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.2066 SYT2 Zornitza Stark Classified gene: SYT2 as Green List (high evidence)
BabyScreen+ newborn screening v0.2066 SYT2 Zornitza Stark Gene: syt2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2065 SYT2 Zornitza Stark Tag treatable tag was added to gene: SYT2.
Tag neurological tag was added to gene: SYT2.
BabyScreen+ newborn screening v0.2065 TBL1X Zornitza Stark Marked gene: TBL1X as ready
BabyScreen+ newborn screening v0.2065 TBL1X Zornitza Stark Gene: tbl1x has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2065 TBL1X Zornitza Stark Classified gene: TBL1X as Green List (high evidence)
BabyScreen+ newborn screening v0.2065 TBL1X Zornitza Stark Gene: tbl1x has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2064 TBL1X Zornitza Stark Tag treatable tag was added to gene: TBL1X.
Tag endocrine tag was added to gene: TBL1X.
Inflammatory bowel disease v0.93 IL21 Aimee Huynh gene: IL21 was added
gene: IL21 was added to Inflammatory bowel disease. Sources: Expert Review
Mode of inheritance for gene: IL21 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IL21 were set to 24746753
Phenotypes for gene: IL21 were set to immunodeficiency; inflammatory bowel disease
Penetrance for gene: IL21 were set to unknown
Review for gene: IL21 was set to AMBER
gene: IL21 was marked as current diagnostic
Added comment: IL-21 deficiency - a novel monogenetic cause of severe, early-onset IBD associated with a CVID-like primary immunodeficiency. One case of a turkish boy born to consanguinous parents, diagnosed with IBD in early years (diarrhea from 2 months of age, worsened over time, biopsy typical of Crohn's). This proband had 2 siblings who had early onset IBD before age 1 year and died.
Sources: Expert Review
BabyScreen+ newborn screening v0.2064 TF Zornitza Stark Marked gene: TF as ready
BabyScreen+ newborn screening v0.2064 TF Zornitza Stark Gene: tf has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2064 TF Zornitza Stark Classified gene: TF as Green List (high evidence)
BabyScreen+ newborn screening v0.2064 TF Zornitza Stark Gene: tf has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2063 TF Zornitza Stark Tag treatable tag was added to gene: TF.
Tag haematological tag was added to gene: TF.
Inflammatory bowel disease v0.93 DKC1 Chris Richmond gene: DKC1 was added
gene: DKC1 was added to Inflammatory bowel disease. Sources: Expert Review
Mode of inheritance for gene: DKC1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: DKC1 were set to 21284747
Phenotypes for gene: DKC1 were set to Dyskeratosis congenita
Penetrance for gene: DKC1 were set to unknown
Review for gene: DKC1 was set to GREEN
gene: DKC1 was marked as current diagnostic
Added comment: 2 unrelated infants with infant-onset DKC - the most prominent clinical finding was the presence of a severe, chronic, non-infectious enteropathy leading to malabsorption and nutrient deficiencies . Histological abnormalities included inflammation and mucosal apoptosis (identical to gut GVHD) in the esophagus, small bowel, or colon. Phenotypic overlap with IBD. Review with Dr. Peter McNaughton (immunologist QCH).
Sources: Expert Review
Stickler Syndrome v1.5 SLC29A3 Krithika Murali changed review comment from: Phenotypic features can overlap with Stickler syndrome (presentation VCGS Dysmorphology meeting 24.3.23)
Sources: Expert list, Literature; to: Phenotypic features can overlap with Stickler syndrome (presentation VCGS Dysmorphology meeting 24.3.23, suggested adding gene to Stickler panel)
Sources: Expert list, Literature
Stickler Syndrome v1.5 SLC29A3 Krithika Murali gene: SLC29A3 was added
gene: SLC29A3 was added to Stickler Syndrome. Sources: Expert list,Literature
Mode of inheritance for gene: SLC29A3 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SLC29A3 were set to Histiocytosis-lymphadenopathy plus syndrome - MIM#602782
Review for gene: SLC29A3 was set to GREEN
Added comment: Phenotypic features can overlap with Stickler syndrome (presentation VCGS Dysmorphology meeting 24.3.23)
Sources: Expert list, Literature
Mendeliome v1.743 STX4 Achchuthan Shanmugasundram reviewed gene: STX4: Rating: AMBER; Mode of pathogenicity: None; Publications: 36355422; Phenotypes: Hearing impairment, HP:0000365; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.743 ARF1 Achchuthan Shanmugasundram edited their review of gene: ARF1: Changed publications: 36345169
Mendeliome v1.743 ARF1 Achchuthan Shanmugasundram reviewed gene: ARF1: Rating: ; Mode of pathogenicity: None; Publications: 3634516; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
BabyScreen+ newborn screening v0.2063 SARS Lilian Downie gene: SARS was added
gene: SARS was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: SARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SARS were set to PMID:34570399, PMID: 34194004
Phenotypes for gene: SARS were set to Neurodevelopmental disorder with microcephaly, ataxia, and seizures MIM#617709
Review for gene: SARS was set to RED
Added comment: developmental delay, deafness, cardiomyopathy, epilepsy, and severe febrile decompensations
Rx serine supplementation - limited evidence and sounds supportive only
Sources: Expert list
BabyScreen+ newborn screening v0.2063 SCARB2 Lilian Downie gene: SCARB2 was added
gene: SCARB2 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: SCARB2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCARB2 were set to PMID: 34337151, PMID: 35346091, PMID: 26677510
Phenotypes for gene: SCARB2 were set to Epilepsy, progressive myoclonic 4, with or without renal failure MIM#254900
Review for gene: SCARB2 was set to RED
Added comment: Onset not <5
Sources: Expert list
BabyScreen+ newborn screening v0.2063 SERPING1 Lilian Downie gene: SERPING1 was added
gene: SERPING1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: SERPING1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: SERPING1 were set to PMID: 32898710
Phenotypes for gene: SERPING1 were set to Angioedema, hereditary, 1 and 2 MIM#106100
Review for gene: SERPING1 was set to RED
Added comment: episodic local subcutaneous edema and submucosal edema involving the upper respiratory and gastrointestinal tracts.

Age of onset not typically <5

Treatment Purified C1 inhibitor concentrate (Cinryze, Berinert, HAEGARDA, or Ruconest), Ecallantide (Kalbitor), Icatibant (Firazyr), Lanadelumab, Orladeyo (berotralstat), FFP or solvent-detergent treated plasma, antisense oligonucleotide treatment (donidalorsen)
Sources: Expert list
BabyScreen+ newborn screening v0.2063 SGPL1 Lilian Downie gene: SGPL1 was added
gene: SGPL1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: SGPL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SGPL1 were set to PMID: 28165343
Phenotypes for gene: SGPL1 were set to Nephrotic syndrome, type 14 MIM#617575
Review for gene: SGPL1 was set to RED
Added comment: infancy or early childhood with progressive renal dysfunction associated with focal segmental glomerulosclerosis (FSGS), resulting in end-stage renal disease within a few years. Other infants present with primary adrenal insufficiency. Some patients present in utero with fetal hydrops and fetal demise. Additional features of the disorder can include ichthyosis, acanthosis, adrenal insufficiency, immunodeficiency, and neurologic defects

Rx Hydrocortisone, kidney transplant (treatment doesn't fit screening model as would need to have ESRD before you had it?)
Sources: Expert list
BabyScreen+ newborn screening v0.2063 SLC1A3 Lilian Downie gene: SLC1A3 was added
gene: SLC1A3 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: SLC1A3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SLC1A3 were set to PMID: 32754645
Phenotypes for gene: SLC1A3 were set to Episodic ataxia, type 6 MIM#612656
Review for gene: SLC1A3 was set to RED
Added comment: ataxia occurs with febrile illnesses
Episodic attacks lasted 2 to 3 hours and were often associated with nausea, vomiting, photophobia, phonophobia, vertigo, diplopia, and/or slurred speech
Not consistently in children <5 and variable severity

Suggested Rx acetazolamide
Sources: Expert list
BabyScreen+ newborn screening v0.2063 SMARCD2 Lilian Downie gene: SMARCD2 was added
gene: SMARCD2 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: SMARCD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SMARCD2 were set to PubMed: 28369036, 33279574, 33025377
Phenotypes for gene: SMARCD2 were set to Specific granule deficiency 2 MIM#617475
Review for gene: SMARCD2 was set to GREEN
Added comment: recurrent infections due to defective neutrophil development. Bone marrow findings include paucity of neutrophil granulocytes, absence of granule proteins in neutrophils, abnormal megakaryocytes, and features of progressive myelofibrosis with blasts. The disorder is apparent from infancy, and patients may die in early childhood unless they undergo hematopoietic stem cell transplantation. Most patients have additional findings, including delayed development, mild dysmorphic features, tooth abnormalities, and distal skeletal defects

Rx bone marrow transplant
Sources: Expert list
BabyScreen+ newborn screening v0.2063 SNX10 Lilian Downie gene: SNX10 was added
gene: SNX10 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: SNX10 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SNX10 were set to PMID: 30885997, PMID: 22499339
Phenotypes for gene: SNX10 were set to Osteopetrosis, autosomal recessive 8 MIM#615085
Review for gene: SNX10 was set to GREEN
Added comment: macrocephaly
failure to thrive
osteopetrosis

Rx bone marrow tranplant
Sources: Expert list
BabyScreen+ newborn screening v0.2063 SORD Lilian Downie gene: SORD was added
gene: SORD was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: SORD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SORD were set to PMID: 32367058
Phenotypes for gene: SORD were set to Sorbitol dehydrogenase deficiency with peripheral neuropathy MIM#618912
Review for gene: SORD was set to RED
Added comment: Slowly progressive, onset not consistently <5

Rx epalrestat and ranirestat
Sources: Expert list
BabyScreen+ newborn screening v0.2063 SOX3 Lilian Downie gene: SOX3 was added
gene: SOX3 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: SOX3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: SOX3 were set to PMID: 31678974, PMID: 15800844
Phenotypes for gene: SOX3 were set to Panhypopituitarism, X-linked MIM#312000
Review for gene: SOX3 was set to AMBER
Added comment: Amber in our mendeliome - reviewed for ID
Green in pituitary disorders

Xq27.1 duplication most common mechanism - inclusion might be a question of whether we can detect CNV's in this region

neonatal hypoglycemia and growth hormone deficiency in addition to variable deficiencies of other pituitary hormones. Brain hypoplasia of the anterior pituitary with hypoplasia or absence of the lower half of the infundibulum

Rx Growth hormone, levothyroxine, hydrocortisone
Sources: Expert list
BabyScreen+ newborn screening v0.2063 STAT1 Lilian Downie gene: STAT1 was added
gene: STAT1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: STAT1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: STAT1 were set to PMID: 31512162, PMID: 27117246
Phenotypes for gene: STAT1 were set to Immunodeficiency 31B, mycobacterial and viral infections, autosomal recessive MIM#613796
Review for gene: STAT1 was set to GREEN
Added comment: combined immunodeficiency
autosomal recessive (AR) complete STAT1 deficiency, AR partial STAT1 deficiency, autosomal dominant (AD) STAT1 deficiency, and AD STAT1 gain-of-function.
gain of function mutations - treat rituxomab
complete - treat BMT
Sources: Expert list
BabyScreen+ newborn screening v0.2063 STIM1 Lilian Downie gene: STIM1 was added
gene: STIM1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: STIM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: STIM1 were set to PMID: 26469693, PMID: 30949876, PMID: 26560041
Phenotypes for gene: STIM1 were set to Immunodeficiency 10 MIM612783
Review for gene: STIM1 was set to GREEN
Added comment: recurrent infections in childhood due to defective T- and NK-cell function, although the severity is variable. Affected individuals may also have hypotonia, hypohidrosis, or dental enamel hypoplasia consistent with amelogenesis imperfecta

Rx bone marrow transpant

Age of onset is consistently <5 but the severity of infections is highly variable - treatment if the phenotype is severe
Sources: Expert list
BabyScreen+ newborn screening v0.2063 STK4 Lilian Downie gene: STK4 was added
gene: STK4 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: STK4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: STK4 were set to PMID: 22294732
Phenotypes for gene: STK4 were set to T-cell immunodeficiency, recurrent infections, autoimmunity, and cardiac malformations MIM#614868
Review for gene: STK4 was set to GREEN
Added comment: primary T-cell immunodeficiency syndrome characterized by progressive loss of naive T cells, recurrent bacterial, viral, and fungal infections, warts, and abscesses, autoimmune manifestations, and cardiac malformations, including atrial septal defect

Rx bone marrow transplant
Sources: Expert list
BabyScreen+ newborn screening v0.2063 STX16 Lilian Downie gene: STX16 was added
gene: STX16 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: STX16 was set to MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Publications for gene: STX16 were set to PMID: 33247854, PMID: 34477200, PMID: 29072892
Phenotypes for gene: STX16 were set to Pseudohypoparathyroidism, type IB MIM#603233
Review for gene: STX16 was set to GREEN
Added comment: characterized clinically by isolated renal PTH resistance manifest as hypocalcemia, hyperphosphatemia, and increased serum PTH
without other features of Albright hereditary osteodystrophy
Rx Calcium, calcitriol, levothyroxine, growth hormone
Sources: Expert list
BabyScreen+ newborn screening v0.2063 SYT2 Lilian Downie gene: SYT2 was added
gene: SYT2 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: SYT2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: SYT2 were set to PMID: 32250532, 32776697
Phenotypes for gene: SYT2 were set to Myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive MIM#619461
Review for gene: SYT2 was set to GREEN
Added comment: Bi-allelic disease: 32250532 and 32776697, 8 individuals from 6 families, with biallelic loss of function variants in SYT2, clinically manifesting with severe congenital onset hypotonia and weakness, with variable degrees of respiratory involvement. Electrodiagnostic findings consistent with a presynaptic congenital myasthenic syndrome (CMS) in some. Treatment with an acetylcholinesterase inhibitor pursued in 4 indviduals showed clinical improvement with increased strength and function.

Only report biallelic for newborn screening ?
monoallelic causes a later onset distal weakness/neuropathy phenotype - still childhood but variable or not clear - not consistently <5yrs
Sources: Expert list
BabyScreen+ newborn screening v0.2063 TBL1X Lilian Downie gene: TBL1X was added
gene: TBL1X was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: TBL1X was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: TBL1X were set to PMID: 27603907
Phenotypes for gene: TBL1X were set to Hypothyroidism, congenital, nongoitrous, 8 MIM#301033
Review for gene: TBL1X was set to GREEN
Added comment: Small thyroid gland
Detected on newborn screening
Can affect carrier females but more mildly
Association with deafness

Rx thyroxine
Sources: Expert list
BabyScreen+ newborn screening v0.2063 TF Lilian Downie gene: TF was added
gene: TF was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: TF was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TF were set to PMID: 32028041, PMID: 19579082, PMID: 11110675
Phenotypes for gene: TF were set to Atransferrinemia MIM#209300
Review for gene: TF was set to GREEN
Added comment: Hypochromic microcytic anaemia from absent transferrin - presents in infancy


Rx Red cell transfusions, deferoxamine
Sources: Expert list
BabyScreen+ newborn screening v0.2063 SAR1B Zornitza Stark Marked gene: SAR1B as ready
BabyScreen+ newborn screening v0.2063 SAR1B Zornitza Stark Gene: sar1b has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2063 SAR1B Zornitza Stark Classified gene: SAR1B as Green List (high evidence)
BabyScreen+ newborn screening v0.2063 SAR1B Zornitza Stark Gene: sar1b has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2062 SAR1B Zornitza Stark gene: SAR1B was added
gene: SAR1B was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, gastrointestinal tags were added to gene: SAR1B.
Mode of inheritance for gene: SAR1B was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SAR1B were set to Chylomicron retention disease, MIM# 246700
Review for gene: SAR1B was set to GREEN
Added comment: Chylomicron retention disease is an autosomal recessive disorder of severe fat malabsorption associated with failure to thrive in infancy. Well established gene-disease association.

Congenital onset.

Treatment: low-fat diet with supplementation of fat-soluble vitamins (A, D, E, and K) and oral essential fatty acid supplementation

Non-genetic confirmatory testing: total cholesterol, triglyceride, LDL-cholesterol, HDL-cholesterol
Sources: Expert list
BabyScreen+ newborn screening v0.2061 SAMD9L Zornitza Stark Marked gene: SAMD9L as ready
BabyScreen+ newborn screening v0.2061 SAMD9L Zornitza Stark Gene: samd9l has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2061 SAMD9L Zornitza Stark Classified gene: SAMD9L as Green List (high evidence)
BabyScreen+ newborn screening v0.2061 SAMD9L Zornitza Stark Gene: samd9l has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2060 SAMD9L Zornitza Stark gene: SAMD9L was added
gene: SAMD9L was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological, haematological tags were added to gene: SAMD9L.
Mode of inheritance for gene: SAMD9L was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SAMD9L were set to 31306780
Phenotypes for gene: SAMD9L were set to Ataxia-pancytopenia syndrome, MIM# 159550
Review for gene: SAMD9L was set to GREEN
Added comment: At least three unrelated families reported, some postulate GoF whereas others postulate LoF as mechanism.

Ataxia-pancytopenia syndrome (ATXPC) is an autosomal dominant disorder characterized by cerebellar ataxia, variable hematologic cytopenias, and predisposition to bone marrow failure and myeloid leukemia. The germline genetic defect is associated with somatic loss of chromosome 7 (monosomy 7) resulting in the deletion of several genes on chromosome 7 that may predispose to the development of myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML).

Treatment: BMT.

Non-genetic confirmatory testing: no.
Sources: Expert list
BabyScreen+ newborn screening v0.2059 SAMD9 Zornitza Stark Marked gene: SAMD9 as ready
BabyScreen+ newborn screening v0.2059 SAMD9 Zornitza Stark Gene: samd9 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2059 SAMD9 Zornitza Stark Classified gene: SAMD9 as Green List (high evidence)
BabyScreen+ newborn screening v0.2059 SAMD9 Zornitza Stark Gene: samd9 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2058 SAMD9 Zornitza Stark gene: SAMD9 was added
gene: SAMD9 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: SAMD9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SAMD9 were set to 31306780
Phenotypes for gene: SAMD9 were set to MIRAGE syndrome, MIM# 617053
Review for gene: SAMD9 was set to GREEN
Added comment: MIRAGE syndrome (MIRAGE) is a form of syndromic adrenal hypoplasia, characterized by myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy. The condition is often fatal within the first decade of life, usually as a result of invasive infection.

Treatment: BMT.

Non-genetic confirmatory testing: no.
Sources: Expert list
Mendeliome v1.743 THAP11 Zornitza Stark Marked gene: THAP11 as ready
Mendeliome v1.743 THAP11 Zornitza Stark Gene: thap11 has been classified as Red List (Low Evidence).
Mendeliome v1.743 THAP11 Zornitza Stark gene: THAP11 was added
gene: THAP11 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: THAP11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: THAP11 were set to 28449119
Phenotypes for gene: THAP11 were set to Inborn disorder of cobalamin metabolism and transport, MONDO:0019220, THAP11-related
Review for gene: THAP11 was set to RED
Added comment: Single individual reported with homozygous missense variant, supportive functional data.
Sources: Expert Review
BabyScreen+ newborn screening v0.2057 THAP11 Zornitza Stark Marked gene: THAP11 as ready
BabyScreen+ newborn screening v0.2057 THAP11 Zornitza Stark Gene: thap11 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2057 THAP11 Zornitza Stark Phenotypes for gene: THAP11 were changed from Combined methylmalonic acidemia and homocystinuria, cblX like 2 to Inborn disorder of cobalamin metabolism and transport, MONDO:0019220, THAP11-related
BabyScreen+ newborn screening v0.2056 THAP11 Zornitza Stark Classified gene: THAP11 as Red List (low evidence)
BabyScreen+ newborn screening v0.2056 THAP11 Zornitza Stark Gene: thap11 has been classified as Red List (Low Evidence).
Miscellaneous Metabolic Disorders v1.26 THAP11 Zornitza Stark Marked gene: THAP11 as ready
Miscellaneous Metabolic Disorders v1.26 THAP11 Zornitza Stark Gene: thap11 has been classified as Red List (Low Evidence).
Miscellaneous Metabolic Disorders v1.26 THAP11 Zornitza Stark gene: THAP11 was added
gene: THAP11 was added to Miscellaneous Metabolic Disorders. Sources: Expert Review
Mode of inheritance for gene: THAP11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: THAP11 were set to 28449119
Phenotypes for gene: THAP11 were set to Inborn disorder of cobalamin metabolism and transport, MONDO:0019220, THAP11-related
Review for gene: THAP11 was set to RED
Added comment: Single individual reported with homozygous missense variant, supportive functional data.
Sources: Expert Review
BabyScreen+ newborn screening v0.2055 TMEM165 Zornitza Stark Marked gene: TMEM165 as ready
BabyScreen+ newborn screening v0.2055 TMEM165 Zornitza Stark Gene: tmem165 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.2055 TMEM165 Zornitza Stark Classified gene: TMEM165 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.2055 TMEM165 Zornitza Stark Gene: tmem165 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.2054 TMEM165 Zornitza Stark Tag metabolic tag was added to gene: TMEM165.
BabyScreen+ newborn screening v0.2054 TMEM165 Zornitza Stark reviewed gene: TMEM165: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital disorder of glycosylation, type IIk MIM#614727; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.2054 TNFRSF13B Zornitza Stark Marked gene: TNFRSF13B as ready
BabyScreen+ newborn screening v0.2054 TNFRSF13B Zornitza Stark Gene: tnfrsf13b has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2054 TNFRSF13B Zornitza Stark Classified gene: TNFRSF13B as Red List (low evidence)
BabyScreen+ newborn screening v0.2054 TNFRSF13B Zornitza Stark Gene: tnfrsf13b has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2053 TNFRSF13B Zornitza Stark Tag treatable tag was added to gene: TNFRSF13B.
Tag immunological tag was added to gene: TNFRSF13B.
BabyScreen+ newborn screening v0.2053 TNFAIP3 Zornitza Stark Marked gene: TNFAIP3 as ready
BabyScreen+ newborn screening v0.2053 TNFAIP3 Zornitza Stark Gene: tnfaip3 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2053 TNFAIP3 Zornitza Stark Classified gene: TNFAIP3 as Red List (low evidence)
BabyScreen+ newborn screening v0.2053 TNFAIP3 Zornitza Stark Gene: tnfaip3 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2052 TNFAIP3 Zornitza Stark Tag treatable tag was added to gene: TNFAIP3.
Tag immunological tag was added to gene: TNFAIP3.
BabyScreen+ newborn screening v0.2052 THAP11 Lilian Downie gene: THAP11 was added
gene: THAP11 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: THAP11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: THAP11 were set to PMID: 28449119, PMID: 31905202
Phenotypes for gene: THAP11 were set to Combined methylmalonic acidemia and homocystinuria, cblX like 2
Review for gene: THAP11 was set to RED
Added comment: Single patient?
Not in our mendeliome
Not enough gene disease validity
Sources: Expert list
BabyScreen+ newborn screening v0.2052 TMEM165 Lilian Downie gene: TMEM165 was added
gene: TMEM165 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: TMEM165 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM165 were set to PMID: 28323990, PMID: 35693943, PMID: 22683087
Phenotypes for gene: TMEM165 were set to Congenital disorder of glycosylation, type IIk MIM#614727
Review for gene: TMEM165 was set to AMBER
Added comment: Affected individuals show psychomotor retardation and growth retardation, and most have short stature. Other features include dysmorphism, hypotonia, eye abnormalities, acquired microcephaly, hepatomegaly, and skeletal dysplasia. Serum transferrin analysis shows a CDG type II pattern

Rx D-galactose (single paper, 2 unrelated patients and an in vitro study) ?inadequete evidence for treatment? Might need to check with JC if we would offer it maybe include
Sources: Expert list
BabyScreen+ newborn screening v0.2052 TNFRSF13B Lilian Downie gene: TNFRSF13B was added
gene: TNFRSF13B was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: TNFRSF13B was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: TNFRSF13B were set to PMID: 31681716, PMID: 18981294
Phenotypes for gene: TNFRSF13B were set to Immunodeficiency, common variable, 2 MIM#240500
Review for gene: TNFRSF13B was set to RED
Added comment: hypogammaglobulinemia with low serum IgG, IgM, and IgA, and recurrent infections, including otitis media, respiratory tract infections, and gastrointestinal tract infections. Serum IgG and IgA were low, and serum antibody response to immunization with pneumococcal vaccine was decreased, although T cell-dependent response to tetanus toxin was normal.

I think the age of onset is too variable .

Rx immunoglobulin
Sources: Expert list
BabyScreen+ newborn screening v0.2052 TNFAIP3 Lilian Downie gene: TNFAIP3 was added
gene: TNFAIP3 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: TNFAIP3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TNFAIP3 were set to PMID: 31587140, PMID: 33101300
Phenotypes for gene: TNFAIP3 were set to Autoinflammatory syndrome, familial, Behcet-like 1 MIM#616744
Review for gene: TNFAIP3 was set to RED
Added comment: Average age of onset 5yrs - too variable re age of onset.

painful and recurrent mucosal ulceration affecting the oral mucosa, gastrointestinal tract, and genital areas. The onset of symptoms is usually in the first decade, although later onset has been reported. Additional more variable features include skin rash, uveitis, and polyarthritis, consistent with a systemic hyperinflammatory state. Many patients have evidence of autoimmune disease. Rare patients may also have concurrent features of immunodeficiency, including recurrent infections with low numbers of certain white blood cells or impaired function of immune cells.

Treatment: Colchicine, glucocorticoid, mesalazine, cyclosporine, methotrexate, azathioprine, anakinra, rituximab, tocilizumab, infliximab
Sources: Expert list
BabyScreen+ newborn screening v0.2052 RNPC3 Zornitza Stark Marked gene: RNPC3 as ready
BabyScreen+ newborn screening v0.2052 RNPC3 Zornitza Stark Gene: rnpc3 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2052 RNPC3 Zornitza Stark Classified gene: RNPC3 as Green List (high evidence)
BabyScreen+ newborn screening v0.2052 RNPC3 Zornitza Stark Gene: rnpc3 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2051 RNPC3 Zornitza Stark gene: RNPC3 was added
gene: RNPC3 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, endocrine tags were added to gene: RNPC3.
Mode of inheritance for gene: RNPC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNPC3 were set to 29866761; 32462814; 33650182
Phenotypes for gene: RNPC3 were set to Pituitary hormone deficiency, combined or isolated, 7, MIM# 618160
Review for gene: RNPC3 was set to GREEN
Added comment: Three unrelated individuals reported with combined and isolated pituitary hormone deficiencies, including GH and TSH.

Onset: congenital.

Treatment: GH, thyroxine.

Non-genetic confirmatory testing: hormone levels.
Sources: Expert list
Mendeliome v1.742 RNPC3 Zornitza Stark Phenotypes for gene: RNPC3 were changed from Growth hormone deficiency; Intellectual disability to Pituitary hormone deficiency, combined or isolated, 7, MIM# 618160
Mendeliome v1.741 RNPC3 Zornitza Stark edited their review of gene: RNPC3: Changed phenotypes: Pituitary hormone deficiency, combined or isolated, 7, MIM# 618160
BabyScreen+ newborn screening v0.2050 RASGRP1 Zornitza Stark Marked gene: RASGRP1 as ready
BabyScreen+ newborn screening v0.2050 RASGRP1 Zornitza Stark Gene: rasgrp1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2050 RASGRP1 Zornitza Stark Classified gene: RASGRP1 as Green List (high evidence)
BabyScreen+ newborn screening v0.2050 RASGRP1 Zornitza Stark Gene: rasgrp1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2049 RASGRP1 Zornitza Stark gene: RASGRP1 was added
gene: RASGRP1 was added to Baby Screen+ newborn screening. Sources: Literature
treatable, immunological tags were added to gene: RASGRP1.
Mode of inheritance for gene: RASGRP1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: RASGRP1 were set to Immunodeficiency 64 (MIM#618534)
Review for gene: RASGRP1 was set to GREEN
Added comment: Immunodeficiency-64 with lymphoproliferation (IMD64) is an autosomal recessive primary immunodeficiency characterized by onset of recurrent bacterial, viral, and fungal infections in early childhood. Laboratory studies show variably decreased numbers of T cells, with lesser deficiencies of B and NK cells. There is impaired T-cell proliferation and activation; functional defects in B cells and NK cells may also be observed. Patients have increased susceptibility to EBV infection and may develop lymphoproliferation or EBV-associated lymphoma. Some patients may develop features of autoimmunity.

Severe disorder, fatal outcomes reported in childhood.

Treatment: BMT.

Non-genetic confirmatory testing: no.
Sources: Literature
Arthrogryposis v0.392 NALCN Zornitza Stark Marked gene: NALCN as ready
Arthrogryposis v0.392 NALCN Zornitza Stark Gene: nalcn has been classified as Green List (High Evidence).
Arthrogryposis v0.392 SLC35A3 Zornitza Stark Marked gene: SLC35A3 as ready
Arthrogryposis v0.392 SLC35A3 Zornitza Stark Gene: slc35a3 has been classified as Green List (High Evidence).
Arthrogryposis v0.392 LIFR Zornitza Stark Marked gene: LIFR as ready
Arthrogryposis v0.392 LIFR Zornitza Stark Gene: lifr has been classified as Green List (High Evidence).
Arthrogryposis v0.392 KY Zornitza Stark Marked gene: KY as ready
Arthrogryposis v0.392 KY Zornitza Stark Gene: ky has been classified as Green List (High Evidence).
Arthrogryposis v0.392 KIF5C Zornitza Stark Marked gene: KIF5C as ready
Arthrogryposis v0.392 KIF5C Zornitza Stark Gene: kif5c has been classified as Green List (High Evidence).
Arthrogryposis v0.392 CNTN1 Zornitza Stark Marked gene: CNTN1 as ready
Arthrogryposis v0.392 CNTN1 Zornitza Stark Gene: cntn1 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v0.392 CNTN1 Zornitza Stark Classified gene: CNTN1 as Amber List (moderate evidence)
Arthrogryposis v0.392 CNTN1 Zornitza Stark Gene: cntn1 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v0.391 CNTN1 Zornitza Stark reviewed gene: CNTN1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital myopathy 12, OMIM #612540; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Arthrogryposis v0.391 CACNA1S Zornitza Stark Marked gene: CACNA1S as ready
Arthrogryposis v0.391 CACNA1S Zornitza Stark Gene: cacna1s has been classified as Green List (High Evidence).
Arthrogryposis v0.391 B3GALT6 Zornitza Stark Marked gene: B3GALT6 as ready
Arthrogryposis v0.391 B3GALT6 Zornitza Stark Gene: b3galt6 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v0.391 VRK1 Zornitza Stark Marked gene: VRK1 as ready
Arthrogryposis v0.391 VRK1 Zornitza Stark Gene: vrk1 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v0.391 PPP3CA Zornitza Stark Marked gene: PPP3CA as ready
Arthrogryposis v0.391 PPP3CA Zornitza Stark Gene: ppp3ca has been classified as Green List (High Evidence).
Arthrogryposis v0.391 PMM2 Zornitza Stark Marked gene: PMM2 as ready
Arthrogryposis v0.391 PMM2 Zornitza Stark Gene: pmm2 has been classified as Green List (High Evidence).
Arthrogryposis v0.391 LMNA Zornitza Stark Marked gene: LMNA as ready
Arthrogryposis v0.391 LMNA Zornitza Stark Gene: lmna has been classified as Green List (High Evidence).
Arthrogryposis v0.391 FLVCR2 Zornitza Stark Marked gene: FLVCR2 as ready
Arthrogryposis v0.391 FLVCR2 Zornitza Stark Gene: flvcr2 has been classified as Green List (High Evidence).
Arthrogryposis v0.391 BIN1 Zornitza Stark Marked gene: BIN1 as ready
Arthrogryposis v0.391 BIN1 Zornitza Stark Gene: bin1 has been classified as Green List (High Evidence).
Arthrogryposis v0.391 TMEM5 Zornitza Stark Marked gene: TMEM5 as ready
Arthrogryposis v0.391 TMEM5 Zornitza Stark Gene: tmem5 has been classified as Red List (Low Evidence).
Arthrogryposis v0.391 TMEM5 Zornitza Stark Phenotypes for gene: TMEM5 were changed from to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 10, MIM# 615041
Arthrogryposis v0.390 TMEM5 Zornitza Stark Mode of inheritance for gene: TMEM5 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Arthrogryposis v0.389 FAM20C Zornitza Stark Marked gene: FAM20C as ready
Arthrogryposis v0.389 FAM20C Zornitza Stark Gene: fam20c has been classified as Amber List (Moderate Evidence).
Arthrogryposis v0.389 FAM20C Zornitza Stark Mode of inheritance for gene: FAM20C was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Arthrogryposis v0.388 FAM20C Zornitza Stark Phenotypes for gene: FAM20C were changed from to Raine syndrome, MIM# 259775
Arthrogryposis v0.387 DAG1 Zornitza Stark Marked gene: DAG1 as ready
Arthrogryposis v0.387 DAG1 Zornitza Stark Gene: dag1 has been classified as Red List (Low Evidence).
Arthrogryposis v0.387 DAG1 Zornitza Stark Phenotypes for gene: DAG1 were changed from to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 9 (MIM#616538)
Arthrogryposis v0.386 B3GALNT2 Zornitza Stark Marked gene: B3GALNT2 as ready
Arthrogryposis v0.386 B3GALNT2 Zornitza Stark Gene: b3galnt2 has been classified as Red List (Low Evidence).
Arthrogryposis v0.386 B3GALNT2 Zornitza Stark Phenotypes for gene: B3GALNT2 were changed from to Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies, type A, 11, MIM# 615181
Arthrogryposis v0.385 SLC35A3 Chirag Patel Classified gene: SLC35A3 as Green List (high evidence)
Arthrogryposis v0.385 SLC35A3 Chirag Patel Gene: slc35a3 has been classified as Green List (High Evidence).
Arthrogryposis v0.384 LIFR Chirag Patel Classified gene: LIFR as Green List (high evidence)
Arthrogryposis v0.384 LIFR Chirag Patel Gene: lifr has been classified as Green List (High Evidence).
Arthrogryposis v0.384 SLC35A3 Chirag Patel gene: SLC35A3 was added
gene: SLC35A3 was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: SLC35A3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC35A3 were set to PMID: 28777481, 24031089, 28328131, 33416188
Phenotypes for gene: SLC35A3 were set to Arthrogryposis, impaired intellectual development, and seizures, OMIM #615553
Review for gene: SLC35A3 was set to GREEN
Added comment: Arthrogryposis, impaired intellectual development, and seizures (AMRS) is an autosomal recessive disorder characterized by skeletal abnormalities, including arthrogryposis, short limbs, and vertebral malformations, impaired intellectual development, and seizures consistent with early-onset epileptic encephalopathy in some patients. Other features may include cleft palate, micrognathia, posterior embryotoxon, talipes valgus, rocker-bottom feet, and dysmorphic facies.

4 families with 12 affected individuals reported with biallelic variants in SLC35A3 gene. Functional studies in one family showed patient cells showed no normal transcript, indicating that they had no functional SLC35A3 protein. Golgi vesicles derived from patient fibroblasts showed significantly reduced transport of UDP-GlcNAc compared to controls.
Sources: Expert list
Arthrogryposis v0.383 LIFR Chirag Patel gene: LIFR was added
gene: LIFR was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: LIFR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LIFR were set to PMID: 9674905, 9674906, 14740318, 24988918, 35663789
Phenotypes for gene: LIFR were set to Stuve-Wiedemann syndrome/Schwartz-Jampel type 2 syndrome, OMIM #601559
Review for gene: LIFR was set to GREEN
Added comment: Patients reported as having either neonatal SJS or STWS presented a combination of a severe, prenatal-onset neuromuscular disorder with congenital joint contractures, respiratory and feeding difficulties, tendency to hyperthermia, and frequent death in infancy and a distinct campomelic-metaphyseal skeletal dysplasia. Multiple families with biallelic variants in LIFR gene reported.
Sources: Expert list
Arthrogryposis v0.382 KY Chirag Patel Classified gene: KY as Green List (high evidence)
Arthrogryposis v0.382 KY Chirag Patel Gene: ky has been classified as Green List (High Evidence).
Arthrogryposis v0.381 KIF5C Chirag Patel Classified gene: KIF5C as Green List (high evidence)
Arthrogryposis v0.381 KIF5C Chirag Patel Gene: kif5c has been classified as Green List (High Evidence).
Arthrogryposis v0.381 KY Chirag Patel gene: KY was added
gene: KY was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: KY was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KY were set to PMID: 27484770, 27485408, 30591934, 35752288
Phenotypes for gene: KY were set to Myopathy, myofibrillar, 7, OMIM #617114
Review for gene: KY was set to GREEN
Added comment: Myofibrillar myopathy-7 (MFM7) is an autosomal recessive muscle disorder characterized by early childhood onset of slowly progressive muscle weakness that primarily affects the lower limbs and is associated with joint contractures. 4 families with 6 affected individuals, with homozygous variants in KY gene. Immunostaining showed absence of the KY protein in patient muscle, consistent with a loss of function in one family.
Sources: Expert list
Arthrogryposis v0.380 KIF5C Chirag Patel gene: KIF5C was added
gene: KIF5C was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: KIF5C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: KIF5C were set to Cortical dysplasia, complex, with other brain malformations 2, OMIM #615282
Review for gene: KIF5C was set to GREEN
Added comment: 2 families with 5 affecteds with severe malformations of cortical development. One family with 4 siblings with severe arthrogryposis. Same heterozygous missense variant found in both families (E237V) in KIF5C gene.

Family 1: unaffected mother was determined to be germline mosaic for the mutation. In vitro functional expression studies in E. coli and COS-7 cells showed that the mutant protein had a complete loss of ATP hydrolysis activity. In COS-7 cells, mutant KIF5C heavily colocalized with microtubules throughout the cell, but did not appear as puncta or accumulate in cortical clusters as did the wildtype protein. Poirier et al. (2013) postulated a dominant-negative effect. The findings extended the association between microtubule-based cellular processes and proper cortical development.
Sources: Expert list
Arthrogryposis v0.379 CACNA1S Chirag Patel Classified gene: CACNA1S as Green List (high evidence)
Arthrogryposis v0.379 CACNA1S Chirag Patel Gene: cacna1s has been classified as Green List (High Evidence).
Arthrogryposis v0.378 CNTN1 Chirag Patel gene: CNTN1 was added
gene: CNTN1 was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: CNTN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CNTN1 were set to PMID:19026398
Phenotypes for gene: CNTN1 were set to Congenital myopathy 12, OMIM #612540
Review for gene: CNTN1 was set to RED
Added comment: Congenital myopathy-12 (CMYP12) is an autosomal recessive disorder characterized by severe neonatal hypotonia resulting in feeding difficulties and respiratory failure within the first months of life. There is evidence of the disorder in utero, with decreased fetal movements and polyhydramnios. Additional features may include high-arched palate and contractures. Skeletal muscle biopsy shows myopathic changes with disrupted sarcomeres and minicore-like structures. One family reported with homozygous mutation in the CNTN1 gene.
Sources: Expert list
Arthrogryposis v0.377 CACNA1S Chirag Patel gene: CACNA1S was added
gene: CACNA1S was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: CACNA1S was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CACNA1S were set to PMID: 33060286, 31227654, 28012042
Phenotypes for gene: CACNA1S were set to Congenital myopathy 18 due to dihydropyridine receptor defect, OMIM #620246
Review for gene: CACNA1S was set to GREEN
Added comment: Congenital myopathy-18 (CMYP18) is a disorder of the skeletal muscle characterized by the onset of symptoms of muscle weakness in early childhood, including in utero and infancy. There is clinical heterogeneity in the manifestations and severity, ranging from fetal akinesia sequence causing early death to onset of symptoms in adulthood.
Sources: Expert list
Arthrogryposis v0.376 B3GALT6 Chirag Patel Classified gene: B3GALT6 as Amber List (moderate evidence)
Arthrogryposis v0.376 B3GALT6 Chirag Patel Gene: b3galt6 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v0.376 VRK1 Chirag Patel Classified gene: VRK1 as Amber List (moderate evidence)
Arthrogryposis v0.376 VRK1 Chirag Patel Gene: vrk1 has been classified as Amber List (Moderate Evidence).
Arthrogryposis v0.375 B3GALT6 Chirag Patel gene: B3GALT6 was added
gene: B3GALT6 was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: B3GALT6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: B3GALT6 were set to PMID: 29443383, 25149931
Phenotypes for gene: B3GALT6 were set to Al-Gazali syndrome, OMIM #609465
Review for gene: B3GALT6 was set to AMBER
Added comment: Al-Gazali syndrome (ALGAZ) is characterized by prenatal growth retardation, skeletal anomalies including joint contractures, camptodactyly, and bilateral talipes equinovarus, small mouth, anterior segment eye anomalies, and early lethality.

In an infant with Al-Gazali syndrome, Sellars et al. (2014) identified compound heterozygous missense mutations in the B3GALT6 gene. The mutation, which was found by exome sequencing, segregated with the disorder in the family.

In 1 of the Palestinian infants with Al-Gazali syndrome reported by al-Gazali et al. (1999), Ben-Mahmoud et al. (2018) identified homozygosity for a missense mutation in the B3GALT6 gene. The parents were heterozygous for the mutation.
Sources: Expert list
Arthrogryposis v0.374 VRK1 Chirag Patel gene: VRK1 was added
gene: VRK1 was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: VRK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VRK1 were set to PMID: 21937992, 21937992
Phenotypes for gene: VRK1 were set to Pontocerebellar hypoplasia type 1A, OMIM# 607596
Review for gene: VRK1 was set to AMBER
Added comment: contractures reported and mutation found in 2 families
Sources: Expert list
Arthrogryposis v0.373 PPP3CA Chirag Patel Classified gene: PPP3CA as Green List (high evidence)
Arthrogryposis v0.373 PPP3CA Chirag Patel Gene: ppp3ca has been classified as Green List (High Evidence).
Arthrogryposis v0.372 PMM2 Chirag Patel Classified gene: PMM2 as Green List (high evidence)
Arthrogryposis v0.372 PMM2 Chirag Patel Gene: pmm2 has been classified as Green List (High Evidence).
Arthrogryposis v0.372 PPP3CA Chirag Patel gene: PPP3CA was added
gene: PPP3CA was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: PPP3CA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PPP3CA were set to PMID: 29432562
Phenotypes for gene: PPP3CA were set to Arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development, OMIM #618265
Review for gene: PPP3CA was set to GREEN
Added comment: 2 unrelated patients with arthrogryposis, cleft palate, craniosynostosis, micrognathia, short stature, and impaired intellectual development. Whole-exome sequencing (+ Sanger confirmation) found de novo heterozygous mutations in the autoinhibitory domain of PPP3CA gene. Using a yeast model, the mutations were found to be constitutively activating.
Sources: Expert list
Arthrogryposis v0.371 PMM2 Chirag Patel gene: PMM2 was added
gene: PMM2 was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: PMM2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: PMM2 were set to Congenital disorder of glycosylation, type Ia, OMIM #212065
Review for gene: PMM2 was set to GREEN
Added comment: Arthrogryposis reported
Sources: Expert list
Arthrogryposis v0.370 LMNA Chirag Patel Classified gene: LMNA as Green List (high evidence)
Arthrogryposis v0.370 LMNA Chirag Patel Gene: lmna has been classified as Green List (High Evidence).
Arthrogryposis v0.369 LMNA Chirag Patel gene: LMNA was added
gene: LMNA was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: LMNA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LMNA were set to PMID:18551513
Phenotypes for gene: LMNA were set to Muscular dystrophy, congenital, OMIM #613205
Review for gene: LMNA was set to GREEN
Added comment: Arthrogryposis reported
Sources: Expert list
Arthrogryposis v0.368 FLVCR2 Chirag Patel Classified gene: FLVCR2 as Green List (high evidence)
Arthrogryposis v0.368 FLVCR2 Chirag Patel Gene: flvcr2 has been classified as Green List (High Evidence).
Arthrogryposis v0.367 FLVCR2 Chirag Patel gene: FLVCR2 was added
gene: FLVCR2 was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: FLVCR2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FLVCR2 were set to PMID: 20206334, 20014121, 20014121
Phenotypes for gene: FLVCR2 were set to Proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome, OMIM #225790
Review for gene: FLVCR2 was set to GREEN
Added comment: Severe arthrogryposis disorder
Sources: Expert list
Arthrogryposis v0.366 BIN1 Chirag Patel Classified gene: BIN1 as Green List (high evidence)
Arthrogryposis v0.366 BIN1 Chirag Patel Gene: bin1 has been classified as Green List (High Evidence).
Arthrogryposis v0.366 BIN1 Chirag Patel Classified gene: BIN1 as Green List (high evidence)
Arthrogryposis v0.366 BIN1 Chirag Patel Gene: bin1 has been classified as Green List (High Evidence).
Arthrogryposis v0.366 BIN1 Chirag Patel Classified gene: BIN1 as Green List (high evidence)
Arthrogryposis v0.366 BIN1 Chirag Patel Gene: bin1 has been classified as Green List (High Evidence).
Arthrogryposis v0.365 BIN1 Chirag Patel gene: BIN1 was added
gene: BIN1 was added to Arthrogryposis. Sources: Expert list
Mode of inheritance for gene: BIN1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: BIN1 were set to Centronuclear myopathy 2; OMIM #255200
Review for gene: BIN1 was set to GREEN
Added comment: Arthrogryposis reported
Sources: Expert list
Arthrogryposis v0.364 TMEM5 Chirag Patel Classified gene: TMEM5 as Red List (low evidence)
Arthrogryposis v0.364 TMEM5 Chirag Patel Gene: tmem5 has been classified as Red List (Low Evidence).
Arthrogryposis v0.364 TMEM5 Chirag Patel Classified gene: TMEM5 as Red List (low evidence)
Arthrogryposis v0.364 TMEM5 Chirag Patel Gene: tmem5 has been classified as Red List (Low Evidence).
Arthrogryposis v0.364 TMEM5 Chirag Patel Classified gene: TMEM5 as Red List (low evidence)
Arthrogryposis v0.364 TMEM5 Chirag Patel Gene: tmem5 has been classified as Red List (Low Evidence).
Arthrogryposis v0.363 TMEM5 Chirag Patel reviewed gene: TMEM5: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Arthrogryposis v0.363 FAM20C Chirag Patel Classified gene: FAM20C as Amber List (moderate evidence)
Arthrogryposis v0.363 FAM20C Chirag Patel Gene: fam20c has been classified as Amber List (Moderate Evidence).
Arthrogryposis v0.362 FAM20C Chirag Patel reviewed gene: FAM20C: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Arthrogryposis v0.362 DAG1 Chirag Patel Classified gene: DAG1 as Red List (low evidence)
Arthrogryposis v0.362 DAG1 Chirag Patel Gene: dag1 has been classified as Red List (Low Evidence).
Arthrogryposis v0.361 DAG1 Chirag Patel reviewed gene: DAG1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Arthrogryposis v0.361 B4GAT1 Chirag Patel Classified gene: B4GAT1 as Red List (low evidence)
Arthrogryposis v0.361 B4GAT1 Chirag Patel Gene: b4gat1 has been classified as Red List (Low Evidence).
Arthrogryposis v0.360 B4GAT1 Chirag Patel reviewed gene: B4GAT1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Arthrogryposis v0.360 B3GALNT2 Chirag Patel Classified gene: B3GALNT2 as Red List (low evidence)
Arthrogryposis v0.360 B3GALNT2 Chirag Patel Gene: b3galnt2 has been classified as Red List (Low Evidence).
Arthrogryposis v0.359 B3GALNT2 Chirag Patel reviewed gene: B3GALNT2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
BabyScreen+ newborn screening v0.2048 RAC2 Zornitza Stark Marked gene: RAC2 as ready
BabyScreen+ newborn screening v0.2048 RAC2 Zornitza Stark Gene: rac2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2048 RAC2 Zornitza Stark Phenotypes for gene: RAC2 were changed from Immunodeficiency 73B with defective neutrophil chemotaxis and lymphopaenia MIM# 618986 to Immunodeficiency 73B with defective neutrophil chemotaxis and lymphopenia MIM# 618986
BabyScreen+ newborn screening v0.2047 RAC2 Zornitza Stark Classified gene: RAC2 as Green List (high evidence)
BabyScreen+ newborn screening v0.2047 RAC2 Zornitza Stark Gene: rac2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2046 RAC2 Zornitza Stark gene: RAC2 was added
gene: RAC2 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: RAC2.
Mode of inheritance for gene: RAC2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: RAC2 were set to Immunodeficiency 73B with defective neutrophil chemotaxis and lymphopaenia MIM# 618986
Review for gene: RAC2 was set to GREEN
Added comment: Immunodeficiency 73B with defective neutrophil chemotaxis and lymphopaenia
13 individuals from 8 unrelated families; mono-allelic; gain of function; multiple mouse models

Mono-allelic missense variants were reported in each individual (5 x De Novo) and resulted in a gain-of -function. (E62K, P34H, N92T, G12R)

These individuals typically presented in infancy with frequent infections, profound leukopaenia, lymphopaenia diarrhoea and hypogammaglobulinaemia.

SCID-like phenotype.

Treatment: IVIG, BMT

Note evidence for the other two immunodeficiency disorders associated with this gene is limited.
Sources: Expert list
BabyScreen+ newborn screening v0.2045 PLS3 Zornitza Stark Marked gene: PLS3 as ready
BabyScreen+ newborn screening v0.2045 PLS3 Zornitza Stark Gene: pls3 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2045 PLS3 Zornitza Stark Classified gene: PLS3 as Green List (high evidence)
BabyScreen+ newborn screening v0.2045 PLS3 Zornitza Stark Gene: pls3 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2044 PLS3 Zornitza Stark Tag treatable tag was added to gene: PLS3.
Tag skeletal tag was added to gene: PLS3.
BabyScreen+ newborn screening v0.2044 PLS3 Zornitza Stark gene: PLS3 was added
gene: PLS3 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: PLS3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: PLS3 were set to 32655496; 25209159; 29736964; 29884797; 28777485; 24088043
Phenotypes for gene: PLS3 were set to Bone mineral density QTL18, osteoporosis - MIM#300910
Review for gene: PLS3 was set to GREEN
Added comment: Females mildly affected: exclude from screening.

Presentation in males similar to OI, though also variable in severity.

Treatment: safe handling techniques, bisphosphonates, pamidronate, zoledronic acid, teriparatide, denosumab, alendronate

Non-genetic confirmatory testing: skeletal survey
Sources: Expert list
BabyScreen+ newborn screening v0.2043 OTULIN Zornitza Stark Marked gene: OTULIN as ready
BabyScreen+ newborn screening v0.2043 OTULIN Zornitza Stark Gene: otulin has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2043 OTULIN Zornitza Stark Classified gene: OTULIN as Green List (high evidence)
BabyScreen+ newborn screening v0.2043 OTULIN Zornitza Stark Gene: otulin has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2042 OTULIN Zornitza Stark gene: OTULIN was added
gene: OTULIN was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: OTULIN.
Mode of inheritance for gene: OTULIN was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: OTULIN were set to Autoinflammation, panniculitis, and dermatosis syndrome, MIM# 617099
Review for gene: OTULIN was set to GREEN
Added comment: Autoinflammation, panniculitis, and dermatosis syndrome (AIPDS) is an autosomal recessive autoinflammatory disease characterized by neonatal onset of recurrent fever, erythematous rash with painful nodules, painful joints, and lipodystrophy. Additional features may include diarrhea, increased serum C-reactive protein (CRP), leukocytosis, and neutrophilia in the absence of any infection.

Onset is generally in infancy.

Treatment: inflixiimab, anakinra, etanercept, corticosteroids.

Non-genetic confirmatory testing: no.
Sources: Expert list
BabyScreen+ newborn screening v0.2041 OAS1 Zornitza Stark Marked gene: OAS1 as ready
BabyScreen+ newborn screening v0.2041 OAS1 Zornitza Stark Gene: oas1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2041 OAS1 Zornitza Stark Classified gene: OAS1 as Green List (high evidence)
BabyScreen+ newborn screening v0.2041 OAS1 Zornitza Stark Gene: oas1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2040 OAS1 Zornitza Stark gene: OAS1 was added
gene: OAS1 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: OAS1.
Mode of inheritance for gene: OAS1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: OAS1 were set to 34145065; 29455859
Phenotypes for gene: OAS1 were set to Immunodeficiency 100 with pulmonary alveolar proteinosis and hypogammaglobulinaemia, MIM#618042
Review for gene: OAS1 was set to GREEN
Added comment: Immunodeficiency-100 with pulmonary alveolar proteinosis and hypogammaglobulinemia (IMD100) is primarily a lung disorder characterized by onset of respiratory insufficiency due to pulmonary alveolar proteinosis (PAP) in the first months of life. Affected individuals may have normal respiratory function at birth. Development of the disorder appears to be influenced or triggered by viral infection, manifest as progressive respiratory insufficiency, confluent consolidations on lung imaging, and diffuse collection of periodic acid-Schiff (PAS)-positive material in pulmonary alveoli associated with small and nonfoamy alveolar macrophages. Patients also have hypogammaglobulinemia, leukocytosis, and splenomegaly. Many patients die of respiratory failure in infancy or early childhood.

Treatment: IVIG; BMT is curative.

Non-genetic confirmatory testing: immunoglobulin levels.
Sources: Expert list
Inflammatory bowel disease v0.93 NLRC4 Zornitza Stark Marked gene: NLRC4 as ready
Inflammatory bowel disease v0.93 NLRC4 Zornitza Stark Gene: nlrc4 has been classified as Amber List (Moderate Evidence).
Inflammatory bowel disease v0.93 NLRC4 Zornitza Stark Phenotypes for gene: NLRC4 were changed from Infantile onset enterocolitis and autoinflammation to Autoinflammation with infantile enterocolitis, MIM# 616050
Inflammatory bowel disease v0.92 NLRC4 Zornitza Stark Publications for gene: NLRC4 were set to PMID: 25217960
Inflammatory bowel disease v0.91 NLRC4 Zornitza Stark edited their review of gene: NLRC4: Changed publications: 25217959, 25217960
Inflammatory bowel disease v0.91 NLRC4 Zornitza Stark edited their review of gene: NLRC4: Changed publications: 25217959
Inflammatory bowel disease v0.91 NLRC4 Zornitza Stark Classified gene: NLRC4 as Amber List (moderate evidence)
Inflammatory bowel disease v0.91 NLRC4 Zornitza Stark Gene: nlrc4 has been classified as Amber List (Moderate Evidence).
Inflammatory bowel disease v0.90 NLRC4 Zornitza Stark reviewed gene: NLRC4: Rating: AMBER; Mode of pathogenicity: None; Publications: 25217960; Phenotypes: Autoinflammation with infantile enterocolitis 616050; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.5192 TAB2 Lucy Spencer gene: TAB2 was added
gene: TAB2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: TAB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TAB2 were set to 35971781
Phenotypes for gene: TAB2 were set to Congenital heart defects, multiple types, 2 MONDO:0014000
Review for gene: TAB2 was set to GREEN
Added comment: PMID: 35971781 - expansion of the phenotype, 14 patients with TAB2 variants 6 have dev delay and 4 are also listed as having ID along with other phenotype features associated with this gene.

Note- there is a previous review of this paper in the mendeilome as amber
Sources: Literature
BabyScreen+ newborn screening v0.2039 NFKBIA Zornitza Stark Marked gene: NFKBIA as ready
BabyScreen+ newborn screening v0.2039 NFKBIA Zornitza Stark Gene: nfkbia has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2039 NFKBIA Zornitza Stark Classified gene: NFKBIA as Green List (high evidence)
BabyScreen+ newborn screening v0.2039 NFKBIA Zornitza Stark Gene: nfkbia has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2038 NFKBIA Zornitza Stark gene: NFKBIA was added
gene: NFKBIA was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: NFKBIA.
Mode of inheritance for gene: NFKBIA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: NFKBIA were set to Ectodermal dysplasia and immunodeficiency 2 MIM# 612132
Review for gene: NFKBIA was set to GREEN
Added comment: 12 heterozygous variants were identified in 15 unrelated individuals (de novo in 14 individuals and somatic mosaicism in 1 individual).

Functional studies & two mouse models; demonstrate reported NFKBIA gain-of-function variants resulting in impaired NFKB1 activity.

The majority of individuals displayed recurrent infections, chronic diarrhoea, agammaglobulinaemia, increased IgM, and defects in teeth (hair, nail, sweat glands).

Onset is generally in infancy.

Treatment: BMT.

Non-genetic confirmatory testing: no
Sources: Expert list
BabyScreen+ newborn screening v0.2037 NAXE Zornitza Stark Marked gene: NAXE as ready
BabyScreen+ newborn screening v0.2037 NAXE Zornitza Stark Gene: naxe has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2037 NAXE Zornitza Stark gene: NAXE was added
gene: NAXE was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, metabolic tags were added to gene: NAXE.
Mode of inheritance for gene: NAXE was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAXE were set to 27122014; 27616477; 31758406
Phenotypes for gene: NAXE were set to Encephalopathy, progressive, early-onset, with brain oedema and/or leukoencephalopathy, MIM# 617186
Review for gene: NAXE was set to RED
Added comment: Early-onset progressive encephalopathy with brain oedema and/or leukoencephalopathy-1 (PEBEL1) is an autosomal recessive severe neurometabolic disorder characterized by rapidly progressive neurologic deterioration that is usually associated with a febrile illness. Affected infants tend to show normal early development followed by acute psychomotor regression with ataxia, hypotonia, respiratory insufficiency, and seizures, resulting in coma and death in the first years of life. Brain imaging shows multiple abnormalities, including brain edema and signal abnormalities in the cortical and subcortical regions. More than 5 unrelated families reported.

Treatment: niacin

However, single case reported. Treatment not established.
Sources: Expert list
BabyScreen+ newborn screening v0.2036 NAXD Zornitza Stark Marked gene: NAXD as ready
BabyScreen+ newborn screening v0.2036 NAXD Zornitza Stark Gene: naxd has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.2036 NAXD Zornitza Stark Classified gene: NAXD as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.2036 NAXD Zornitza Stark Gene: naxd has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.2035 NAXD Zornitza Stark gene: NAXD was added
gene: NAXD was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, metabolic tags were added to gene: NAXD.
Mode of inheritance for gene: NAXD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAXD were set to 30576410; 31755961; 32462209; 35231119
Phenotypes for gene: NAXD were set to Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 2 MIM#618321
Review for gene: NAXD was set to AMBER
Added comment: Seven unrelated cases, episodes of fever/infection prior to deterioration reported. Variable phenotype: one patient reported with neurodevelopmental disorder, autism spectrum disorder and a muscular-dystrophy-like myopathy; another with progressive encephalopathy with brain oedema. Patient cells and muscle biopsies also showed impaired mitochondrial function, higher sensitivity to metabolic stress, and decreased mitochondrial reactive oxygen species production. In vitro functional assays also conducted.

Treatment: niacin

However, only two cases reported. Treatment not established.
Sources: Expert list
BabyScreen+ newborn screening v0.2034 MYD88 Zornitza Stark Marked gene: MYD88 as ready
BabyScreen+ newborn screening v0.2034 MYD88 Zornitza Stark Gene: myd88 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2034 MYD88 Zornitza Stark Classified gene: MYD88 as Green List (high evidence)
BabyScreen+ newborn screening v0.2034 MYD88 Zornitza Stark Gene: myd88 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2033 MYD88 Zornitza Stark gene: MYD88 was added
gene: MYD88 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: MYD88.
Mode of inheritance for gene: MYD88 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYD88 were set to 18669862; 20538326; 31301515
Phenotypes for gene: MYD88 were set to Immunodeficiency 68, MIM# 612260
Review for gene: MYD88 was set to GREEN
Added comment: Immunodeficiency-68 (IMD68) is an autosomal recessive primary immunodeficiency characterized by severe systemic and invasive bacterial infections beginning in infancy or early childhood. The most common organisms implicated are Streptococcus pneumoniae, Staphylococcus aureus, and Pseudomonas, although other organisms may be observed.

At least 7 families and a mouse model.

Treatment: Prophylactic antibiotic treatment, pneumococcal, meningococcal, haemophilus influenzae vaccines, and immunoglobulin replacement.

Non-genetic confirmatory testing: toll-like receptor function
Sources: Expert list
BabyScreen+ newborn screening v0.2032 MTHFS Zornitza Stark Marked gene: MTHFS as ready
BabyScreen+ newborn screening v0.2032 MTHFS Zornitza Stark Gene: mthfs has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2032 MTHFS Zornitza Stark gene: MTHFS was added
gene: MTHFS was added to Baby Screen+ newborn screening. Sources: Expert list
metabolic tags were added to gene: MTHFS.
Mode of inheritance for gene: MTHFS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MTHFS were set to 30031689; 31844630; 22303332
Phenotypes for gene: MTHFS were set to Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination, 618367
Review for gene: MTHFS was set to RED
Added comment: Established gene-disease association.

Onset in infancy. Severe disorder.

Treatment: single report of some improvement with combination of oral L-5- methyltetrahydrofolate and intramuscular methylcobalamin
Sources: Expert list
BabyScreen+ newborn screening v0.2031 MTHFD1 Zornitza Stark Marked gene: MTHFD1 as ready
BabyScreen+ newborn screening v0.2031 MTHFD1 Zornitza Stark Gene: mthfd1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2031 MTHFD1 Zornitza Stark Classified gene: MTHFD1 as Green List (high evidence)
BabyScreen+ newborn screening v0.2031 MTHFD1 Zornitza Stark Gene: mthfd1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2030 MTHFD1 Zornitza Stark gene: MTHFD1 was added
gene: MTHFD1 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological, haematological tags were added to gene: MTHFD1.
Mode of inheritance for gene: MTHFD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MTHFD1 were set to 32414565; 19033438
Phenotypes for gene: MTHFD1 were set to Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinaemia MIM # 617780
Review for gene: MTHFD1 was set to GREEN
Added comment: 8 individuals from 4 unrelated families have been reported; multiple mouse models

7 individuals were Compound heterozygous (nonsense & missense) and 1 was homozygous (missense) for MTHFD1 variants often resulting in alteration of highly conserved residues in binding-sites.

Individuals typically present with megaloblastic anaemia, atypical hemolytic uremic syndrome, hyperhomocysteinaemia, microangiopathy, recurrent infections and autoimmune diseases.

Treatment: hydroxocobalamin, folinic acid and betaine

Non-genetic confirmatory testing: T and B Lymphocyte and Natural Killer Cell Profile, complete blood count with MCV, plasma homocysteine and methylmalonic acid levels, CSF
Sources: Expert list
Intellectual disability syndromic and non-syndromic v0.5192 UBE3C Zornitza Stark Phenotypes for gene: UBE3C were changed from Neurodevelopmental disorder, MONDO:0700092, UBE3C-related to Neurodevelopmental disorder with absent speech and movement and behavioral abnormalities, MIM# 620270
Intellectual disability syndromic and non-syndromic v0.5191 UBE3C Zornitza Stark edited their review of gene: UBE3C: Changed phenotypes: Neurodevelopmental disorder with absent speech and movement and behavioral abnormalities, MIM# 620270
Mendeliome v1.741 UBE3C Zornitza Stark Phenotypes for gene: UBE3C were changed from Neurodevelopmental disorder, MONDO:0700092, UBE3C-related to Neurodevelopmental disorder with absent speech and movement and behavioral abnormalities, MIM# 620270
Mendeliome v1.740 UBE3C Zornitza Stark edited their review of gene: UBE3C: Changed phenotypes: Neurodevelopmental disorder with absent speech and movement and behavioral abnormalities, MIM# 620270
Angelman Rett like syndromes v1.8 UBE3C Zornitza Stark Phenotypes for gene: UBE3C were changed from Neurodevelopmental disorder, MONDO:0700092, UBE3C-related to Neurodevelopmental disorder with absent speech and movement and behavioral abnormalities, MIM# 620270
Angelman Rett like syndromes v1.7 UBE3C Zornitza Stark edited their review of gene: UBE3C: Changed phenotypes: Neurodevelopmental disorder with absent speech and movement and behavioral abnormalities, MIM# 620270
Mendeliome v1.740 MS4A1 Zornitza Stark Publications for gene: MS4A1 were set to 20038800
Mendeliome v1.739 MS4A1 Zornitza Stark Classified gene: MS4A1 as Amber List (moderate evidence)
Mendeliome v1.739 MS4A1 Zornitza Stark Gene: ms4a1 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.2029 MNX1 Zornitza Stark Marked gene: MNX1 as ready
BabyScreen+ newborn screening v0.2029 MNX1 Zornitza Stark Gene: mnx1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2029 MNX1 Zornitza Stark Classified gene: MNX1 as Green List (high evidence)
BabyScreen+ newborn screening v0.2029 MNX1 Zornitza Stark Gene: mnx1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2028 MNX1 Zornitza Stark gene: MNX1 was added
gene: MNX1 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, endocrine tags were added to gene: MNX1.
Mode of inheritance for gene: MNX1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MNX1 were set to 36586106
Phenotypes for gene: MNX1 were set to Permanent neonatal diabetes mellitus, MONDO:0100164, MNX1-related
Review for gene: MNX1 was set to GREEN
Added comment: Three unrelated families reported. Presentation is in newborn period.

Treatment: insulin.

Non-genetic confirmatory testing: glucose tolerance test, hemoglobin A1C, insulin level, glucose level
Sources: Expert list
Mendeliome v1.738 MNX1 Zornitza Stark Phenotypes for gene: MNX1 were changed from Currarino syndrome, MIM# 176450 to Currarino syndrome, MIM# 176450; Permanent neonatal diabetes mellitus, MONDO:0100164, MNX1-related
Mendeliome v1.737 MNX1 Zornitza Stark Mode of inheritance for gene: MNX1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Monogenic Diabetes v0.38 MNX1 Zornitza Stark Marked gene: MNX1 as ready
Monogenic Diabetes v0.38 MNX1 Zornitza Stark Gene: mnx1 has been classified as Green List (High Evidence).
Monogenic Diabetes v0.38 MNX1 Zornitza Stark Phenotypes for gene: MNX1 were changed from to Permanent neonatal diabetes mellitus, MONDO:0100164, MNX1-related
Monogenic Diabetes v0.37 MNX1 Zornitza Stark reviewed gene: MNX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36586106; Phenotypes: Permanent neonatal diabetes mellitus, MONDO:0100164, MNX1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.736 MNX1 Zornitza Stark reviewed gene: MNX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36586106; Phenotypes: Permanent neonatal diabetes mellitus, MONDO:0100164, MNX1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.2027 MALT1 Zornitza Stark Marked gene: MALT1 as ready
BabyScreen+ newborn screening v0.2027 MALT1 Zornitza Stark Gene: malt1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2027 MALT1 Zornitza Stark Classified gene: MALT1 as Green List (high evidence)
BabyScreen+ newborn screening v0.2027 MALT1 Zornitza Stark Gene: malt1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2026 MALT1 Zornitza Stark gene: MALT1 was added
gene: MALT1 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: MALT1.
Mode of inheritance for gene: MALT1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: MALT1 were set to Immunodeficiency 12 MIM# 615468
Review for gene: MALT1 was set to GREEN
Added comment: 5 individuals from 3 unrelated families with immunodeficiency phenotype have reported variants in MALT1; two MALT1-knockout mouse models displaying primary T- and B-cell lymphocyte deficiency.

Variants identified were homozygous missense variants resulting in the alteration of highly conserved residue domains.

All individuals reported onset in infancy of recurrent bacterial/ fungal/ viral infections leading to bronchiectasis and poor T-cell proliferation.

Treatment: prophylactic antibiotics, IVIG, BMT.

Non-genetic confirmatory testing: no
Sources: Expert list
Ectodermal Dysplasia v0.81 RIPK4 Bryony Thompson Marked gene: RIPK4 as ready
Ectodermal Dysplasia v0.81 RIPK4 Bryony Thompson Gene: ripk4 has been classified as Green List (High Evidence).
Ectodermal Dysplasia v0.81 RIPK4 Bryony Thompson Classified gene: RIPK4 as Green List (high evidence)
Ectodermal Dysplasia v0.81 RIPK4 Bryony Thompson Gene: ripk4 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2025 MAGT1 Zornitza Stark Marked gene: MAGT1 as ready
BabyScreen+ newborn screening v0.2025 MAGT1 Zornitza Stark Gene: magt1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2025 MAGT1 Zornitza Stark Classified gene: MAGT1 as Green List (high evidence)
BabyScreen+ newborn screening v0.2025 MAGT1 Zornitza Stark Gene: magt1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2024 MAGT1 Zornitza Stark gene: MAGT1 was added
gene: MAGT1 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: MAGT1.
Mode of inheritance for gene: MAGT1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: MAGT1 were set to 31036665; 31714901
Phenotypes for gene: MAGT1 were set to Immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasia (MIM# 300853)
Review for gene: MAGT1 was set to GREEN
Added comment: XMEN is an X-linked recessive immunodeficiency characterized by CD4 lymphopenia, severe chronic viral infections, and defective T-lymphocyte activation. Affected individuals have chronic Epstein-Barr virus (EBV) infection and are susceptible to the development of EBV-associated B-cell lymphoproliferative disorders.

Variable age of onset, including in early childhood.

Treatment: Mg supplementation; IVIG, BMT.

Non-genetic confirmatory testing: immunoglobulin levels, T and B Lymphocyte and Natural Killer Cell Profile, Carbohydrate deficient glycosylation profile
Sources: Expert list
BabyScreen+ newborn screening v0.2023 LRBA Zornitza Stark Marked gene: LRBA as ready
BabyScreen+ newborn screening v0.2023 LRBA Zornitza Stark Gene: lrba has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2023 LRBA Zornitza Stark Classified gene: LRBA as Green List (high evidence)
BabyScreen+ newborn screening v0.2023 LRBA Zornitza Stark Gene: lrba has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2022 LRBA Zornitza Stark gene: LRBA was added
gene: LRBA was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: LRBA.
Mode of inheritance for gene: LRBA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LRBA were set to 22608502; 22721650; 25468195; 26206937; 33155142; 31887391
Phenotypes for gene: LRBA were set to Immunodeficiency, common variable, 8, with autoimmunity MIM# 614700
Review for gene: LRBA was set to GREEN
Added comment: Well established gene-disease association.

Generally childhood onset with recurrent infections and autoimmune phenomena.

Treatment: abatacept, BMT.

Non-genetic confirmatory testing: immunoglobulin levels.
Sources: Expert list
BabyScreen+ newborn screening v0.2021 LIG1 Zornitza Stark Marked gene: LIG1 as ready
BabyScreen+ newborn screening v0.2021 LIG1 Zornitza Stark Gene: lig1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2021 LIG1 Zornitza Stark Classified gene: LIG1 as Green List (high evidence)
BabyScreen+ newborn screening v0.2021 LIG1 Zornitza Stark Gene: lig1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2020 LIG1 Zornitza Stark gene: LIG1 was added
gene: LIG1 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: LIG1.
Mode of inheritance for gene: LIG1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LIG1 were set to 30395541
Phenotypes for gene: LIG1 were set to Immunodeficiency 96, MIM# 619774
Review for gene: LIG1 was set to GREEN
Added comment: Established gene-disease association.

Onset is generally in early childhood.

Presents with recurrent severe infections.

Treatment: IVIG, BMT.

Non-genetic confirmatory testing: immunoglobulin levels, T and B Lymphocyte and Natural Killer Cell Profile, complete blood count
Sources: Expert list
BabyScreen+ newborn screening v0.2019 LEP Zornitza Stark Marked gene: LEP as ready
BabyScreen+ newborn screening v0.2019 LEP Zornitza Stark Gene: lep has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2019 LEP Zornitza Stark Classified gene: LEP as Green List (high evidence)
BabyScreen+ newborn screening v0.2019 LEP Zornitza Stark Gene: lep has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2018 LEP Zornitza Stark gene: LEP was added
gene: LEP was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, endocrine tags were added to gene: LEP.
Mode of inheritance for gene: LEP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LEP were set to 26567097
Phenotypes for gene: LEP were set to Obesity, morbid, due to leptin deficiency (MIM#614962)
Review for gene: LEP was set to GREEN
Added comment: Established gene-disease association.

Onset is in infancy/early childhood. Similar disorders included.

Treatment: metreleptin.

Non-genetic confirmatory testing: leptin level.
Sources: Expert list
BabyScreen+ newborn screening v0.2017 JAGN1 Zornitza Stark Marked gene: JAGN1 as ready
BabyScreen+ newborn screening v0.2017 JAGN1 Zornitza Stark Gene: jagn1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2017 JAGN1 Zornitza Stark Classified gene: JAGN1 as Green List (high evidence)
BabyScreen+ newborn screening v0.2017 JAGN1 Zornitza Stark Gene: jagn1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2016 JAGN1 Zornitza Stark gene: JAGN1 was added
gene: JAGN1 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: JAGN1.
Mode of inheritance for gene: JAGN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: JAGN1 were set to 25129144
Phenotypes for gene: JAGN1 were set to Neutropenia, severe congenital, 6, autosomal recessive, MIM# 616022
Review for gene: JAGN1 was set to GREEN
Added comment: Established gene-disease association.

Typically presents in early childhood with severe infections.

Treatment: G-CSF, BMT.

Non-genetic confirmatory testing: complete blood count, bone marrow aspiration and biopsy
Sources: Expert list
BabyScreen+ newborn screening v0.2015 TNFRSF13C Zornitza Stark Marked gene: TNFRSF13C as ready
BabyScreen+ newborn screening v0.2015 TNFRSF13C Zornitza Stark Gene: tnfrsf13c has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2015 TNFRSF13C Zornitza Stark Classified gene: TNFRSF13C as Red List (low evidence)
BabyScreen+ newborn screening v0.2015 TNFRSF13C Zornitza Stark Gene: tnfrsf13c has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.2014 ITK Zornitza Stark Marked gene: ITK as ready
BabyScreen+ newborn screening v0.2014 ITK Zornitza Stark Gene: itk has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2014 ITK Zornitza Stark Classified gene: ITK as Green List (high evidence)
BabyScreen+ newborn screening v0.2014 ITK Zornitza Stark Gene: itk has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2013 ITK Zornitza Stark gene: ITK was added
gene: ITK was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: ITK.
Mode of inheritance for gene: ITK was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ITK were set to Lymphoproliferative syndrome 1, MIM# 613011
Review for gene: ITK was set to GREEN
Added comment: 7 individuals from 5 unrelated families reported homozygous (missense/ nonsense) ITK variants consistent with Lymphoproliferative syndrome phenotype. Triggered by EBV infection.

Two ITK-deficient mouse models demonstrated reduced T cells (CD4+), causing decreased CD4 to CD8 ratio.

Patients displayed early onset of features typically including fever, lymphadenopathy, autoimmune disorders, low immunoglobulins and high EBV viral load.

Fatal without BMT.

Non-genetic confirmatory testing: immunoglobulin levels, T and B Lymphocyte and Natural Killer Cell Profile.
Sources: Expert list
BabyScreen+ newborn screening v0.2012 IRS4 Zornitza Stark changed review comment from: Nongoitrous congenital hypothyroidism-9 (CHNG9) is characterized by a small thyroid gland with low free T4 (FT4) levels and inappropriately normal levels of thyroid-stimulating hormone (TSH). Five unrelated families reported.

Most identified through standard NBS.
Sources: Expert list; to: Nongoitrous congenital hypothyroidism-9 (CHNG9) is characterized by a small thyroid gland with low free T4 (FT4) levels and inappropriately normal levels of thyroid-stimulating hormone (TSH). Five unrelated families reported.

Most identified through standard NBS.

Treatment: thyroxine.
Sources: Expert list
BabyScreen+ newborn screening v0.2012 IRS4 Zornitza Stark Marked gene: IRS4 as ready
BabyScreen+ newborn screening v0.2012 IRS4 Zornitza Stark Gene: irs4 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2012 IRS4 Zornitza Stark Classified gene: IRS4 as Green List (high evidence)
BabyScreen+ newborn screening v0.2012 IRS4 Zornitza Stark Gene: irs4 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2011 IRS4 Zornitza Stark gene: IRS4 was added
gene: IRS4 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, endocrine tags were added to gene: IRS4.
Mode of inheritance for gene: IRS4 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: IRS4 were set to 30061370
Phenotypes for gene: IRS4 were set to Hypothyroidism, congenital, nongoitrous, 9, MIM# 301035
Review for gene: IRS4 was set to GREEN
Added comment: Nongoitrous congenital hypothyroidism-9 (CHNG9) is characterized by a small thyroid gland with low free T4 (FT4) levels and inappropriately normal levels of thyroid-stimulating hormone (TSH). Five unrelated families reported.

Most identified through standard NBS.
Sources: Expert list
Mendeliome v1.736 IRS4 Zornitza Stark Marked gene: IRS4 as ready
Mendeliome v1.736 IRS4 Zornitza Stark Gene: irs4 has been classified as Green List (High Evidence).
Mendeliome v1.736 IRS4 Zornitza Stark Classified gene: IRS4 as Green List (high evidence)
Mendeliome v1.736 IRS4 Zornitza Stark Gene: irs4 has been classified as Green List (High Evidence).
Mendeliome v1.735 IRS4 Zornitza Stark gene: IRS4 was added
gene: IRS4 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: IRS4 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: IRS4 were set to 30061370
Phenotypes for gene: IRS4 were set to Hypothyroidism, congenital, nongoitrous, 9, MIM# 301035
Review for gene: IRS4 was set to GREEN
Added comment: Nongoitrous congenital hypothyroidism-9 (CHNG9) is characterized by a small thyroid gland with low free T4 (FT4) levels and inappropriately normal levels of thyroid-stimulating hormone (TSH). Five unrelated families reported.
Sources: Expert Review
Congenital hypothyroidism v0.38 IRS4 Zornitza Stark Marked gene: IRS4 as ready
Congenital hypothyroidism v0.38 IRS4 Zornitza Stark Gene: irs4 has been classified as Green List (High Evidence).
Congenital hypothyroidism v0.38 IRS4 Zornitza Stark Phenotypes for gene: IRS4 were changed from Congenital central hypothyroidism to Hypothyroidism, congenital, nongoitrous, 9, MIM# 301035
Congenital hypothyroidism v0.37 IRS4 Zornitza Stark reviewed gene: IRS4: Rating: GREEN; Mode of pathogenicity: None; Publications: 30061370; Phenotypes: Hypothyroidism, congenital, nongoitrous, 9, MIM# 301035; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
BabyScreen+ newborn screening v0.2010 TNFRSF13C Lilian Downie gene: TNFRSF13C was added
gene: TNFRSF13C was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: TNFRSF13C was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TNFRSF13C were set to PMID: 19666484, PMID: 27250108, PMID: 18025937
Phenotypes for gene: TNFRSF13C were set to Immunodeficiency, common variable, 4 MIM#613494
Review for gene: TNFRSF13C was set to RED
Added comment: Amber in our mendeliome
Later childhood or adult onset.
BAFFR deficiency in humans is characterized by very few circulating B cells, very low IgM and IgG serum concentrations but normal or high IgA levels.
Sources: Expert list
BabyScreen+ newborn screening v0.2010 IL36RN Zornitza Stark Marked gene: IL36RN as ready
BabyScreen+ newborn screening v0.2010 IL36RN Zornitza Stark Gene: il36rn has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2010 IL36RN Zornitza Stark Classified gene: IL36RN as Green List (high evidence)
BabyScreen+ newborn screening v0.2010 IL36RN Zornitza Stark Gene: il36rn has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2009 IL36RN Zornitza Stark gene: IL36RN was added
gene: IL36RN was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: IL36RN.
Mode of inheritance for gene: IL36RN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IL36RN were set to 31286990
Phenotypes for gene: IL36RN were set to Psoriasis 14, pustular, MIM# 614204
Review for gene: IL36RN was set to GREEN
Added comment: Generalized pustular psoriasis (GPP) is a life-threatening disease characterized by sudden, repeated episodes of high-grade fever, generalized rash, and disseminated pustules, with hyperleukocytosis and elevated serum levels of C-reactive protein.

Variable age of onset but predominantly in infancy/early childhood.

Treatment: ustekinumab, secukinumab, etanercept.
Sources: Expert list
BabyScreen+ newborn screening v0.2008 IL2RA Zornitza Stark Marked gene: IL2RA as ready
BabyScreen+ newborn screening v0.2008 IL2RA Zornitza Stark Gene: il2ra has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2008 IL2RA Zornitza Stark Classified gene: IL2RA as Green List (high evidence)
BabyScreen+ newborn screening v0.2008 IL2RA Zornitza Stark Gene: il2ra has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2007 IL2RA Zornitza Stark gene: IL2RA was added
gene: IL2RA was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: IL2RA.
Mode of inheritance for gene: IL2RA was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: IL2RA were set to Immunodeficiency 41 with lymphoproliferation and autoimmunity, MIM# 606367
Review for gene: IL2RA was set to GREEN
Added comment: Immunodeficiency-41 is a disorder of immune dysregulation. Affected individuals present in infancy with recurrent viral, fungal, and bacterial infections, lymphadenopathy, and variable autoimmune features, such as autoimmune enteropathy and eczematous skin lesions. Immunologic studies show a defect in T-cell regulation.

At least 4 unrelated families reported.

Treatment: rapamycin, bone marrow transplant.

Confirmatory non-genetic testing: flow cytometric analysis.
Sources: Expert list
BabyScreen+ newborn screening v0.2006 IL21R Zornitza Stark Marked gene: IL21R as ready
BabyScreen+ newborn screening v0.2006 IL21R Zornitza Stark Gene: il21r has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2006 IL21R Zornitza Stark Classified gene: IL21R as Green List (high evidence)
BabyScreen+ newborn screening v0.2006 IL21R Zornitza Stark Gene: il21r has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2005 IL21R Zornitza Stark gene: IL21R was added
gene: IL21R was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: IL21R.
Mode of inheritance for gene: IL21R was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: IL21R were set to Immunodeficiency 56, MIM# 615207
Review for gene: IL21R was set to GREEN
Added comment: Biallelic inactivating mutations in IL21R causes a combined immunodeficiency that is often complicated by cryptosporidium infections.

More than 20 individuals reported. Recent series of 13 individuals: the main clinical manifestations were recurrent bacterial (84.6%), fungal (46.2%), and viral (38.5%) infections; cryptosporidiosis-associated cholangitis (46.2%); and asthma (23.1%). Inflammatory skin diseases (15.3%) and recurrent anaphylaxis (7.9%) constitute novel phenotypes of this combined immunodeficiency. Most patients exhibited hypogammaglobulinaemia and reduced proportions of memory B cells, circulating T follicular helper cells, MAIT cells and terminally differentiated NK cells. However, IgE levels were elevated in 50% of IL-21R-deficient patients.

Onset: infancy/early childhood.

Treatment: BMT.

Non-genetic confirmatory testing: immunoglobulin levels.
Sources: Expert list
BabyScreen+ newborn screening v0.2004 IL1RN Zornitza Stark Marked gene: IL1RN as ready
BabyScreen+ newborn screening v0.2004 IL1RN Zornitza Stark Gene: il1rn has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2004 IL1RN Zornitza Stark Classified gene: IL1RN as Green List (high evidence)
BabyScreen+ newborn screening v0.2004 IL1RN Zornitza Stark Gene: il1rn has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2003 IL1RN Zornitza Stark gene: IL1RN was added
gene: IL1RN was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: IL1RN.
Mode of inheritance for gene: IL1RN was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: IL1RN were set to Interleukin 1 receptor antagonist deficiency, MIM# 612852
Review for gene: IL1RN was set to GREEN
Added comment: Severe immunodeficiency, onset in infancy. Multi-system involvement, can be fatal if untreated.

Treatment: anakinra, etanercept, methotrexate, corticosteroid
Sources: Expert list
BabyScreen+ newborn screening v0.2002 IKZF1 Zornitza Stark Marked gene: IKZF1 as ready
BabyScreen+ newborn screening v0.2002 IKZF1 Zornitza Stark Gene: ikzf1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2002 IKZF1 Zornitza Stark Classified gene: IKZF1 as Green List (high evidence)
BabyScreen+ newborn screening v0.2002 IKZF1 Zornitza Stark Gene: ikzf1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2001 IKZF1 Zornitza Stark Tag treatable tag was added to gene: IKZF1.
Tag immunological tag was added to gene: IKZF1.
BabyScreen+ newborn screening v0.2001 IKZF1 Zornitza Stark edited their review of gene: IKZF1: Changed rating: GREEN
BabyScreen+ newborn screening v0.2001 IKZF1 Zornitza Stark gene: IKZF1 was added
gene: IKZF1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: IKZF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: IKZF1 were set to Immunodeficiency, common variable, 13 MIM# 616873
Added comment: Over 25 individuals from 9 unrelated families with variants in IKZF1 displaying Immunodeficiency; three mouse models Heterozygous missense, frameshift and deletion variants in IKZF1 gene resulting in loss or alteration of a zinc finger DNA contact site cause LoF. Typically presents with recurrent bacterial respiratory infections, hypogammaglobulinaemia and low Ig levels; variable age of onset.

PMID 35333544: Eight individuals harboring heterozygous IKZF1R183H or IKZF1R183C variants associated with GOF effects reported. The clinical phenotypes and pathophysiology associated with IKZF1R183H/C differ from those of previously reported patients with IKZF1HI, IKZF1DN, and IKZF1DD and should therefore be considered as a novel IKAROS-associated disease entity. This condition is characterized by immune dysregulation manifestations including inflammation, autoimmunity, atopy, and polyclonal PC proliferation.

Included primarily for LoF phenotype.

Treatment: IVIG and BMT.

Non-genetic confirmatory testing: immunoglobulin levels
Sources: Expert list
BabyScreen+ newborn screening v0.2000 IKBKB Zornitza Stark changed review comment from: Primary immunodeficiency disorder characterized by onset in infancy of life-threatening bacterial, fungal, and viral infections and failure to thrive. Laboratory studies show hypo- or agammaglobulinaemia with relatively normal numbers of B and T cells.

Treatment: bone marrow transplant.
Sources: Expert list; to: Primary immunodeficiency disorder characterized by onset in infancy of life-threatening bacterial, fungal, and viral infections and failure to thrive. Laboratory studies show hypo- or agammaglobulinaemia with relatively normal numbers of B and T cells.

Treatment: bone marrow transplant.

Limited evidence for mono-allelic disease.
Sources: Expert list
BabyScreen+ newborn screening v0.2000 IKBKB Zornitza Stark Marked gene: IKBKB as ready
BabyScreen+ newborn screening v0.2000 IKBKB Zornitza Stark Gene: ikbkb has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.2000 IKBKB Zornitza Stark Classified gene: IKBKB as Green List (high evidence)
BabyScreen+ newborn screening v0.2000 IKBKB Zornitza Stark Gene: ikbkb has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1999 IKBKB Zornitza Stark gene: IKBKB was added
gene: IKBKB was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: IKBKB.
Mode of inheritance for gene: IKBKB was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: IKBKB were set to Immunodeficiency 15B, MIM# 615592
Review for gene: IKBKB was set to GREEN
Added comment: Primary immunodeficiency disorder characterized by onset in infancy of life-threatening bacterial, fungal, and viral infections and failure to thrive. Laboratory studies show hypo- or agammaglobulinaemia with relatively normal numbers of B and T cells.

Treatment: bone marrow transplant.
Sources: Expert list
BabyScreen+ newborn screening v0.1998 IFNGR2 Zornitza Stark Marked gene: IFNGR2 as ready
BabyScreen+ newborn screening v0.1998 IFNGR2 Zornitza Stark Gene: ifngr2 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1998 IFNGR2 Zornitza Stark Classified gene: IFNGR2 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.1998 IFNGR2 Zornitza Stark Gene: ifngr2 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1997 IFNGR2 Zornitza Stark gene: IFNGR2 was added
gene: IFNGR2 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: IFNGR2.
Mode of inheritance for gene: IFNGR2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: IFNGR2 were set to Immunodeficiency 28, mycobacteriosis, MIM# 614889
Review for gene: IFNGR2 was set to AMBER
Added comment: At least 5 unrelated families reported.

Commonest trigger is BCG vaccination, which is not part of the routine schedule in Australia, therefore exclude.

Treatment: BMT; avoidance of BCG.
Sources: Expert list
BabyScreen+ newborn screening v0.1996 IFNGR1 Zornitza Stark Marked gene: IFNGR1 as ready
BabyScreen+ newborn screening v0.1996 IFNGR1 Zornitza Stark Gene: ifngr1 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1996 IFNGR1 Zornitza Stark Classified gene: IFNGR1 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.1996 IFNGR1 Zornitza Stark Gene: ifngr1 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1995 IFNGR1 Zornitza Stark Tag treatable tag was added to gene: IFNGR1.
Tag immunological tag was added to gene: IFNGR1.
BabyScreen+ newborn screening v0.1995 IFNGR1 Zornitza Stark gene: IFNGR1 was added
gene: IFNGR1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: IFNGR1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: IFNGR1 were set to Immunodeficiency 27A, mycobacteriosis, AR, MIM# 209950; Immunodeficiency 27B, mycobacteriosis, AD, MIM# 615978
Review for gene: IFNGR1 was set to AMBER
Added comment: Variable age of onset. Most common precipitant is BCG vaccination, which is not part of the routine schedule in Australia, therefore exclude.

Treatment: BMT; avoidance of BCG.
Sources: Expert list
BabyScreen+ newborn screening v0.1994 IFITM5 Zornitza Stark Marked gene: IFITM5 as ready
BabyScreen+ newborn screening v0.1994 IFITM5 Zornitza Stark Gene: ifitm5 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1994 IFITM5 Zornitza Stark Classified gene: IFITM5 as Green List (high evidence)
BabyScreen+ newborn screening v0.1994 IFITM5 Zornitza Stark Gene: ifitm5 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1993 IFITM5 Zornitza Stark gene: IFITM5 was added
gene: IFITM5 was added to Baby Screen+ newborn screening. Sources: Expert list
5'UTR, treatable, skeletal tags were added to gene: IFITM5.
Mode of inheritance for gene: IFITM5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IFITM5 were set to 22863190; 22863195; 32383316; 24519609
Phenotypes for gene: IFITM5 were set to Osteogenesis imperfecta, type V MIM#610967
Review for gene: IFITM5 was set to GREEN
Added comment: A recurrent c.-14C>T variant has been reported in many patients with type V OI. It introduces an alternative in-frame start codon upstream that is stronger than the reference start codon in transfected HEK cells (PMIDs: 22863190, 22863195). However, the effect of mutant protein (5 amino acids longer) remains unknown but neomorphic mechanism is a widely accepted hypothesis (PMIDs: 25251575, 32383316).

Variable severity, including within families. However, severe perinatal presentations reported.

Treatment: bisphosphanates.

Non-genetic confirmatory testing: skeletal survey.
Sources: Expert list
BabyScreen+ newborn screening v0.1992 ICOS Zornitza Stark Marked gene: ICOS as ready
BabyScreen+ newborn screening v0.1992 ICOS Zornitza Stark Gene: icos has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1992 ICOS Zornitza Stark Classified gene: ICOS as Green List (high evidence)
BabyScreen+ newborn screening v0.1992 ICOS Zornitza Stark Gene: icos has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1991 ICOS Zornitza Stark gene: ICOS was added
gene: ICOS was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: ICOS.
Mode of inheritance for gene: ICOS was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ICOS were set to Immunodeficiency, common variable, 1 MIM# 607594
Review for gene: ICOS was set to GREEN
Added comment: 15 affected individuals from 8 unrelated families reported with ICOS variants and displayed immunodeficiency, common variable, 1 phenotype; three mouse models.

Homozygous and compound heterozygous deletion and missense variants, with the most frequent variant being a 442 nucleotide deletion.

Patients typically presented with recurrent bacterial respiratory & gastrointestinal infections and low IgG/IgA.

Congenital onset.

Treatment: replacement immunoglobulin treatment, bone marrow transplant.

Non-genetic confirmatory testing: immunoglobulin levels.
Sources: Expert list
BabyScreen+ newborn screening v0.1990 IARS Zornitza Stark Marked gene: IARS as ready
BabyScreen+ newborn screening v0.1990 IARS Zornitza Stark Gene: iars has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1990 IARS Zornitza Stark Classified gene: IARS as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.1990 IARS Zornitza Stark Gene: iars has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1989 IARS Zornitza Stark Tag treatable tag was added to gene: IARS.
Tag metabolic tag was added to gene: IARS.
BabyScreen+ newborn screening v0.1989 IARS Zornitza Stark gene: IARS was added
gene: IARS was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: IARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IARS were set to 27426735; 34194004
Phenotypes for gene: IARS were set to Growth retardation, impaired intellectual development, hypotonia, and hepatopathy, MIM#617093
Review for gene: IARS was set to AMBER
Added comment: Established gene-disease association.

Congenital, multi-system metabolic disorder.

N=1 study of Isoleucine supplementation and protein fortification (2.5mg/kg/day, during illness 3.5 g/kg/day) with some clinical improvement.
Sources: Expert list
Intellectual disability syndromic and non-syndromic v0.5191 HECTD4 Zornitza Stark Phenotypes for gene: HECTD4 were changed from Neurodevelopmental disorder, MONDO:0700092, HECTD4-related to Neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum, MIM# 620250
Intellectual disability syndromic and non-syndromic v0.5190 HECTD4 Zornitza Stark edited their review of gene: HECTD4: Changed phenotypes: Neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum, MIM# 620250
Mendeliome v1.734 HECTD4 Zornitza Stark Marked gene: HECTD4 as ready
Mendeliome v1.734 HECTD4 Zornitza Stark Gene: hectd4 has been classified as Green List (High Evidence).
Mendeliome v1.734 HECTD4 Zornitza Stark Phenotypes for gene: HECTD4 were changed from Neurodevelopmental disorder overlapping Angelman syndrome, no OMIM# to Neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum, MIM# 620250
Mendeliome v1.733 HECTD4 Zornitza Stark reviewed gene: HECTD4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum, MIM# 620250; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Angelman Rett like syndromes v1.7 HECTD4 Zornitza Stark Phenotypes for gene: HECTD4 were changed from Neurodevelopmental disorder, MONDO:0700092, HECTD4-related to Neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum, MIM# 620250
Angelman Rett like syndromes v1.6 HECTD4 Zornitza Stark edited their review of gene: HECTD4: Changed phenotypes: Neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum, MIM# 620250
Disorders of immune dysregulation v0.167 TNFRSF9 Zornitza Stark Phenotypes for gene: TNFRSF9 were changed from EBV lymphoproliferation; B-cell lymphoma; Chronic active EBV infection to Immunodeficiency 109 with lymphoproliferation, MIM# 620282; EBV lymphoproliferation; B-cell lymphoma; Chronic active EBV infection
Disorders of immune dysregulation v0.166 TNFRSF9 Zornitza Stark edited their review of gene: TNFRSF9: Changed phenotypes: Immunodeficiency 109 with lymphoproliferation, MIM# 620282, EBV lymphoproliferation, B-cell lymphoma, Chronic active EBV infection
Mendeliome v1.733 TNFRSF9 Zornitza Stark Phenotypes for gene: TNFRSF9 were changed from EBV lymphoproliferation; B-cell lymphoma; Chronic active EBV infection to Immunodeficiency 109 with lymphoproliferation, MIM# 620282; EBV lymphoproliferation; B-cell lymphoma; Chronic active EBV infection
Mendeliome v1.732 TNFRSF9 Zornitza Stark edited their review of gene: TNFRSF9: Changed phenotypes: Immunodeficiency 109 with lymphoproliferation, MIM# 620282, EBV lymphoproliferation, B-cell lymphoma, Chronic active EBV infection
BabyScreen+ newborn screening v0.1988 TNFRSF1A Zornitza Stark Marked gene: TNFRSF1A as ready
BabyScreen+ newborn screening v0.1988 TNFRSF1A Zornitza Stark Gene: tnfrsf1a has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1988 TNFRSF1A Zornitza Stark Classified gene: TNFRSF1A as Red List (low evidence)
BabyScreen+ newborn screening v0.1988 TNFRSF1A Zornitza Stark Gene: tnfrsf1a has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1987 TOP2B Zornitza Stark Marked gene: TOP2B as ready
BabyScreen+ newborn screening v0.1987 TOP2B Zornitza Stark Gene: top2b has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1987 TOP2B Zornitza Stark Classified gene: TOP2B as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.1987 TOP2B Zornitza Stark Gene: top2b has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1986 TOP2B Zornitza Stark reviewed gene: TOP2B: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: B-cell immunodeficiency, distal limb anomalies, and urogenital malformations MIM#609296; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
BabyScreen+ newborn screening v0.1986 TPK1 Zornitza Stark Marked gene: TPK1 as ready
BabyScreen+ newborn screening v0.1986 TPK1 Zornitza Stark Gene: tpk1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1986 TPK1 Zornitza Stark Classified gene: TPK1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1986 TPK1 Zornitza Stark Gene: tpk1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1985 TPK1 Zornitza Stark Tag treatable tag was added to gene: TPK1.
Tag metabolic tag was added to gene: TPK1.
BabyScreen+ newborn screening v0.1985 TRNT1 Zornitza Stark Marked gene: TRNT1 as ready
BabyScreen+ newborn screening v0.1985 TRNT1 Zornitza Stark Gene: trnt1 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1985 TRNT1 Zornitza Stark Classified gene: TRNT1 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.1985 TRNT1 Zornitza Stark Gene: trnt1 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1984 TRNT1 Zornitza Stark Tag treatable tag was added to gene: TRNT1.
Tag immunological tag was added to gene: TRNT1.
BabyScreen+ newborn screening v0.1984 TRNT1 Zornitza Stark reviewed gene: TRNT1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay MIM#616084; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1984 TRPM6 Zornitza Stark Marked gene: TRPM6 as ready
BabyScreen+ newborn screening v0.1984 TRPM6 Zornitza Stark Gene: trpm6 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1984 TRPM6 Zornitza Stark Classified gene: TRPM6 as Green List (high evidence)
BabyScreen+ newborn screening v0.1984 TRPM6 Zornitza Stark Gene: trpm6 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1983 TRPM6 Zornitza Stark Tag treatable tag was added to gene: TRPM6.
Tag endocrine tag was added to gene: TRPM6.
BabyScreen+ newborn screening v0.1983 UCP2 Zornitza Stark Marked gene: UCP2 as ready
BabyScreen+ newborn screening v0.1983 UCP2 Zornitza Stark Gene: ucp2 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1983 UCP2 Zornitza Stark Publications for gene: UCP2 were set to
BabyScreen+ newborn screening v0.1982 TNFRSF1A Lilian Downie gene: TNFRSF1A was added
gene: TNFRSF1A was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: TNFRSF1A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TNFRSF1A were set to PMID: 11175303, PMID: 32066461, PMID: 29773275, PMID: 32831641
Phenotypes for gene: TNFRSF1A were set to Periodic fever, familial MIM#142680
Penetrance for gene: TNFRSF1A were set to Incomplete
Review for gene: TNFRSF1A was set to RED
Added comment: Strong gene disease association
Childhood onset but age not consistently under 5 and cases of adult onset
reports of variable penetrance
Rx
NSAIDs, corticosteroids, Etanercept , anakinra, canakinumab, tocilizumab

because there is no non-molecular confirmatory test I think should be red for variability of age of onset and severity of symptoms.
Sources: Expert list
BabyScreen+ newborn screening v0.1982 TOP2B Lilian Downie gene: TOP2B was added
gene: TOP2B was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: TOP2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TOP2B were set to PMID: 31409799, PMID: 35063500, PMID: 32128574, PMID: 33459963
Phenotypes for gene: TOP2B were set to B-cell immunodeficiency, distal limb anomalies, and urogenital malformations MIM#609296
Review for gene: TOP2B was set to AMBER
Added comment: congenital onset
humoral immunodeficiency with undetectable B cells, distal limb anomalies, dysmorphic facial features, and urogenital malformations

Treatment immunoglobulin (only partially treats phenotype) no literature for evidence around immunoglobulin treatment.

Suggest RED but maybe discuss with immunologist?
Sources: Expert list
BabyScreen+ newborn screening v0.1982 TPK1 Lilian Downie gene: TPK1 was added
gene: TPK1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: TPK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TPK1 were set to PMID: 33086386, 32679198, 22152682, PMID: 33231275
Phenotypes for gene: TPK1 were set to Thiamine metabolism dysfunction syndrome 5 (episodic encephalopathy type) MIM#614458
Review for gene: TPK1 was set to GREEN
Added comment: Strong gene disease association
Variable age of onset but always under 5years

Thiamine metabolism dysfunction syndrome-5 (THMD5) is an autosomal recessive metabolic disorder due to an inborn error of thiamine metabolism. The phenotype is highly variable, but in general, affected individuals have onset in early childhood of acute encephalopathic episodes associated with increased serum and CSF lactate. These episodes result in progressive neurologic dysfunction manifest as gait disturbances, ataxia, dystonia, and spasticity, which in some cases may result in loss of ability to walk. Cognitive function is usually preserved, although mildly delayed development has been reported. These episodes are usually associated with infection and metabolic decompensation. Some patients may have recovery of some neurologic deficits (Mayr et al., 2011).

Biotin and thiamine therapy - newer evidence (2021) suggests early thiamine therapy may prevent any neurologic deficits.
Sources: Expert list
BabyScreen+ newborn screening v0.1982 TRNT1 Lilian Downie gene: TRNT1 was added
gene: TRNT1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: TRNT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRNT1 were set to PMID: 25193871, PMID: 23553769, PMID: 33936027, PMID: 26494905
Phenotypes for gene: TRNT1 were set to Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay MIM#616084
Review for gene: TRNT1 was set to AMBER
Added comment: Onset infancy
Strong gene disease association

Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD) is an autosomal recessive syndromic disorder characterized by onset of severe sideroblastic anemia in the neonatal period or infancy. Affected individuals show delayed psychomotor development with variable neurodegeneration. Recurrent periodic fevers without an infectious etiology occur throughout infancy and childhood; immunologic work-up shows B-cell lymphopenia and hypogammaglobulinemia. Other more variable features include sensorineural hearing loss, retinitis pigmentosa, nephrocalcinosis, and cardiomyopathy. Death in the first decade may occur (summary by Wiseman et al., 2013).

Bone marrow transplant (hematopoietic stem cell transplantation (HSCT)), replacement immunoglobulin treatment

Allelic disease: Retinitis pigmentosa and erythrocytic microcytosis MIM#616959. Also AR.
DeLuca et al. (2016) concluded that hypomorphic TRNT1 mutations can cause a recessive disease that is almost entirely limited to the retina - this has teenage onset and is not treatable. can we exclude these variants?
Sources: Expert list
BabyScreen+ newborn screening v0.1982 TRPM6 Lilian Downie gene: TRPM6 was added
gene: TRPM6 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: TRPM6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRPM6 were set to PMID: 35903165, PMID: 18818955
Phenotypes for gene: TRPM6 were set to Hypomagnesemia 1, intestinal MIM#602014
Review for gene: TRPM6 was set to GREEN
Added comment: Hypomagnaesemia and hypocalcaemia
Hypocalcemia is a secondary consequence of parathyroid failure and parathyroid hormone resistance as a result of severe magnesium deficiency. The disease typically manifests during the first months of life with generalized convulsions or signs of increased neuromuscular excitability, such as muscle spasms or tetany. Untreated, the disease may be fatal or lead to severe neurologic damage. Treatment includes immediate administration of magnesium, usually intravenously, followed by life-long high-dose oral magnesium (review by Knoers, 2009).
Sources: Expert list
BabyScreen+ newborn screening v0.1982 UCP2 Lilian Downie reviewed gene: UCP2: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 28681398, PMID: 27967291; Phenotypes: UCP2 associated hyperinsulinism; Mode of inheritance: None
Hereditary Neuropathy_CMT - isolated v1.29 SPTLC1 Zornitza Stark Phenotypes for gene: SPTLC1 were changed from HSAN/SFN; Hereditary Sensory and Autonomic Neuropathy, Type II; Neuropathy, hereditary sensory and autonomic, type IA, 162400 to Juvenile amyotrophic lateral sclerosis-27, MIM#620285; HSAN/SFN; Hereditary Sensory and Autonomic Neuropathy, Type II; Neuropathy, hereditary sensory and autonomic, type IA, 162400
Hereditary Neuropathy_CMT - isolated v1.28 SPTLC1 Zornitza Stark edited their review of gene: SPTLC1: Changed phenotypes: Neuropathy, hereditary sensory and autonomic, type IA, MIM# 162400, Juvenile amyotrophic lateral sclerosis-27, MIM#620285
Mendeliome v1.732 SPTLC1 Zornitza Stark Phenotypes for gene: SPTLC1 were changed from Neuropathy, hereditary sensory and autonomic, type IA, MIM# 162400; Serine palmitoyl transferase deficiency (Disorders of complex lipid synthesis) to Juvenile amyotrophic lateral sclerosis-27, MIM#620285; Neuropathy, hereditary sensory and autonomic, type IA, MIM# 162400; Serine palmitoyl transferase deficiency (Disorders of complex lipid synthesis)
Mendeliome v1.731 SPTLC1 Zornitza Stark edited their review of gene: SPTLC1: Changed phenotypes: Juvenile amyotrophic lateral sclerosis-27, MIM#620285, Neuropathy, hereditary sensory and autonomic, type IA, MIM# 162400, Serine palmitoyl transferase deficiency (Disorders of complex lipid synthesis)
Hyperinsulinism v1.9 GLUD1 Zornitza Stark Mode of inheritance for gene: GLUD1 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hyperinsulinism v1.8 GLUD1 Zornitza Stark edited their review of gene: GLUD1: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fatty Acid Oxidation Defects v1.10 GLUD1 Zornitza Stark Mode of inheritance for gene: GLUD1 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fatty Acid Oxidation Defects v1.9 GLUD1 Zornitza Stark edited their review of gene: GLUD1: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.731 GLUD1 Zornitza Stark Mode of inheritance for gene: GLUD1 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.730 GLUD1 Zornitza Stark edited their review of gene: GLUD1: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.730 GLUD1 Zornitza Stark edited their review of gene: GLUD1: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1982 UNG Zornitza Stark Marked gene: UNG as ready
BabyScreen+ newborn screening v0.1982 UNG Zornitza Stark Gene: ung has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1982 UNG Zornitza Stark Classified gene: UNG as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.1982 UNG Zornitza Stark Gene: ung has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1981 UNG Zornitza Stark Tag treatable tag was added to gene: UNG.
Tag immunological tag was added to gene: UNG.
BabyScreen+ newborn screening v0.1981 UNG Zornitza Stark reviewed gene: UNG: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Immunodeficiency with hyper IgM, type 5 MIM#608106; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1981 UMPS Zornitza Stark Marked gene: UMPS as ready
BabyScreen+ newborn screening v0.1981 UMPS Zornitza Stark Gene: umps has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1981 UMPS Zornitza Stark Classified gene: UMPS as Green List (high evidence)
BabyScreen+ newborn screening v0.1981 UMPS Zornitza Stark Gene: umps has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1980 UMPS Zornitza Stark Tag for review tag was added to gene: UMPS.
Tag treatable tag was added to gene: UMPS.
Tag metabolic tag was added to gene: UMPS.
Neurodegeneration with brain iron accumulation v0.22 BCAS3 Zornitza Stark Marked gene: BCAS3 as ready
Neurodegeneration with brain iron accumulation v0.22 BCAS3 Zornitza Stark Gene: bcas3 has been classified as Green List (High Evidence).
Neurodegeneration with brain iron accumulation v0.22 BCAS3 Zornitza Stark Phenotypes for gene: BCAS3 were changed from spasticity; intellectual disability; global developmental delay; microcephaly; short stature to Hengel-Maroofian-Schols syndrome, MIM# 619641
Neurodegeneration with brain iron accumulation v0.21 BCAS3 Zornitza Stark Publications for gene: BCAS3 were set to DOI:10.1002/mds.28915 Corpus ID: 245670502
Neurodegeneration with brain iron accumulation v0.20 BCAS3 Zornitza Stark Classified gene: BCAS3 as Green List (high evidence)
Neurodegeneration with brain iron accumulation v0.20 BCAS3 Zornitza Stark Gene: bcas3 has been classified as Green List (High Evidence).
Neurodegeneration with brain iron accumulation v0.19 BCAS3 Zornitza Stark reviewed gene: BCAS3: Rating: GREEN; Mode of pathogenicity: None; Publications: 34981858; Phenotypes: Hengel-Maroofian-Schols syndrome, MIM# 619641; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Neurodegeneration with brain iron accumulation v0.19 AFG3L2 Zornitza Stark Marked gene: AFG3L2 as ready
Neurodegeneration with brain iron accumulation v0.19 AFG3L2 Zornitza Stark Gene: afg3l2 has been classified as Red List (Low Evidence).
Neurodegeneration with brain iron accumulation v0.19 AFG3L2 Zornitza Stark Phenotypes for gene: AFG3L2 were changed from ataxia; visual impairment; neuroregression to Spastic ataxia 5, autosomal recessive, MIM# 614487; Spinocerebellar ataxia 28, MIM# 610246
Neurodegeneration with brain iron accumulation v0.18 AFG3L2 Zornitza Stark Classified gene: AFG3L2 as Red List (low evidence)
Neurodegeneration with brain iron accumulation v0.18 AFG3L2 Zornitza Stark Gene: afg3l2 has been classified as Red List (Low Evidence).
Neurodegeneration with brain iron accumulation v0.17 AFG3L2 Zornitza Stark reviewed gene: AFG3L2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic ataxia 5, autosomal recessive, MIM# 614487, Spinocerebellar ataxia 28, MIM# 610246; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Neurodegeneration with brain iron accumulation v0.17 GTPBP2 Zornitza Stark Marked gene: GTPBP2 as ready
Neurodegeneration with brain iron accumulation v0.17 GTPBP2 Zornitza Stark Gene: gtpbp2 has been classified as Amber List (Moderate Evidence).
Neurodegeneration with brain iron accumulation v0.17 GTPBP2 Zornitza Stark Phenotypes for gene: GTPBP2 were changed from dystonia; ataxia; cognitive dysfunction; motor neuropathy; retinal abnormalities; sparse thin and brittle hair to Jaberi-Elahi syndrome, MIM# 617988
Neurodegeneration with brain iron accumulation v0.16 GTPBP2 Zornitza Stark Classified gene: GTPBP2 as Amber List (moderate evidence)
Neurodegeneration with brain iron accumulation v0.16 GTPBP2 Zornitza Stark Gene: gtpbp2 has been classified as Amber List (Moderate Evidence).
Neurodegeneration with brain iron accumulation v0.15 GTPBP2 Zornitza Stark reviewed gene: GTPBP2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Jaberi-Elahi syndrome, MIM# 617988; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1980 NLGN4X Zornitza Stark Marked gene: NLGN4X as ready
BabyScreen+ newborn screening v0.1980 NLGN4X Zornitza Stark Gene: nlgn4x has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1980 NLGN4X Zornitza Stark Phenotypes for gene: NLGN4X were changed from Autism to Intellectual developmental disorder, X-linked MIM#300495
BabyScreen+ newborn screening v0.1979 NLGN4X Zornitza Stark Mode of inheritance for gene: NLGN4X was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
BabyScreen+ newborn screening v0.1978 NLGN4X Zornitza Stark reviewed gene: NLGN4X: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, X-linked MIM#300495; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.730 NLGN4X Zornitza Stark Classified gene: NLGN4X as Green List (high evidence)
Mendeliome v1.730 NLGN4X Zornitza Stark Gene: nlgn4x has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5190 Zornitza Stark removed gene:MTSS1 from the panel
Microcephaly v1.195 Zornitza Stark removed gene:MTSS1 from the panel
Mendeliome v1.729 Zornitza Stark removed gene:MTSS1 from the panel
Autism v0.188 NLGN4X Elena Savva commented on gene: NLGN4X
Autism v0.188 NLGN4X Elena Savva Classified gene: NLGN4X as Green List (high evidence)
Autism v0.188 NLGN4X Elena Savva Gene: nlgn4x has been classified as Green List (High Evidence).
Mendeliome v1.728 TAB2 Achchuthan Shanmugasundram reviewed gene: TAB2: Rating: AMBER; Mode of pathogenicity: None; Publications: 35971781; Phenotypes: intellectual disability, MONDO:0001071; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
BabyScreen+ newborn screening v0.1978 HSD11B2 Zornitza Stark Marked gene: HSD11B2 as ready
BabyScreen+ newborn screening v0.1978 HSD11B2 Zornitza Stark Gene: hsd11b2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1978 HSD11B2 Zornitza Stark Classified gene: HSD11B2 as Green List (high evidence)
BabyScreen+ newborn screening v0.1978 HSD11B2 Zornitza Stark Gene: hsd11b2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1977 HSD11B2 Zornitza Stark gene: HSD11B2 was added
gene: HSD11B2 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, endocrine tags were added to gene: HSD11B2.
Mode of inheritance for gene: HSD11B2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: HSD11B2 were set to Apparent mineralocorticoid excess, MIM# 218030; MONDO:0009025
Review for gene: HSD11B2 was set to GREEN
Added comment: Apparent mineralocorticoid excess (AME) is an autosomal recessive form of low-renin hypertension associated with low aldosterone, metabolic alkalosis, hypernatremia, and hypokalemia. The disorder is due to a congenital defect in 11-beta-hydroxysteroid dehydrogenase type II (HSD11B2) activity, resulting in decreased conversion of biologically active cortisol to inactive cortisone; this defect allows cortisol to act as a ligand for the mineralocorticoid receptor, resulting in sodium retention and volume expansion. There is a favorable therapeutic response to spironolactone. More than 10 unrelated families reported.

Onset is usually in infancy or early childhood.

Non-genetic confirmatory testing: aldosterone, renin, potassium levels
Sources: Expert list
BabyScreen+ newborn screening v0.1976 HOGA1 Zornitza Stark Marked gene: HOGA1 as ready
BabyScreen+ newborn screening v0.1976 HOGA1 Zornitza Stark Gene: hoga1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1976 HOGA1 Zornitza Stark Classified gene: HOGA1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1976 HOGA1 Zornitza Stark Gene: hoga1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1975 HOGA1 Zornitza Stark gene: HOGA1 was added
gene: HOGA1 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, metabolic tags were added to gene: HOGA1.
Mode of inheritance for gene: HOGA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HOGA1 were set to 20797690; 21896830; 22391140
Phenotypes for gene: HOGA1 were set to Hyperoxaluria, primary, type III MIM#613616
Review for gene: HOGA1 was set to GREEN
Added comment: Well-established association with primary hyperoxaluria type III. c.700+5G>T is a recurrent pathogenic variant in European populations (possibly founder) and has high frequency in gnomad (0.2-0.3%).

Onset in infancy, progressive multi-system disorder.

Treatment: pyridoxine, drinking large volumes, alkalinzation of urine, pyrophosphate-containing solutions, liver-kidney transplant

Non-genetic confirmatory testing: urinary oxalate
Sources: Expert list
Neurodegeneration with brain iron accumulation v0.15 GTPBP2 Shekeeb Mohammad gene: GTPBP2 was added
gene: GTPBP2 was added to Neuroferritinopathies. Sources: Literature
Mode of inheritance for gene: GTPBP2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GTPBP2 were set to 26675814; 29449720
Phenotypes for gene: GTPBP2 were set to dystonia; ataxia; cognitive dysfunction; motor neuropathy; retinal abnormalities; sparse thin and brittle hair
Review for gene: GTPBP2 was set to GREEN
gene: GTPBP2 was marked as current diagnostic
Added comment: Sources: Literature
Neurodegeneration with brain iron accumulation v0.15 BCAS3 Shekeeb Mohammad gene: BCAS3 was added
gene: BCAS3 was added to Neuroferritinopathies. Sources: Expert Review,Literature
Mode of inheritance for gene: BCAS3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BCAS3 were set to DOI:10.1002/mds.28915 Corpus ID: 245670502
Phenotypes for gene: BCAS3 were set to spasticity; intellectual disability; global developmental delay; microcephaly; short stature
Penetrance for gene: BCAS3 were set to unknown
Review for gene: BCAS3 was set to GREEN
gene: BCAS3 was marked as current diagnostic
Added comment: Sources: Expert Review, Literature
Neurodegeneration with brain iron accumulation v0.15 AFG3L2 Shekeeb Mohammad gene: AFG3L2 was added
gene: AFG3L2 was added to Neuroferritinopathies. Sources: Literature
Mode of inheritance for gene: AFG3L2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: AFG3L2 were set to 32237276
Phenotypes for gene: AFG3L2 were set to ataxia; visual impairment; neuroregression
Review for gene: AFG3L2 was set to GREEN
gene: AFG3L2 was marked as current diagnostic
Added comment: Sources: Literature
Neurodegeneration with brain iron accumulation v0.15 SCP2 Shekeeb Mohammad edited their review of gene: SCP2: Changed rating: AMBER
Neurodegeneration with brain iron accumulation v0.15 SCP2 Shekeeb Mohammad reviewed gene: SCP2: Rating: RED; Mode of pathogenicity: None; Publications: 35996156; Phenotypes: progressive bulbar dysfunction, dementia, azoospermia, cardiac dysrhythmia; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
BabyScreen+ newborn screening v0.1974 UMPS Lilian Downie changed review comment from: megaloblastic anemia and orotic acid crystalluria that is frequently associated with some degree of physical and mental retardation. These features respond to appropriate pyrimidine replacement therapy, and most cases appear to have a good prognosis. A minority of cases have additional features, particularly congenital malformations and immune deficiencies, which may adversely affect this prognosis (summary by Webster et al., 2001).

Treat uridine
Very rare only 20 cases but treatable.
Sources: Expert list; to: megaloblastic anemia and orotic acid crystalluria that is frequently associated with some degree of physical and mental retardation. These features respond to appropriate pyrimidine replacement therapy, and most cases appear to have a good prognosis. A minority of cases have additional features, particularly congenital malformations and immune deficiencies, which may adversely affect this prognosis (summary by Webster et al., 2001).

Better check with John who wrote the paper!! PMID: 25030255

Treat uridine
Very rare only 20 cases but treatable.
Sources: Expert list
BabyScreen+ newborn screening v0.1974 UMPS Lilian Downie gene: UMPS was added
gene: UMPS was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: UMPS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UMPS were set to PMID: 9042911, PMID: 28205048, PMID: 25757096, PMID: 33489760
Phenotypes for gene: UMPS were set to Orotic aciduria MIM#258900
Review for gene: UMPS was set to GREEN
Added comment: megaloblastic anemia and orotic acid crystalluria that is frequently associated with some degree of physical and mental retardation. These features respond to appropriate pyrimidine replacement therapy, and most cases appear to have a good prognosis. A minority of cases have additional features, particularly congenital malformations and immune deficiencies, which may adversely affect this prognosis (summary by Webster et al., 2001).

Treat uridine
Very rare only 20 cases but treatable.
Sources: Expert list
BabyScreen+ newborn screening v0.1974 UNG Lilian Downie gene: UNG was added
gene: UNG was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: UNG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UNG were set to PubMed: 12958596, PMID: 15967827, PMID: 19202054, PMID: 16860315
Phenotypes for gene: UNG were set to Immunodeficiency with hyper IgM, type 5 MIM#608106
Review for gene: UNG was set to RED
Added comment: normal or increased serum IgM concentrations associated with low or absent serum IgG, IgA, and IgE concentrations.
susceptibility to bacterial infections, lymphoid hyperplasia
only 3 patients reported in a single paper ?
Rx immunoglobulin replacement according to Rx genes but I can't find actual papers - i don't think there is enough evidence regarding age of onset or treatability.
Sources: Expert list
BabyScreen+ newborn screening v0.1974 HELLS Zornitza Stark Marked gene: HELLS as ready
BabyScreen+ newborn screening v0.1974 HELLS Zornitza Stark Gene: hells has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1974 HELLS Zornitza Stark Classified gene: HELLS as Green List (high evidence)
BabyScreen+ newborn screening v0.1974 HELLS Zornitza Stark Gene: hells has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1973 HELLS Zornitza Stark Tag treatable tag was added to gene: HELLS.
Tag immunological tag was added to gene: HELLS.
BabyScreen+ newborn screening v0.1973 HELLS Zornitza Stark gene: HELLS was added
gene: HELLS was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: HELLS was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: HELLS were set to Immunodeficiency-centromeric instability-facial anomalies syndrome 4, MIM# 616911
Review for gene: HELLS was set to GREEN
Added comment: Congenital onset.

Immunodeficiency-centromeric instability-facial anomalies syndrome-4 is characterized by recurrent infections in childhood and variable dysmorphic facial features. Laboratory studies show hypomethylation of certain chromosomal regions. Additional features, including delayed development, are variable. At least 4 unrelated families reported.

Treatment: bone marrow transplant.
Sources: Expert list
BabyScreen+ newborn screening v0.1972 USP18 Zornitza Stark Marked gene: USP18 as ready
BabyScreen+ newborn screening v0.1972 USP18 Zornitza Stark Gene: usp18 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1972 USP18 Zornitza Stark Classified gene: USP18 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.1972 USP18 Zornitza Stark Gene: usp18 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1971 USP18 Zornitza Stark reviewed gene: USP18: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Pseudo-TORCH syndrome 2 MIM#617397; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1971 VKORC1 Zornitza Stark Marked gene: VKORC1 as ready
BabyScreen+ newborn screening v0.1971 VKORC1 Zornitza Stark Gene: vkorc1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1971 VKORC1 Zornitza Stark Mode of inheritance for gene: VKORC1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1970 VKORC1 Zornitza Stark Classified gene: VKORC1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1970 VKORC1 Zornitza Stark Gene: vkorc1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1969 VKORC1 Zornitza Stark Tag treatable tag was added to gene: VKORC1.
Tag haematological tag was added to gene: VKORC1.
BabyScreen+ newborn screening v0.1969 VKORC1 Zornitza Stark reviewed gene: VKORC1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Vitamin K-dependent clotting factors, combined deficiency of, 2 MIM#607473; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1969 WDR1 Zornitza Stark Marked gene: WDR1 as ready
BabyScreen+ newborn screening v0.1969 WDR1 Zornitza Stark Gene: wdr1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1969 WDR1 Zornitza Stark Classified gene: WDR1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1969 WDR1 Zornitza Stark Gene: wdr1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1968 WDR1 Zornitza Stark Tag treatable tag was added to gene: WDR1.
Tag immunological tag was added to gene: WDR1.
Tag haematological tag was added to gene: WDR1.
Mendeliome v1.728 ACTA1 Zornitza Stark Phenotypes for gene: ACTA1 were changed from Myopathy, actin, congenital, with cores, MIM#161800; Myopathy, actin, congenital, with excess of thin myofilaments, MIM#161800; Myopathy, congenital, with fiber-type disproportion 1, MIM#255310; Nemaline myopathy 3, MIM#161800; ?Myopathy, scapulohumeroperoneal to Congenital myopathy 2C, severe infantile, autosomal dominant, MIM# 620278; Myopathy, actin, congenital, with cores, MIM#161800; Myopathy, actin, congenital, with excess of thin myofilaments, MIM#161800; Myopathy, congenital, with fiber-type disproportion 1, MIM#255310; Nemaline myopathy 3, MIM#161800; ?Myopathy, scapulohumeroperoneal
Mendeliome v1.727 ACTA1 Zornitza Stark reviewed gene: ACTA1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Congenital myopathy 2C, severe infantile, autosomal dominant, MIM# 620278; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
BabyScreen+ newborn screening v0.1968 GPIHBP1 Zornitza Stark Marked gene: GPIHBP1 as ready
BabyScreen+ newborn screening v0.1968 GPIHBP1 Zornitza Stark Gene: gpihbp1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1968 GPIHBP1 Zornitza Stark Classified gene: GPIHBP1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1968 GPIHBP1 Zornitza Stark Gene: gpihbp1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1967 GPIHBP1 Zornitza Stark Tag treatable tag was added to gene: GPIHBP1.
Tag metabolic tag was added to gene: GPIHBP1.
BabyScreen+ newborn screening v0.1967 GPIHBP1 Zornitza Stark gene: GPIHBP1 was added
gene: GPIHBP1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: GPIHBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GPIHBP1 were set to 31390500
Phenotypes for gene: GPIHBP1 were set to Hyperlipoproteinemia, type 1D MIM#615947; familial chylomicronemia syndrome
Review for gene: GPIHBP1 was set to GREEN
Added comment: Well-established gene-disease association.

Usually presents in childhood with episodes of abdominal pain, recurrent acute pancreatitis, eruptive cutaneous xanthomata, and hepatosplenomegaly.

Approximately 25% of affected children develop symptoms before age one year and the majority develop symptoms before age ten years; however, some individuals present for the first time during pregnancy.

Treatment: volanesorsen, dietary fat restriction

Non-genetic confirmatory testing: triglyceride level
Sources: Expert list
BabyScreen+ newborn screening v0.1966 GHRHR Zornitza Stark Marked gene: GHRHR as ready
BabyScreen+ newborn screening v0.1966 GHRHR Zornitza Stark Gene: ghrhr has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1966 GHRHR Zornitza Stark Classified gene: GHRHR as Green List (high evidence)
BabyScreen+ newborn screening v0.1966 GHRHR Zornitza Stark Gene: ghrhr has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1965 GHRHR Zornitza Stark Tag treatable tag was added to gene: GHRHR.
Tag endocrine tag was added to gene: GHRHR.
BabyScreen+ newborn screening v0.1965 GHRHR Zornitza Stark gene: GHRHR was added
gene: GHRHR was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: GHRHR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GHRHR were set to 8528260; 10084571; 11232012
Phenotypes for gene: GHRHR were set to Growth hormone deficiency, isolated, type IV, MIM# 618157
Review for gene: GHRHR was set to GREEN
Added comment: IGHD type IV is characterized by early and severe growth failure (height SDS up to -7.4), a blunted growth hormone (GH) response to different provocation tests and low insulin-like growth factor-I and IGF-binding protein-3 concentrations, and a good response to growth hormone treatment. At least three unrelated families reported.

Non-genetic confirmatory testing: growth hormone stimulation test
Sources: Expert list
BabyScreen+ newborn screening v0.1964 GHR Zornitza Stark Marked gene: GHR as ready
BabyScreen+ newborn screening v0.1964 GHR Zornitza Stark Gene: ghr has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1964 GHR Zornitza Stark Classified gene: GHR as Green List (high evidence)
BabyScreen+ newborn screening v0.1964 GHR Zornitza Stark Gene: ghr has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1963 GHR Zornitza Stark Tag treatable tag was added to gene: GHR.
Tag endocrine tag was added to gene: GHR.
BabyScreen+ newborn screening v0.1963 GHR Zornitza Stark gene: GHR was added
gene: GHR was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: GHR was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: GHR were set to Growth hormone insensitivity, partial, MIM# 604271; Laron dwarfism, MIM# 262500
Review for gene: GHR was set to GREEN
Added comment: Well established gene-disease association.

Congenital onset.

Treatment: growth hormone.

Non-genetic confirmatory testing: growth hormone stimulation test
Sources: Expert list
BabyScreen+ newborn screening v0.1962 GH1 Zornitza Stark Marked gene: GH1 as ready
BabyScreen+ newborn screening v0.1962 GH1 Zornitza Stark Gene: gh1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1962 GH1 Zornitza Stark Classified gene: GH1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1962 GH1 Zornitza Stark Gene: gh1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1961 GH1 Zornitza Stark Tag treatable tag was added to gene: GH1.
Tag endocrine tag was added to gene: GH1.
BabyScreen+ newborn screening v0.1961 GH1 Zornitza Stark gene: GH1 was added
gene: GH1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: GH1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: GH1 were set to Growth hormone deficiency, isolated, type IA, MIM# 262400; Growth hormone deficiency, isolated, type II, MIM# 173100; Kowarski syndrome, MIM# 262650
Review for gene: GH1 was set to GREEN
Added comment: Well established gene-disease association. Congenital onset.

Treatment: growth hormone.

Non-genetic confirmatory test: growth hormone stimulation test
Sources: Expert list
BabyScreen+ newborn screening v0.1960 GFI1 Zornitza Stark Marked gene: GFI1 as ready
BabyScreen+ newborn screening v0.1960 GFI1 Zornitza Stark Gene: gfi1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1960 GFI1 Zornitza Stark Classified gene: GFI1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1960 GFI1 Zornitza Stark Gene: gfi1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1959 GFI1 Zornitza Stark gene: GFI1 was added
gene: GFI1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: GFI1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GFI1 were set to 12778173; 20560965; 11810106; 22684987
Phenotypes for gene: GFI1 were set to Neutropenia, severe congenital 2, autosomal dominant, MIM# 613107
Review for gene: GFI1 was set to GREEN
Added comment: At least three unrelated families reported, and supportive functional data.

Severe congenital immunodeficiency.

Treatment: granulocyte colony-stimulating factor (G-CSF), Bone marrow transplant

Non-genetic confirmatory testing: FBE.
Sources: Expert list
Neurodegeneration with brain iron accumulation v0.15 Zornitza Stark Panel types changed to Victorian Clinical Genetics Services; Royal Melbourne Hospital; Rare Disease
Neurodegeneration with brain iron accumulation v0.14 SCP2 Zornitza Stark Phenotypes for gene: SCP2 were changed from Neurodegeneration with brain iron accumulation; ataxia to Leukoencephalopathy with dystonia and motor neuropathy, MIM#613724; Neurodegeneration with brain iron accumulation; ataxia
Neurodegeneration with brain iron accumulation v0.13 SCP2 Zornitza Stark Publications for gene: SCP2 were set to 26497993
Neurodegeneration with brain iron accumulation v0.12 SCP2 Zornitza Stark Classified gene: SCP2 as Amber List (moderate evidence)
Neurodegeneration with brain iron accumulation v0.12 SCP2 Zornitza Stark Gene: scp2 has been classified as Amber List (Moderate Evidence).
Neurodegeneration with brain iron accumulation v0.11 SCP2 Zornitza Stark reviewed gene: SCP2: Rating: AMBER; Mode of pathogenicity: None; Publications: 26497993; Phenotypes: Leukoencephalopathy with dystonia and motor neuropathy, MIM#613724; Mode of inheritance: None
Mendeliome v1.727 REPS1 Zornitza Stark Marked gene: REPS1 as ready
Mendeliome v1.727 REPS1 Zornitza Stark Gene: reps1 has been classified as Red List (Low Evidence).
Mendeliome v1.727 REPS1 Zornitza Stark gene: REPS1 was added
gene: REPS1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: REPS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: REPS1 were set to 29395073
Phenotypes for gene: REPS1 were set to Neurodegeneration with brain iron accumulation 7 , MIM# 617916
Review for gene: REPS1 was set to RED
Added comment: Two siblings reported with compound het missense variants in this gene and a neurodegenerative course in childhood.
Sources: Literature
Neurodegeneration with brain iron accumulation v0.11 REPS1 Zornitza Stark Marked gene: REPS1 as ready
Neurodegeneration with brain iron accumulation v0.11 REPS1 Zornitza Stark Gene: reps1 has been classified as Red List (Low Evidence).
Neurodegeneration with brain iron accumulation v0.11 REPS1 Zornitza Stark gene: REPS1 was added
gene: REPS1 was added to Neuroferritinopathies. Sources: Literature
Mode of inheritance for gene: REPS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: REPS1 were set to 29395073
Phenotypes for gene: REPS1 were set to Neurodegeneration with brain iron accumulation 7 , MIM# 617916
Review for gene: REPS1 was set to RED
Added comment: Two siblings reported with compound het missense variants in this gene and a neurodegenerative course in childhood.
Sources: Literature
Hydrops fetalis v0.298 GLA Zornitza Stark Marked gene: GLA as ready
Hydrops fetalis v0.298 GLA Zornitza Stark Gene: gla has been classified as Red List (Low Evidence).
Hydrops fetalis v0.298 GLA Zornitza Stark Phenotypes for gene: GLA were changed from to Fabry disease, MIM# 301500
Hydrops fetalis v0.297 GLA Zornitza Stark Mode of inheritance for gene: GLA was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Hydrops fetalis v0.296 GLA Zornitza Stark Classified gene: GLA as Red List (low evidence)
Hydrops fetalis v0.296 GLA Zornitza Stark Gene: gla has been classified as Red List (Low Evidence).
Hydrops fetalis v0.295 GLA Zornitza Stark reviewed gene: GLA: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Fabry disease, MIM# 301500; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.726 MCF2L Zornitza Stark Mode of inheritance for gene: MCF2L was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.276 MCF2L Zornitza Stark Marked gene: MCF2L as ready
Congenital Heart Defect v0.276 MCF2L Zornitza Stark Gene: mcf2l has been classified as Red List (Low Evidence).
Congenital Heart Defect v0.276 MCF2L Zornitza Stark Mode of inheritance for gene: MCF2L was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital Heart Defect v0.275 MCF2L Zornitza Stark Classified gene: MCF2L as Red List (low evidence)
Congenital Heart Defect v0.275 MCF2L Zornitza Stark Gene: mcf2l has been classified as Red List (Low Evidence).
Mendeliome v1.725 FTH1 Zornitza Stark Phenotypes for gene: FTH1 were changed from Hemochromatosis, type 5, MIM# 615517 to Hemochromatosis, type 5, MIM# 615517; Neuroferritinopathy (MONDO:0011638)
Mendeliome v1.724 FTH1 Zornitza Stark Publications for gene: FTH1 were set to 11389486
Mendeliome v1.723 FTH1 Zornitza Stark Classified gene: FTH1 as Amber List (moderate evidence)
Mendeliome v1.723 FTH1 Zornitza Stark Gene: fth1 has been classified as Amber List (Moderate Evidence).
Regression v0.521 FTH1 Zornitza Stark Marked gene: FTH1 as ready
Regression v0.521 FTH1 Zornitza Stark Gene: fth1 has been classified as Amber List (Moderate Evidence).
Regression v0.521 FTH1 Zornitza Stark Classified gene: FTH1 as Amber List (moderate evidence)
Regression v0.521 FTH1 Zornitza Stark Gene: fth1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.722 TLN1 Zornitza Stark Phenotypes for gene: TLN1 were changed from idiopathic spontaneous coronary artery dissection MONDO:0007385 to idiopathic spontaneous coronary artery dissection MONDO:0007385; thrombocytopenia, MONDO:0002049, TLN1-related
Mendeliome v1.721 TLN1 Zornitza Stark Publications for gene: TLN1 were set to 30888838
Bleeding and Platelet Disorders v1.18 TLN1 Zornitza Stark Marked gene: TLN1 as ready
Bleeding and Platelet Disorders v1.18 TLN1 Zornitza Stark Gene: tln1 has been classified as Red List (Low Evidence).
Bleeding and Platelet Disorders v1.18 TLN1 Zornitza Stark Phenotypes for gene: TLN1 were changed from thrombocytopenia, MONDO:0002049 to thrombocytopenia, MONDO:0002049, TLN1-related
Bleeding and Platelet Disorders v1.17 TLN1 Zornitza Stark Classified gene: TLN1 as Red List (low evidence)
Bleeding and Platelet Disorders v1.17 TLN1 Zornitza Stark Gene: tln1 has been classified as Red List (Low Evidence).
Mendeliome v1.720 DPYSL2 Zornitza Stark Marked gene: DPYSL2 as ready
Mendeliome v1.720 DPYSL2 Zornitza Stark Gene: dpysl2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.720 DPYSL2 Zornitza Stark Classified gene: DPYSL2 as Amber List (moderate evidence)
Mendeliome v1.720 DPYSL2 Zornitza Stark Gene: dpysl2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.719 DPYSL2 Zornitza Stark gene: DPYSL2 was added
gene: DPYSL2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: DPYSL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DPYSL2 were set to 27249678; 35861646
Phenotypes for gene: DPYSL2 were set to intellectual disability, MONDO:0001071, DPYSL2-related
Review for gene: DPYSL2 was set to AMBER
Added comment: Two unrelated cases with monoallelic variants in DPYSL2/ CRMP2, supported by functional studies. However, the evidence is not sufficient for green rating as there are variants reported in other (but different) genes in the two patients.

PMID:35861646 reported two cases identified with heterozygous variants (patient1: c.1693C>T (p.Arg565Cys); patient 2: c.42C>A (p.Ser14Arg). These patients had overlapping phenotypes including dysmorphic features, severe global developmental delay and hypoplasia of the corpus callosum. In addition, patient 2 was bed-ridden and could not roll out and had a history of myoclonic seizures and status epilepticus.

It should be noted that patient 1 is compound heterozygous for 2 missense variants in the EFCAB5 gene and was hemizygous for a maternally inherited missense variant in the GPKOW gene and patient 2 had 1 de novo missense variant in the COBLL1 gene and was compound heterozygous for 2 missense variants in the POTEF gene. The severity of the phenotypes between the two cases differs significantly and the additional variants may have possibly contributed to this phenotype.

Brain-specific Crmp2 knockout mice display neuronal development deficits and behavioural impairments associated with hypoplasia of the corpus callosum. In addition, functional studies performed in zebrafish and cell lines that the CRMP2 variants lead to the loss-of-function of CRMP2 protein and can cause intellectual disability.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5189 DPYSL2 Zornitza Stark Marked gene: DPYSL2 as ready
Intellectual disability syndromic and non-syndromic v0.5189 DPYSL2 Zornitza Stark Gene: dpysl2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5189 DPYSL2 Zornitza Stark Phenotypes for gene: DPYSL2 were changed from intellectual disability, MONDO:0001071; Aplasia/Hypoplasia of the corpus callosum, HP:0007370 to intellectual disability, MONDO:0001071, DPYSL2-related
Intellectual disability syndromic and non-syndromic v0.5188 DPYSL2 Zornitza Stark Classified gene: DPYSL2 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.5188 DPYSL2 Zornitza Stark Gene: dpysl2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5187 CTR9 Zornitza Stark Publications for gene: CTR9 were set to PMID: 35499524
Mendeliome v1.718 RBSN Zornitza Stark Marked gene: RBSN as ready
Mendeliome v1.718 RBSN Zornitza Stark Gene: rbsn has been classified as Green List (High Evidence).
Mendeliome v1.718 RBSN Zornitza Stark Classified gene: RBSN as Green List (high evidence)
Mendeliome v1.718 RBSN Zornitza Stark Gene: rbsn has been classified as Green List (High Evidence).
Mendeliome v1.717 RBSN Zornitza Stark gene: RBSN was added
gene: RBSN was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RBSN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RBSN were set to 25233840; 29784638; 35652444
Phenotypes for gene: RBSN were set to intellectual disability, MONDO:0001071, RBSN-related
Review for gene: RBSN was set to GREEN
Added comment: Four unrelated families reported, consistent feature is ID.

PMID:25233840 reported a 6.5 year old female patient with a homozygous missense variant c.1273G > A (p.Gly425Arg) and her clinical presentation included intractable seizures, developmental delay, microcephaly, dysostosis, osteopenia, craniofacial dysmorphism, macrocytosis and megaloblastoid erythropoiesis.

PMID:29784638 reported three siblings with homozygous variant c.289G>C (p.Gly97Arg) in RBSN. The proband presented global developmental delay, had complete 46,XY male-to-female sex reversal and died at age 20 months after multiple infections. The other 2 affected siblings underwent unrelated-donor bone marrow or stem cell transplantation at 8 and 6.5 months of age, respectively. Both have severe intellectual disability and are nonambulatory and nonverbal.

PMID:35652444 reported two unrelated families (three siblings from a family of Iranian descent identified with homozygous variant c.547G>A (p.Gly183Arg) and four members from a family of indigenous Cree descent identified with homozygous variant c.538C>G (p.Arg180Gly)) with overlapping phenotypes including developmental delay, intellectual disability, distal motor axonal neuropathy and facial dysmorphism.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5186 RBSN Zornitza Stark Marked gene: RBSN as ready
Intellectual disability syndromic and non-syndromic v0.5186 RBSN Zornitza Stark Gene: rbsn has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5186 RBSN Zornitza Stark Classified gene: RBSN as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5186 RBSN Zornitza Stark Gene: rbsn has been classified as Green List (High Evidence).
Mendeliome v1.716 SRPRA Zornitza Stark Marked gene: SRPRA as ready
Mendeliome v1.716 SRPRA Zornitza Stark Gene: srpra has been classified as Amber List (Moderate Evidence).
Mendeliome v1.716 SRPRA Zornitza Stark Classified gene: SRPRA as Amber List (moderate evidence)
Mendeliome v1.716 SRPRA Zornitza Stark Gene: srpra has been classified as Amber List (Moderate Evidence).
Mendeliome v1.715 SRPRA Zornitza Stark gene: SRPRA was added
gene: SRPRA was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SRPRA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SRPRA were set to 36223592
Phenotypes for gene: SRPRA were set to Schwachman-Diamond syndrome MONDO:0009833, SRPA-related
Review for gene: SRPRA was set to AMBER
Added comment: De novo variant; zebrafish model. Schwachman-Diamond like.
Sources: Literature
Phagocyte Defects v1.14 SRPRA Zornitza Stark Marked gene: SRPRA as ready
Phagocyte Defects v1.14 SRPRA Zornitza Stark Gene: srpra has been classified as Amber List (Moderate Evidence).
Phagocyte Defects v1.14 SRPRA Zornitza Stark Phenotypes for gene: SRPRA were changed from neutropenia; myeloid maturation arrest; exocrine pancreatic insufficiency; growth deficiency to Schwachman-Diamond syndrome MONDO:0009833, SRPA-related
Phagocyte Defects v1.14 SRPRA Zornitza Stark Classified gene: SRPRA as Amber List (moderate evidence)
Phagocyte Defects v1.14 SRPRA Zornitza Stark Gene: srpra has been classified as Amber List (Moderate Evidence).
Phagocyte Defects v1.13 SRPRA Zornitza Stark Classified gene: SRPRA as Amber List (moderate evidence)
Phagocyte Defects v1.13 SRPRA Zornitza Stark Gene: srpra has been classified as Amber List (Moderate Evidence).
Phagocyte Defects v1.12 SRPRA Zornitza Stark reviewed gene: SRPRA: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Schwachman-Diamond syndrome MONDO:0009833, SRPA-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Bone Marrow Failure v1.32 SRPRA Zornitza Stark Marked gene: SRPRA as ready
Bone Marrow Failure v1.32 SRPRA Zornitza Stark Gene: srpra has been classified as Amber List (Moderate Evidence).
Bone Marrow Failure v1.32 SRPRA Zornitza Stark Phenotypes for gene: SRPRA were changed from neutropenia; myeloid maturation arrest; exocrine pancreatic insufficiency; growth deficiency to Schwachman-Diamond syndrome MONDO:0009833, SRPA-related
Bone Marrow Failure v1.31 SRPRA Zornitza Stark Classified gene: SRPRA as Amber List (moderate evidence)
Bone Marrow Failure v1.31 SRPRA Zornitza Stark Gene: srpra has been classified as Amber List (Moderate Evidence).
Bone Marrow Failure v1.30 SRPRA Zornitza Stark reviewed gene: SRPRA: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Schwachman-Diamond syndrome MONDO:0009833, SRPA-relatted; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.714 SRP19 Zornitza Stark Marked gene: SRP19 as ready
Mendeliome v1.714 SRP19 Zornitza Stark Gene: srp19 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.714 SRP19 Zornitza Stark Classified gene: SRP19 as Amber List (moderate evidence)
Mendeliome v1.714 SRP19 Zornitza Stark Gene: srp19 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.713 SRP19 Zornitza Stark gene: SRP19 was added
gene: SRP19 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SRP19 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SRP19 were set to 36223592
Phenotypes for gene: SRP19 were set to Neutropenia, MONDO:0001475, SRP19-related
Review for gene: SRP19 was set to AMBER
Added comment: Five individuals from two branches of a consanguineous family, good segregation data. Zebrafish model.
Sources: Literature
Bone Marrow Failure v1.30 SRP19 Zornitza Stark Classified gene: SRP19 as Amber List (moderate evidence)
Bone Marrow Failure v1.30 SRP19 Zornitza Stark Gene: srp19 has been classified as Amber List (Moderate Evidence).
Bone Marrow Failure v1.29 SRP19 Zornitza Stark edited their review of gene: SRP19: Added comment: Five individuals from two branches of a consanguineous family, good segregation data. Zebrafish model.; Changed rating: AMBER
Phagocyte Defects v1.12 SRP19 Zornitza Stark changed review comment from: Five individuals from two branches of a consanguineous family, good segregation data. Zebrafish model.; to: Five individuals from two branches of a consanguineous family, good segregation data. Zebrafish model.
Phagocyte Defects v1.12 SRP19 Zornitza Stark Marked gene: SRP19 as ready
Phagocyte Defects v1.12 SRP19 Zornitza Stark Gene: srp19 has been classified as Amber List (Moderate Evidence).
Phagocyte Defects v1.12 SRP19 Zornitza Stark Phenotypes for gene: SRP19 were changed from neutropenia; myeloid maturation arrest; growth deficiency to Neutropenia, MONDO:0001475, SRP19-related
Phagocyte Defects v1.11 SRP19 Zornitza Stark Classified gene: SRP19 as Amber List (moderate evidence)
Phagocyte Defects v1.11 SRP19 Zornitza Stark Gene: srp19 has been classified as Amber List (Moderate Evidence).
Phagocyte Defects v1.10 SRP19 Zornitza Stark edited their review of gene: SRP19: Added comment: Five individuals from two branches of a consanguineous family, good segregation data. Zebrafish model.; Changed rating: AMBER
Bone Marrow Failure v1.29 SRP19 Zornitza Stark Marked gene: SRP19 as ready
Bone Marrow Failure v1.29 SRP19 Zornitza Stark Gene: srp19 has been classified as Red List (Low Evidence).
Bone Marrow Failure v1.29 SRP19 Zornitza Stark Phenotypes for gene: SRP19 were changed from Neutropenia, MONDO:0001475, SRP19-related to Neutropenia, MONDO:0001475, SRP19-related
Bone Marrow Failure v1.29 SRP19 Zornitza Stark Phenotypes for gene: SRP19 were changed from neutropenia; myeloid maturation arrest; growth deficiency to Neutropenia, MONDO:0001475, SRP19-related
Phagocyte Defects v1.10 SRP19 Zornitza Stark reviewed gene: SRP19: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neutropenia, MONDO:0001475, SRP19-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Bone Marrow Failure v1.28 SRP19 Zornitza Stark Classified gene: SRP19 as Red List (low evidence)
Bone Marrow Failure v1.28 SRP19 Zornitza Stark Gene: srp19 has been classified as Red List (Low Evidence).
Bone Marrow Failure v1.27 SRP19 Zornitza Stark reviewed gene: SRP19: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Neutropenia, MONDO:0001475, SRP19-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.712 ATP5B Zornitza Stark Publications for gene: ATP5B were set to 36860166
Mendeliome v1.711 ATP5B Zornitza Stark changed review comment from: Two families only, clinical presentation with dystonia; incomplete penetrance observed. Some functional data.

Note also PMID 36239646 reporting de novo variant in identical twins with hypermetabolism.
Sources: Literature; to: PMID 36860166: Two families only, clinical presentation with dystonia; incomplete penetrance observed. Some functional data.

Note also PMID 36239646 reporting de novo variant in identical twins with hypermetabolism.
Sources: Literature
Mendeliome v1.711 ATP5B Zornitza Stark edited their review of gene: ATP5B: Changed publications: 36860166, 36239646
Mendeliome v1.711 ATP5B Zornitza Stark changed review comment from: Two families only, clinical presentation with dystonia; incomplete penetrance observed. Some functional data.
Sources: Literature; to: Two families only, clinical presentation with dystonia; incomplete penetrance observed. Some functional data.

Note also PMID 36239646 reporting de novo variant in identical twins with hypermetabolism.
Sources: Literature
Mitochondrial disease v0.859 ATP5B Zornitza Stark Marked gene: ATP5B as ready
Mitochondrial disease v0.859 ATP5B Zornitza Stark Gene: atp5b has been classified as Amber List (Moderate Evidence).
Mitochondrial disease v0.859 ATP5B Zornitza Stark Classified gene: ATP5B as Amber List (moderate evidence)
Mitochondrial disease v0.859 ATP5B Zornitza Stark Gene: atp5b has been classified as Amber List (Moderate Evidence).
Mitochondrial disease v0.858 ATP5B Zornitza Stark gene: ATP5B was added
gene: ATP5B was added to Mitochondrial disease. Sources: Literature
Mode of inheritance for gene: ATP5B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP5B were set to 36860166; 36239646
Phenotypes for gene: ATP5B were set to Inherited dystonia, MONDO:0044807, ATP5B-related
Review for gene: ATP5B was set to AMBER
Added comment: PMID 36860166: Two families, clinical presentation with dystonia; incomplete penetrance observed. Some functional data.

ATP5F1B is a subunit of the mitochondrial ATP synthase or complex V of the mitochondrial respiratory chain.

Note also PMID 36239646 reporting de novo variant in identical twins with hypermetabolism.
Sources: Literature
Mendeliome v1.711 EPHA10 Achchuthan Shanmugasundram changed review comment from: Comment on rating: This gene should be rated RED as this gene has been associated with post-lingual autosomal dominant non-syndromic hearing loss from a single family, and supported by functional studies.

PMID:36048850 reported the identification of a heterozygous non-coding variant c.-81_-73delinsAGC cosegregating with hearing loss. Although variants have been identified in KIF17 and USP48 in several members of this family, they did not cosegregate with hearing loss. One affected member of this family had an ideal hearing restoration after cochlear implantation.

Epha10 was expressed in mouse cochlea at both transcription and translation levels. In addition, EPHA10 mRNA was detected upregulated in patients compared with controls by qRT-PCR. Overexpression of Eph (the homolog of human EPHA10) altered the structure and function of chordotonal organ (equivalent to mammalian auditory organs) in fly model. These functional evidence suggests that 'gain of function' may be responsible for the hearing loss phenotype.

This gene has not yet been associated with any phenotypes in OMIM or Gene2Phenotype.
Sources: Literature; to: Comment on rating: This gene should be rated RED as this gene has been associated with post-lingual autosomal dominant non-syndromic hearing loss from a single family, and supported by functional studies.

PMID:36048850 reported the identification of a heterozygous non-coding variant c.-81_-73delinsAGC cosegregating with hearing loss. Although variants have been identified in KIF17 and USP48 in several members of this family, they did not cosegregate with hearing loss. One affected member of this family had an ideal hearing restoration after cochlear implantation.

Epha10 was expressed in mouse cochlea at both transcription and translation levels. In addition, EPHA10 mRNA was detected upregulated in patients compared with controls by qRT-PCR. Overexpression of Eph (the homolog of human EPHA10) altered the structure and function of chordotonal organ (equivalent to mammalian auditory organs) in fly model. Particularly, Eph overexpressed flies had a poorer performance compared to controls in negative geotaxis assay. These functional evidence suggests that 'gain of function' may be responsible for the hearing loss phenotype.

This gene has not yet been associated with any phenotypes in OMIM or Gene2Phenotype.
Sources: Literature
Mendeliome v1.711 OXR1 Achchuthan Shanmugasundram changed review comment from: Comment on gene rating: This gene should be rated AMBER as there is one case and supportive functional data to associate OXR1 with hearing loss.

A four years old girl was identified with a novel homozygous missense variant (c.233A > G, p.Lys78Arg) in OXR1 gene and was reported with sensorineural hearing loss.

Functional studies in zebrafish model showed that the ortholog orx1b gene is expressed in the statoacoustic ganglion (SAG, a sensory ganglion of ear) and posterior lateral line ganglion (pLL). In addition, knockdown of oxr1b resulted in a significant developmental defect of SAG and pLL and this phenotype was rescued by co-injection of wild-type human OXR1 mRNAs, but not mutant OXR1 (c.233A > G) mRNAs.; to: Comment on gene rating: This gene should be rated AMBER as there is one case and supportive functional data to associate OXR1 with hearing loss.

A four years old girl was identified with a novel homozygous missense variant (c.233A > G, p.Lys78Arg) in OXR1 gene and was reported with sensorineural hearing loss.

Functional studies in zebrafish model showed that the ortholog orx1b gene is expressed in the statoacoustic ganglion (SAG, a sensory ganglion of ear) and posterior lateral line ganglion (pLL). In addition, knockdown of oxr1b resulted in a significant developmental defect of SAG and pLL and this phenotype was rescued by co-injection of wild-type human OXR1 mRNAs, but not mutant OXR1 (c.233A > G) mRNAs.

This gene has not yet been associated with hearing loss either in OMIM or in Gene2Phenotype.
Mendeliome v1.711 EPHA10 Achchuthan Shanmugasundram changed review comment from: Comment on rating: This gene should be rated RED as this gene has been associated with post-lingual autosomal dominant non-syndromic hearing loss from a single family, and supported by functional studies.

PMID:36048850 reported the identification of a heterozygous non-coding variant c.-81_-73delinsAGC cosegregating with hearing loss. Although variants have been identified in KIF17 and USP48 in several members of this family, they did not cosegregate with hearing loss. One affected member of this family had an ideal hearing restoration after cochlear implantation.

Epha10 was expressed in mouse cochlea at both transcription and translation levels. In addition, EPHA10 mRNA was detected upregulated in patients compared with controls by qRT-PCR. Overexpression of Eph (the homolog of human EPHA10) altered the structure and function of chordotonal organ (equivalent to mammalian auditory organs) in fly model. These functional evidence suggests that 'gain of function' may be responsible for the hearing loss phenotype.

This gene has not yet been associated with any phenotypes in OMIM or Gene2Phenotype.
Sources: Literature; to: Comment on rating: This gene should be rated RED as this gene has been associated with post-lingual autosomal dominant non-syndromic hearing loss from a single family, and supported by functional studies.

PMID:36048850 reported the identification of a heterozygous non-coding variant c.-81_-73delinsAGC cosegregating with hearing loss. Although variants have been identified in KIF17 and USP48 in several members of this family, they did not cosegregate with hearing loss. One affected member of this family had an ideal hearing restoration after cochlear implantation.

Epha10 was expressed in mouse cochlea at both transcription and translation levels. In addition, EPHA10 mRNA was detected upregulated in patients compared with controls by qRT-PCR. Overexpression of Eph (the homolog of human EPHA10) altered the structure and function of chordotonal organ (equivalent to mammalian auditory organs) in fly model. These functional evidence suggests that 'gain of function' may be responsible for the hearing loss phenotype.

This gene has not yet been associated with any phenotypes in OMIM or Gene2Phenotype.
Sources: Literature
Mendeliome v1.711 OXR1 Achchuthan Shanmugasundram reviewed gene: OXR1: Rating: AMBER; Mode of pathogenicity: None; Publications: 36130215; Phenotypes: sensorineural hearing loss disorder, MONDO:0020678; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.711 EPHA10 Achchuthan Shanmugasundram gene: EPHA10 was added
gene: EPHA10 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EPHA10 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EPHA10 were set to 36048850
Phenotypes for gene: EPHA10 were set to postlingual non-syndromic genetic hearing loss, MONDO:0016298
Mode of pathogenicity for gene: EPHA10 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: EPHA10 was set to RED
Added comment: Comment on rating: This gene should be rated RED as this gene has been associated with post-lingual autosomal dominant non-syndromic hearing loss from a single family, and supported by functional studies.

PMID:36048850 reported the identification of a heterozygous non-coding variant c.-81_-73delinsAGC cosegregating with hearing loss. Although variants have been identified in KIF17 and USP48 in several members of this family, they did not cosegregate with hearing loss. One affected member of this family had an ideal hearing restoration after cochlear implantation.

Epha10 was expressed in mouse cochlea at both transcription and translation levels. In addition, EPHA10 mRNA was detected upregulated in patients compared with controls by qRT-PCR. Overexpression of Eph (the homolog of human EPHA10) altered the structure and function of chordotonal organ (equivalent to mammalian auditory organs) in fly model. These functional evidence suggests that 'gain of function' may be responsible for the hearing loss phenotype.

This gene has not yet been associated with any phenotypes in OMIM or Gene2Phenotype.
Sources: Literature
BabyScreen+ newborn screening v0.1958 USP18 Lilian Downie gene: USP18 was added
gene: USP18 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: USP18 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: USP18 were set to PMID: 31940699, 27325888, 12833411
Phenotypes for gene: USP18 were set to Pseudo-TORCH syndrome 2 MIM#617397
Review for gene: USP18 was set to AMBER
Added comment: antenatal onset of intracranial hemorrhage, calcification, brain malformations, liver dysfunction, and often thrombocytopenia. Affected individuals tend to have respiratory insufficiency and seizures, and die in infancy. The phenotype resembles the sequelae of intrauterine infection, but there is no evidence of an infectious agent. The disorder results from inappropriate activation of the interferon (IFN) immunologic pathway

Treatment Ruxolitinib (single patient only) - is a single patient with successful treatment enough?
Sources: Expert list
BabyScreen+ newborn screening v0.1958 VKORC1 Lilian Downie gene: VKORC1 was added
gene: VKORC1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: VKORC1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: VKORC1 were set to PMID:14765194, PMID: 26287237
Phenotypes for gene: VKORC1 were set to Vitamin K-dependent clotting factors, combined deficiency of, 2 MIM#607473
Review for gene: VKORC1 was set to AMBER
Added comment: Risk of intracranial haemmorhage in first weeks of life
Treatable with vitamin K
See below summary - feels like should be green for that homozygous mutation but not sure how to manage the gene overall? not report other variants?
Monoallelic - warfarin resistance

There is only one mutation known to result in the VKCFD2 phenotype. VKORC1:p.Arg98Trp causes diminished vitamin K epoxide reductase (VKOR) activity compared to that of the wild-type enzyme [15]. VKCFD2 patients exhibit severely diminished activities for the VKD coagulation factors and suffer spontaneous or surgery/injury induced bleeding episodes [16,17]. In addition to this haemorrhagic phenotype, abnormalities in epiphyseal growth have been reported in one case [18]. This phenotype is very rare. Worldwide, there are only four unrelated families known to be affected with VKCFD2 [16,17,18].
Sources: Expert list
BabyScreen+ newborn screening v0.1958 WDR1 Lilian Downie gene: WDR1 was added
gene: WDR1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: WDR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDR1 were set to PMID: 32960541, 27994071, 27557945
Phenotypes for gene: WDR1 were set to Periodic fever, immunodeficiency, and thrombocytopenia syndrome MIM#150550
Review for gene: WDR1 was set to GREEN
Added comment: Strong gene disease association
Phenotype is early onset immunodeficiency with infections ++ and severe stomatitis
Treatable with bone marrow transplant.
Sources: Expert list
Mendeliome v1.711 ATP5B Zornitza Stark Marked gene: ATP5B as ready
Mendeliome v1.711 ATP5B Zornitza Stark Gene: atp5b has been classified as Amber List (Moderate Evidence).
Mendeliome v1.711 ATP5B Zornitza Stark Classified gene: ATP5B as Amber List (moderate evidence)
Mendeliome v1.711 ATP5B Zornitza Stark Gene: atp5b has been classified as Amber List (Moderate Evidence).
Mendeliome v1.710 ATP5B Zornitza Stark gene: ATP5B was added
gene: ATP5B was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATP5B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATP5B were set to 36860166
Phenotypes for gene: ATP5B were set to Inherited dystonia, MONDO:0044807, ATP5B-related
Review for gene: ATP5B was set to AMBER
Added comment: Two families only, clinical presentation with dystonia; incomplete penetrance observed. Some functional data.
Sources: Literature
Dystonia - isolated/combined v1.32 ATP5B Zornitza Stark Marked gene: ATP5B as ready
Dystonia - isolated/combined v1.32 ATP5B Zornitza Stark Gene: atp5b has been classified as Amber List (Moderate Evidence).
Dystonia - isolated/combined v1.32 ATP5B Zornitza Stark Phenotypes for gene: ATP5B were changed from DYSTONIA; PROGRESSIVE DYSTONIA to Inherited dystonia, MONDO:0044807, ATP5B-related
Dystonia - isolated/combined v1.31 ATP5B Zornitza Stark Classified gene: ATP5B as Amber List (moderate evidence)
Dystonia - isolated/combined v1.31 ATP5B Zornitza Stark Gene: atp5b has been classified as Amber List (Moderate Evidence).
Dystonia - isolated/combined v1.30 ATP5B Zornitza Stark reviewed gene: ATP5B: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Inherited dystonia, MONDO:0044807, ATP5B-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paroxysmal Dyskinesia v0.109 SHQ1 Zornitza Stark Marked gene: SHQ1 as ready
Paroxysmal Dyskinesia v0.109 SHQ1 Zornitza Stark Gene: shq1 has been classified as Amber List (Moderate Evidence).
Paroxysmal Dyskinesia v0.109 SHQ1 Zornitza Stark Phenotypes for gene: SHQ1 were changed from PAROXYSMAL DYSTONIA; INTELLECTUAL DISABILITY; HYPOTONIA; CHOREOATHETOSIS; EPILEPSY to Neurodevelopmental disorder with dystonia and seizures, MIM# 619922
Mendeliome v1.709 SHQ1 Zornitza Stark Publications for gene: SHQ1 were set to 34542157; 29178645
Mendeliome v1.708 SHQ1 Zornitza Stark edited their review of gene: SHQ1: Added comment: Fourth family reported in PMID 36847845 with hypotonia and paroxysmal dyskinesia.; Changed publications: 34542157, 29178645, 36847845
Paroxysmal Dyskinesia v0.108 SHQ1 Zornitza Stark Publications for gene: SHQ1 were set to
Paroxysmal Dyskinesia v0.107 SHQ1 Zornitza Stark edited their review of gene: SHQ1: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paroxysmal Dyskinesia v0.107 SHQ1 Zornitza Stark Classified gene: SHQ1 as Amber List (moderate evidence)
Paroxysmal Dyskinesia v0.107 SHQ1 Zornitza Stark Gene: shq1 has been classified as Amber List (Moderate Evidence).
Paroxysmal Dyskinesia v0.106 SHQ1 Zornitza Stark commented on gene: SHQ1: Four unrelated families reported. Family 1: isolated dystonia only; Family 2: dystonia, and neurodegeneration; Family 3: neurodegeneration; now Family 4: paroxysmal dyskinesia and hypotonia.

All likely represent a spectrum but caution warranted.
Paroxysmal Dyskinesia v0.106 SHQ1 Zornitza Stark edited their review of gene: SHQ1: Changed rating: AMBER; Changed publications: 36847845
Paroxysmal Dyskinesia v0.106 SHQ1 Zornitza Stark reviewed gene: SHQ1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with dystonia and seizures, MIM# 619922; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.708 YWHAZ Zornitza Stark Marked gene: YWHAZ as ready
Mendeliome v1.708 YWHAZ Zornitza Stark Gene: ywhaz has been classified as Red List (Low Evidence).
Mendeliome v1.708 YWHAZ Zornitza Stark gene: YWHAZ was added
gene: YWHAZ was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: YWHAZ was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: YWHAZ were set to 36001342
Phenotypes for gene: YWHAZ were set to Intellectual disability, MONDO:0001071
Review for gene: YWHAZ was set to RED
Added comment: PMID:36001342 reported one large three-generation family with intellectual disability and global developmental delay, where all affected members were identified with a heterozygous missense variant (c.147A>T/ p.Lys49Asn) in YWHAZ gene. Although there were 10 other rare variants located in 10 genes (ARHGAP4, AGPS, APOL3, CES3, DACT2, ECH1, FAM71E2, KREMEN1, YWHAZ, ZFYVE26) that co-segregated with the ID/GDD phenotype were identified in the family, they were either not present in all affected members or present in unaffected members. In addition, computational modeling and knockdown/ knockin studies with Drosophila also confirmed the role of this YWHAZ variant in intellectual disability.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5185 YWHAZ Zornitza Stark Marked gene: YWHAZ as ready
Intellectual disability syndromic and non-syndromic v0.5185 YWHAZ Zornitza Stark Gene: ywhaz has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.5185 YWHAZ Zornitza Stark Classified gene: YWHAZ as Red List (low evidence)
Intellectual disability syndromic and non-syndromic v0.5185 YWHAZ Zornitza Stark Gene: ywhaz has been classified as Red List (Low Evidence).
Mendeliome v1.707 KIF5B Zornitza Stark Publications for gene: KIF5B were set to PMID: 35342932
Fetal anomalies v1.91 PLXND1 Zornitza Stark Marked gene: PLXND1 as ready
Fetal anomalies v1.91 PLXND1 Zornitza Stark Gene: plxnd1 has been classified as Green List (High Evidence).
Fetal anomalies v1.91 PLXND1 Zornitza Stark Classified gene: PLXND1 as Green List (high evidence)
Fetal anomalies v1.91 PLXND1 Zornitza Stark Gene: plxnd1 has been classified as Green List (High Evidence).
Fetal anomalies v1.90 PLXND1 Zornitza Stark gene: PLXND1 was added
gene: PLXND1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: PLXND1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLXND1 were set to 35396997
Phenotypes for gene: PLXND1 were set to Congenital heart disease, MONDO:0005453, PLXND1-related
Review for gene: PLXND1 was set to GREEN
Added comment: 10 individuals including four fetal cases from five unrelated families were identified with biallelic variants in PLXND1 gene and they presented with cardiac defects. The most frequent defect is common arterial trunk (CAT)/truncus arteriosus.
Sources: Literature
Congenital Heart Defect v0.274 PLXND1 Zornitza Stark Marked gene: PLXND1 as ready
Congenital Heart Defect v0.274 PLXND1 Zornitza Stark Gene: plxnd1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.274 PLXND1 Zornitza Stark Classified gene: PLXND1 as Green List (high evidence)
Congenital Heart Defect v0.274 PLXND1 Zornitza Stark Gene: plxnd1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.273 PLXND1 Zornitza Stark gene: PLXND1 was added
gene: PLXND1 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: PLXND1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLXND1 were set to 35396997
Phenotypes for gene: PLXND1 were set to Congenital heart disease, MONDO:0005453, PLXND1-related
Review for gene: PLXND1 was set to GREEN
Added comment: 10 individuals including four fetal cases from five unrelated families were identified with biallelic variants in PLXND1 gene and they presented with cardiac defects. The most frequent defect is common arterial trunk (CAT)/truncus arteriosus.
Sources: Literature
Mendeliome v1.706 PLXND1 Zornitza Stark Phenotypes for gene: PLXND1 were changed from Möbius syndrome to Möbius syndrome, MONDO:0008006; Congenital heart disease, MONDO:0005453, PLXND1-related
Mendeliome v1.705 PLXND1 Zornitza Stark Publications for gene: PLXND1 were set to 26068067
Mendeliome v1.704 PLXND1 Zornitza Stark Mode of inheritance for gene: PLXND1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.703 PLXND1 Zornitza Stark edited their review of gene: PLXND1: Changed phenotypes: Möbius syndrome, Congenital heart disease, MONDO:0005453, PLXND1-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Dystonia - complex v0.222 TRPM3 Zornitza Stark Marked gene: TRPM3 as ready
Dystonia - complex v0.222 TRPM3 Zornitza Stark Gene: trpm3 has been classified as Green List (High Evidence).
Dystonia - complex v0.222 TRPM3 Zornitza Stark Phenotypes for gene: TRPM3 were changed from Intellectual disability; epilepsy; chorea; athetosis; hypotonia; dysmorphic features to Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures, MIM# 620224
Dystonia - complex v0.221 TRPM3 Zornitza Stark Classified gene: TRPM3 as Green List (high evidence)
Dystonia - complex v0.221 TRPM3 Zornitza Stark Gene: trpm3 has been classified as Green List (High Evidence).
Dystonia - complex v0.220 TRPM3 Zornitza Stark reviewed gene: TRPM3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures, MIM# 620224; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
BabyScreen+ newborn screening v0.1958 WDR72 Zornitza Stark Marked gene: WDR72 as ready
BabyScreen+ newborn screening v0.1958 WDR72 Zornitza Stark Gene: wdr72 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1958 WDR72 Zornitza Stark Phenotypes for gene: WDR72 were changed from Distal renal tubular acidosis to Amelogenesis imperfecta, type IIA3, MIM# 613211; Distal RTA MONDO:0015827
BabyScreen+ newborn screening v0.1957 WDR72 Zornitza Stark Classified gene: WDR72 as Green List (high evidence)
BabyScreen+ newborn screening v0.1957 WDR72 Zornitza Stark Gene: wdr72 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1956 WDR72 Zornitza Stark Tag treatable tag was added to gene: WDR72.
Tag renal tag was added to gene: WDR72.
BabyScreen+ newborn screening v0.1956 WDR72 Zornitza Stark reviewed gene: WDR72: Rating: GREEN; Mode of pathogenicity: None; Publications: 30028003; Phenotypes: Amelogenesis imperfecta, type IIA3, MIM# 613211, Distal RTA MONDO:0015827; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1956 WIPF1 Zornitza Stark Marked gene: WIPF1 as ready
BabyScreen+ newborn screening v0.1956 WIPF1 Zornitza Stark Gene: wipf1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1956 WIPF1 Zornitza Stark Classified gene: WIPF1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1956 WIPF1 Zornitza Stark Gene: wipf1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1955 WIPF1 Zornitza Stark Tag treatable tag was added to gene: WIPF1.
Tag immunological tag was added to gene: WIPF1.
Tag haematological tag was added to gene: WIPF1.
Dystonia - complex v0.220 TRPM3 Shekeeb Mohammad gene: TRPM3 was added
gene: TRPM3 was added to Dystonia - complex. Sources: Literature
Mode of inheritance for gene: TRPM3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TRPM3 were set to 31278393; 35146895
Phenotypes for gene: TRPM3 were set to Intellectual disability; epilepsy; chorea; athetosis; hypotonia; dysmorphic features
Penetrance for gene: TRPM3 were set to Complete
Review for gene: TRPM3 was set to GREEN
gene: TRPM3 was marked as current diagnostic
Added comment: Sources: Literature
BabyScreen+ newborn screening v0.1955 WNK4 Zornitza Stark Marked gene: WNK4 as ready
BabyScreen+ newborn screening v0.1955 WNK4 Zornitza Stark Gene: wnk4 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1955 WNK4 Zornitza Stark Classified gene: WNK4 as Green List (high evidence)
BabyScreen+ newborn screening v0.1955 WNK4 Zornitza Stark Gene: wnk4 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1954 WNK4 Zornitza Stark Tag treatable tag was added to gene: WNK4.
Tag endocrine tag was added to gene: WNK4.
BabyScreen+ newborn screening v0.1954 ZBTB24 Zornitza Stark Marked gene: ZBTB24 as ready
BabyScreen+ newborn screening v0.1954 ZBTB24 Zornitza Stark Gene: zbtb24 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1954 ZBTB24 Zornitza Stark Classified gene: ZBTB24 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.1954 ZBTB24 Zornitza Stark Gene: zbtb24 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1953 ZBTB24 Zornitza Stark Tag treatable tag was added to gene: ZBTB24.
Tag immunological tag was added to gene: ZBTB24.
BabyScreen+ newborn screening v0.1953 ZBTB24 Zornitza Stark reviewed gene: ZBTB24: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Immunodeficiency-centromeric instability-facial anomalies syndrome 2 MIM#614069; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Miscellaneous Metabolic Disorders v1.25 ZNF143 Zornitza Stark Marked gene: ZNF143 as ready
Miscellaneous Metabolic Disorders v1.25 ZNF143 Zornitza Stark Gene: znf143 has been classified as Red List (Low Evidence).
Miscellaneous Metabolic Disorders v1.25 ZNF143 Zornitza Stark gene: ZNF143 was added
gene: ZNF143 was added to Miscellaneous Metabolic Disorders. Sources: Expert Review
Mode of inheritance for gene: ZNF143 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF143 were set to 27349184
Phenotypes for gene: ZNF143 were set to Combined methylmalonic acidemia and homocystinuria, cblX like 1, MONDO:0002012, ZNF143-related
Review for gene: ZNF143 was set to RED
Added comment: Single individual reported with compound heterozygous variants.
Sources: Expert Review
Mendeliome v1.703 ZNF143 Zornitza Stark Marked gene: ZNF143 as ready
Mendeliome v1.703 ZNF143 Zornitza Stark Gene: znf143 has been classified as Red List (Low Evidence).
Mendeliome v1.703 ZNF143 Zornitza Stark gene: ZNF143 was added
gene: ZNF143 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ZNF143 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF143 were set to 27349184
Phenotypes for gene: ZNF143 were set to Combined methylmalonic acidemia and homocystinuria, cblX like 1, MONDO:0002012, ZNF143-related
Review for gene: ZNF143 was set to RED
Added comment: Single individual reported with compound heterozygous variants.
Sources: Literature
BabyScreen+ newborn screening v0.1953 ZNF143 Zornitza Stark Marked gene: ZNF143 as ready
BabyScreen+ newborn screening v0.1953 ZNF143 Zornitza Stark Gene: znf143 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1953 ZNF143 Zornitza Stark Classified gene: ZNF143 as Red List (low evidence)
BabyScreen+ newborn screening v0.1953 ZNF143 Zornitza Stark Gene: znf143 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1952 ZNF143 Zornitza Stark reviewed gene: ZNF143: Rating: RED; Mode of pathogenicity: None; Publications: 27349184; Phenotypes: Combined methylmalonic acidemia and homocystinuria, cblX like 1; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1952 WDR72 Lilian Downie gene: WDR72 was added
gene: WDR72 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: WDR72 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDR72 were set to PMID: 30028003, PMID: 30779877, PMID:36836560, PMID: 33033857
Phenotypes for gene: WDR72 were set to Distal renal tubular acidosis
Review for gene: WDR72 was set to GREEN
Added comment: Amelogenesis imperecta - thickened and disoloured dental enamal with RTA
Reduced penetrance or variable expression? Some patients only have the tooth phenotype...
Presents with polyuria and growth restriction
Treat with oral alkali replacement therapy, potassium chloride
Sources: Expert list
BabyScreen+ newborn screening v0.1952 WIPF1 Lilian Downie gene: WIPF1 was added
gene: WIPF1 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: WIPF1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WIPF1 were set to PMID: 27742395, PMID: 30450104, PMID: 22231303
Phenotypes for gene: WIPF1 were set to Wiskott-Aldrich syndrome 2 MIM#614493
Review for gene: WIPF1 was set to GREEN
Added comment: Infant onset
recurrent infections, thrombycytopenia and eczema
Immunology testing to correlate
Treatment/cure with bone marrow transplant
Sources: Expert list
BabyScreen+ newborn screening v0.1952 WNK4 Lilian Downie gene: WNK4 was added
gene: WNK4 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: WNK4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: WNK4 were set to PMID: 22073419, PMID: 31795491, PMID: 10869238,
Phenotypes for gene: WNK4 were set to Pseudohypoaldosteronism, type IIB MIM#614491
Review for gene: WNK4 was set to GREEN
Added comment: Hyperkalaemia and hypertension
Hypercalciuria
Hypocalcaemia
Decreased bone mineral density
Renal calcium stones
Treatable with thiazide diuretics
Variable age of onset from infancy to adulthood but highly effective treatment so leaning toward include.
Sources: Expert list
BabyScreen+ newborn screening v0.1952 ZBTB24 Lilian Downie gene: ZBTB24 was added
gene: ZBTB24 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: ZBTB24 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZBTB24 were set to PMID: 28128455, 21906047, 21596365, 23486536
Phenotypes for gene: ZBTB24 were set to Immunodeficiency-centromeric instability-facial anomalies syndrome 2 MIM#614069
Review for gene: ZBTB24 was set to AMBER
Added comment: INfant onset
Agammaglobulinemia, facial anomalies, and mental retardation. Facial anomalies included broad, flat nasal bridge, hypertelorism, and epicanthal folds.
Treat immunoglobulin and bone marrow transplant however, this only treats the immune deficiency
Consider exclusion due to untreatable ID phenotype?
Sources: Expert list
BabyScreen+ newborn screening v0.1952 ZNF143 Lilian Downie gene: ZNF143 was added
gene: ZNF143 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: ZNF143 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZNF143 were set to PMID: 20301503, PMID: 27349184
Phenotypes for gene: ZNF143 were set to Combined methylmalonic acidemia and homocystinuria, cblX like 1
Review for gene: ZNF143 was set to RED
Added comment: Not in our mendeliome
Single case
Sources: Expert list
Mendeliome v1.702 PLXND1 Achchuthan Shanmugasundram changed review comment from: 10 individuals including four foetal cases from five unrelated families were identified with biallelic variants in PLXND1 gene and they presented with cardiac defects. The most frequent defect is common arterial trunk (CAT), which is also known as truncus arteriosus, a conotruncal malformation characterized by a single vessel exiting both ventricles.

This gene has already been associated with PLXND1-related cardiac malformation syndrome with the confidence category of 'strong' in DD panel of Gene2Phenotype. However, no relevant phenotypes have been currently reported in OMIM.; to: 10 individuals including four foetal cases from five unrelated families were identified with biallelic variants in PLXND1 gene and they presented with cardiac defects. The most frequent defect is common arterial trunk (CAT), which is also known as truncus arteriosus, a conotruncal malformation characterized by a single vessel exiting both ventricles.

This gene has already been associated with PLXND1-related cardiac malformation syndrome with the confidence category of 'strong' in DD panel of Gene2Phenotype. However, no relevant phenotypes have been currently reported in OMIM.
Mendeliome v1.702 PLXND1 Achchuthan Shanmugasundram changed review comment from: 10 individuals including four foetal cases from five unrelated families were identified with biallelic variants in PLXND1 gene and they presented with cardiac defects. The most frequent defect is common arterial trunk (CAT), which is also known as truncus arteriosus, a conotruncal malformation characterized by a single vessel exiting both ventricles.; to: 10 individuals including four foetal cases from five unrelated families were identified with biallelic variants in PLXND1 gene and they presented with cardiac defects. The most frequent defect is common arterial trunk (CAT), which is also known as truncus arteriosus, a conotruncal malformation characterized by a single vessel exiting both ventricles.

This gene has already been associated with PLXND1-related cardiac malformation syndrome with the confidence category of 'strong' in DD panel of Gene2Phenotype. However, no relevant phenotypes have been currently reported in OMIM.
Mendeliome v1.702 PLXND1 Achchuthan Shanmugasundram edited their review of gene: PLXND1: Changed phenotypes: Truncus arteriosus, HP:0001660
Mendeliome v1.702 PLXND1 Achchuthan Shanmugasundram reviewed gene: PLXND1: Rating: ; Mode of pathogenicity: None; Publications: 35396997; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.702 KIF5B Achchuthan Shanmugasundram reviewed gene: KIF5B: Rating: ; Mode of pathogenicity: None; Publications: 36018820; Phenotypes: dilated cardiomyopathy, MONDO:0005021, ophthalmoplegia, MONDO:0003425, myopathy, MONDO:0005336, Hypotonia, HP:0001252, Seizure, HP:0001250; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.5184 YWHAZ Achchuthan Shanmugasundram gene: YWHAZ was added
gene: YWHAZ was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: YWHAZ was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: YWHAZ were set to 36001342
Phenotypes for gene: YWHAZ were set to Intellectual disability, MONDO:0001071
Review for gene: YWHAZ was set to RED
Added comment: PMID:36001342 reported one large three-generation family with intellectual disability and global developmental delay, where all affected members were identified with a heterozygous missense variant (c.147A>T/ p.Lys49Asn) in YWHAZ gene. Although there were 10 other rare variants located in 10 genes (ARHGAP4, AGPS, APOL3, CES3, DACT2, ECH1, FAM71E2, KREMEN1, YWHAZ, ZFYVE26) that co-segregated with the ID/GDD phenotype were identified in the family, they were either not present in all affected members or present in unaffected members.

In addition, computational modeling and knockdown/ knockin studies with Drosophila also confirmed the role of this YWHAZ variant in intellectual disability.
Sources: Literature
BabyScreen+ newborn screening v0.1952 FOLR1 Zornitza Stark Marked gene: FOLR1 as ready
BabyScreen+ newborn screening v0.1952 FOLR1 Zornitza Stark Gene: folr1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1952 FOLR1 Zornitza Stark Classified gene: FOLR1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1952 FOLR1 Zornitza Stark Gene: folr1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1951 FOLR1 Zornitza Stark gene: FOLR1 was added
gene: FOLR1 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, metabolic tags were added to gene: FOLR1.
Mode of inheritance for gene: FOLR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FOLR1 were set to 19732866; 30420205; 27743887
Phenotypes for gene: FOLR1 were set to Neurodegeneration due to cerebral folate transport deficiency, MIM# 613068
Review for gene: FOLR1 was set to GREEN
Added comment: Folate is a neurotransmitter precursor. Onset is apparent in late infancy with severe developmental regression, movement disturbances, epilepsy, and leukodystrophy. Recognition and diagnosis of this disorder is critical because folinic acid therapy can reverse the clinical symptoms and improve brain abnormalities and function.

Treatment: folinic acid

Non-genetic confirmatory testing: cerebrospinal fluid 5-methyltetrahydrofolate level
Sources: Expert list
BabyScreen+ newborn screening v0.1950 FCHO1 Zornitza Stark Marked gene: FCHO1 as ready
BabyScreen+ newborn screening v0.1950 FCHO1 Zornitza Stark Gene: fcho1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1950 FCHO1 Zornitza Stark Classified gene: FCHO1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1950 FCHO1 Zornitza Stark Gene: fcho1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1949 FCHO1 Zornitza Stark edited their review of gene: FCHO1: Changed rating: GREEN
BabyScreen+ newborn screening v0.1949 FCHO1 Zornitza Stark gene: FCHO1 was added
gene: FCHO1 was added to Baby Screen+ newborn screening. Sources: Expert list
treatable, immunological tags were added to gene: FCHO1.
Mode of inheritance for gene: FCHO1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FCHO1 were set to 32098969; 30822429
Phenotypes for gene: FCHO1 were set to Immunodeficiency 76, MIM# 619164
Added comment: More than 10 affected individuals with bi-allelic variants in this gene reported. Functional data.

Immunodeficiency-76 (IMD76) is an autosomal recessive primary immunologic disorder characterized by onset of recurrent bacterial, viral, and fungal infections in early childhood. Laboratory studies show T-cell lymphopenia and may show variable B-cell or immunoglobulin abnormalities. More variable features found in some patients include lymphoma and neurologic features.

Treatment: bone marrow transplant.

Non-genetic confirmatory testing: T and B Lymphocyte and Natural Killer Cell Profile, immunoglobulin levels
Sources: Expert list
BabyScreen+ newborn screening v0.1948 FAM111A Zornitza Stark Marked gene: FAM111A as ready
BabyScreen+ newborn screening v0.1948 FAM111A Zornitza Stark Gene: fam111a has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1948 FAM111A Zornitza Stark Classified gene: FAM111A as Green List (high evidence)
BabyScreen+ newborn screening v0.1948 FAM111A Zornitza Stark Gene: fam111a has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1947 FAM111A Zornitza Stark Tag treatable tag was added to gene: FAM111A.
Tag skeletal tag was added to gene: FAM111A.
BabyScreen+ newborn screening v0.1947 FAM111A Zornitza Stark gene: FAM111A was added
gene: FAM111A was added to Baby Screen+ newborn screening. Sources: Expert Review
Mode of inheritance for gene: FAM111A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: FAM111A were set to Kenny-Caffey syndrome, type 2, MIM# 127000
Review for gene: FAM111A was set to GREEN
Added comment: Condition is characterised by impaired skeletal development with small and dense bones, short stature, ocular abnormalities, and primary hypoparathyroidism with hypocalcemia. At least 10 unrelated cases reported with de novo missense variants. Intellectual disability/developmental delay is a rare feature of the condition.

Treatment: magnesium, calcium and calcitriol or alfacalcidol

Non-genetic confirmatory testing: serum calcium, parathyroid hormone level, calcitonin level
Sources: Expert Review
BabyScreen+ newborn screening v0.1946 ERCC6L2 Zornitza Stark Marked gene: ERCC6L2 as ready
BabyScreen+ newborn screening v0.1946 ERCC6L2 Zornitza Stark Gene: ercc6l2 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1946 ERCC6L2 Zornitza Stark Classified gene: ERCC6L2 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.1946 ERCC6L2 Zornitza Stark Gene: ercc6l2 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1945 ERCC6L2 Zornitza Stark gene: ERCC6L2 was added
gene: ERCC6L2 was added to Baby Screen+ newborn screening. Sources: Expert Review
treatable, haematological tags were added to gene: ERCC6L2.
Mode of inheritance for gene: ERCC6L2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERCC6L2 were set to 24507776; 27185855
Phenotypes for gene: ERCC6L2 were set to Bone marrow failure syndrome 2, MIM# 615715
Review for gene: ERCC6L2 was set to AMBER
Added comment: Trilineage bone marrow failure, learning disabilities, and microcephaly. Three consanguineous families reported, but two with the same truncating variant, founder effect likely.

Treatment: bone marrow transplant.

Amber rating due to limited number of families reported.
Sources: Expert Review
BabyScreen+ newborn screening v0.1944 DOCK2 Zornitza Stark Marked gene: DOCK2 as ready
BabyScreen+ newborn screening v0.1944 DOCK2 Zornitza Stark Gene: dock2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1944 DOCK2 Zornitza Stark Tag treatable tag was added to gene: DOCK2.
Tag immunological tag was added to gene: DOCK2.
BabyScreen+ newborn screening v0.1944 DOCK2 Zornitza Stark Classified gene: DOCK2 as Green List (high evidence)
BabyScreen+ newborn screening v0.1944 DOCK2 Zornitza Stark Gene: dock2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1943 DOCK2 Zornitza Stark gene: DOCK2 was added
gene: DOCK2 was added to Baby Screen+ newborn screening. Sources: Expert Review
Mode of inheritance for gene: DOCK2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DOCK2 were set to 26083206; 29204803; 33928462; 30826364; 30838481; 11518968
Phenotypes for gene: DOCK2 were set to Immunodeficiency 40 MIM# 616433
Review for gene: DOCK2 was set to GREEN
Added comment: 13 unrelated individuals; two mouse models; 10 biallelic mutations found (6 led to premature termination of the protein & 4 missense mutations affecting conserved residues) All patients presented with combined immunodeficiency in infancy (defective IFN-mediated immunity), early onset of invasive bacterial and viral infections, functional defects in T/B/NK cells and elevated IgM (normal IgG/IgA).

Treatment: bone marrow transplant.

Non-genetic confirmatory testing: T and B Lymphocyte and Natural Killer Cell Profile
Sources: Expert Review
BabyScreen+ newborn screening v0.1942 DNASE2 Zornitza Stark Marked gene: DNASE2 as ready
BabyScreen+ newborn screening v0.1942 DNASE2 Zornitza Stark Gene: dnase2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1942 DNASE2 Zornitza Stark Classified gene: DNASE2 as Green List (high evidence)
BabyScreen+ newborn screening v0.1942 DNASE2 Zornitza Stark Gene: dnase2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1941 DNASE2 Zornitza Stark Tag treatable tag was added to gene: DNASE2.
Tag immunological tag was added to gene: DNASE2.
BabyScreen+ newborn screening v0.1941 DNASE2 Zornitza Stark gene: DNASE2 was added
gene: DNASE2 was added to Baby Screen+ newborn screening. Sources: Expert Review
Mode of inheritance for gene: DNASE2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNASE2 were set to 29259162; 31775019
Phenotypes for gene: DNASE2 were set to Autoinflammatory-pancytopenia syndrome, MIM# 619858
Review for gene: DNASE2 was set to GREEN
Added comment: Inflammatory disorder characterized by splenomegaly, glomerulonephritis, liver fibrosis, circulating anti-DNA autoantibodies, and progressive arthritis. Three families and functional data.

Treatment: baricitinib

Non-genetic confirmatory testing: Interferon signature
Sources: Expert Review
BabyScreen+ newborn screening v0.1940 DNAJC21 Zornitza Stark Marked gene: DNAJC21 as ready
BabyScreen+ newborn screening v0.1940 DNAJC21 Zornitza Stark Gene: dnajc21 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1940 DNAJC21 Zornitza Stark Tag treatable tag was added to gene: DNAJC21.
Tag haematological tag was added to gene: DNAJC21.
BabyScreen+ newborn screening v0.1940 DNAJC21 Zornitza Stark Classified gene: DNAJC21 as Green List (high evidence)
BabyScreen+ newborn screening v0.1940 DNAJC21 Zornitza Stark Gene: dnajc21 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1939 DNAJC21 Zornitza Stark gene: DNAJC21 was added
gene: DNAJC21 was added to Baby Screen+ newborn screening. Sources: Expert Review
Mode of inheritance for gene: DNAJC21 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DNAJC21 were set to 29700810; 28062395; 27346687
Phenotypes for gene: DNAJC21 were set to Bone marrow failure syndrome 3, MIM# 617052
Review for gene: DNAJC21 was set to GREEN
Added comment: Onset of pancytopenia in early childhood; variable nonspecific somatic abnormalities, including poor growth, microcephaly, and skin anomalies.

Treatment: oral pancreatic enzymes, fat-soluble vitamins, blood and/or platelet transfusions, granulocyte-colony stimulation factor, bone marrow transplant

Confirmatory non-genetic testing: no; FBE as pancytopenia evolves.
Sources: Expert Review
BabyScreen+ newborn screening v0.1938 CYP2R1 Zornitza Stark Marked gene: CYP2R1 as ready
BabyScreen+ newborn screening v0.1938 CYP2R1 Zornitza Stark Gene: cyp2r1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1938 CYP2R1 Zornitza Stark Tag treatable tag was added to gene: CYP2R1.
Tag endocrine tag was added to gene: CYP2R1.
BabyScreen+ newborn screening v0.1938 CYP2R1 Zornitza Stark Classified gene: CYP2R1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1938 CYP2R1 Zornitza Stark Gene: cyp2r1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1937 CYP2R1 Zornitza Stark gene: CYP2R1 was added
gene: CYP2R1 was added to Baby Screen+ newborn screening. Sources: Expert Review
Mode of inheritance for gene: CYP2R1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CYP2R1 were set to 15128933; 28548312
Phenotypes for gene: CYP2R1 were set to Rickets due to defect in vitamin D 25-hydroxylation deficiency MIM#600081
Review for gene: CYP2R1 was set to GREEN
Added comment: At least 6 unrelated families reported.

Onset is generally in infancy.

Good response to vitamin D (calcifediol (25_OH_D3).

Confirmatory non-genetic testing: serum calcium, parathyroid hormone, 25-hydroxy vitamin D levels
Sources: Expert Review
BabyScreen+ newborn screening v0.1936 C17orf62 Zornitza Stark Marked gene: C17orf62 as ready
BabyScreen+ newborn screening v0.1936 C17orf62 Zornitza Stark Gene: c17orf62 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1936 C17orf62 Zornitza Stark Classified gene: C17orf62 as Green List (high evidence)
BabyScreen+ newborn screening v0.1936 C17orf62 Zornitza Stark Gene: c17orf62 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1935 C17orf62 Zornitza Stark gene: C17orf62 was added
gene: C17orf62 was added to Baby Screen+ newborn screening. Sources: Expert Review
new gene name, treatable, immunological tags were added to gene: C17orf62.
Mode of inheritance for gene: C17orf62 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C17orf62 were set to 30361506; 30312704; 28351984
Phenotypes for gene: C17orf62 were set to Chronic granulomatous disease 5, autosomal recessive, MIM# 618935
Review for gene: C17orf62 was set to GREEN
Added comment: Seven Icelandic families reported with same homozygous variant, p.Tyr2Ter and an additional family from different ethnic background with different homozygous splice site variant. Functional data, including mouse model. Gene also known as EROS and CYBC1 (HGNC approved name)

Primary immunodeficiency characterized by onset of recurrent infections and severe colitis in the first decade of life. Patients often present with features of inflammatory bowel disease and may show granulomata on biopsy. Patients are particularly susceptible to catalase-positive organisms, including Burkholderia cepacia, Legionella, and Candida albicans. Some patients may develop autoinflammatory symptoms, including recurrent fever in the absence of infection, hemolytic anemia, and lymphopenia. Additional features may include short stature, viral infections, cutaneous abscesses, pulmonary infections, and lymphadenitis. Haematopoietic bone marrow transplant is curative.

Non-genetic confirmatory assay: dihydrorhodamine assay
Sources: Expert Review
Mendeliome v1.702 CYB561 Zornitza Stark Marked gene: CYB561 as ready
Mendeliome v1.702 CYB561 Zornitza Stark Gene: cyb561 has been classified as Green List (High Evidence).
Mendeliome v1.702 CYB561 Zornitza Stark Classified gene: CYB561 as Green List (high evidence)
Mendeliome v1.702 CYB561 Zornitza Stark Gene: cyb561 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1934 CYB561 Zornitza Stark Marked gene: CYB561 as ready
BabyScreen+ newborn screening v0.1934 CYB561 Zornitza Stark Gene: cyb561 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1934 CYB561 Zornitza Stark Classified gene: CYB561 as Green List (high evidence)
BabyScreen+ newborn screening v0.1934 CYB561 Zornitza Stark Gene: cyb561 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1933 CYB561 Zornitza Stark Tag treatable tag was added to gene: CYB561.
Tag endocrine tag was added to gene: CYB561.
Mendeliome v1.701 CYB561 Zornitza Stark gene: CYB561 was added
gene: CYB561 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: CYB561 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CYB561 were set to 29343526; 31822578
Phenotypes for gene: CYB561 were set to Orthostatic hypotension 2, MIM# 618182
Review for gene: CYB561 was set to GREEN
Added comment: Three families reported.

Severe orthostatic hypotension, recurrent hypoglycemia, and low norepinephrine levels. The disorder has onset in infancy or early childhood.

Treatment: L-threo-3,4-dihydroxyphenylserine (droxidopa)
Sources: Expert Review
BabyScreen+ newborn screening v0.1933 CYB561 Zornitza Stark gene: CYB561 was added
gene: CYB561 was added to Baby Screen+ newborn screening. Sources: Expert list
Mode of inheritance for gene: CYB561 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CYB561 were set to 29343526; 31822578
Phenotypes for gene: CYB561 were set to Orthostatic hypotension 2, MIM# 618182
Review for gene: CYB561 was set to GREEN
Added comment: Three families reported.

Severe orthostatic hypotension, recurrent hypoglycemia, and low norepinephrine levels. The disorder has onset in infancy or early childhood.

Treatment: L-threo-3,4-dihydroxyphenylserine (droxidopa)

Non-genetic confirmatory testing: plasma norepinephrine, epinephrine, dopamine
Sources: Expert list
BabyScreen+ newborn screening v0.1932 Zornitza Stark Panel name changed from gNBS to Baby Screen+ newborn screening
Panel status changed from internal to public
BabyScreen+ newborn screening v0.1931 CR2 Zornitza Stark Marked gene: CR2 as ready
BabyScreen+ newborn screening v0.1931 CR2 Zornitza Stark Gene: cr2 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1931 CR2 Zornitza Stark Phenotypes for gene: CR2 were changed from Hypogammaglobulinaemia to Immunodeficiency, common variable, 7, MIM# 614699
BabyScreen+ newborn screening v0.1930 CR2 Zornitza Stark Tag treatable tag was added to gene: CR2.
Tag immunological tag was added to gene: CR2.
BabyScreen+ newborn screening v0.1930 CR2 Zornitza Stark reviewed gene: CR2: Rating: RED; Mode of pathogenicity: None; Publications: 22035880, 26325596; Phenotypes: Immunodeficiency, common variable, 7, MIM# 614699; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1930 CORO1A Zornitza Stark Marked gene: CORO1A as ready
BabyScreen+ newborn screening v0.1930 CORO1A Zornitza Stark Gene: coro1a has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1930 CORO1A Zornitza Stark Classified gene: CORO1A as Green List (high evidence)
BabyScreen+ newborn screening v0.1930 CORO1A Zornitza Stark Gene: coro1a has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1929 CORO1A Zornitza Stark gene: CORO1A was added
gene: CORO1A was added to gNBS. Sources: Expert list
Mode of inheritance for gene: CORO1A was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CORO1A were set to Immunodeficiency 8 MIM# 615401
Review for gene: CORO1A was set to GREEN
Added comment: 3 unrelated families and 1 unrelated individual reported with bi-allelic (deletion, missense, insertion) variants, resulting in premature stop codons and truncated protein/ alter a highly conserved residue in binding domain; one mouse model

All patients displayed T−B+NK+ SCID or CID presenting in early-onset recurrent infections and additional features that included EBV-associated lymphoproliferative disease and low immunoglobulin levels.

Congenital onset.

Treatment: bone marrow transplant

Non-genetic confirmatory testing: T and B Lymphocyte and Natural Killer Cell Profile
Sources: Expert list
BabyScreen+ newborn screening v0.1928 CDCA7 Zornitza Stark Marked gene: CDCA7 as ready
BabyScreen+ newborn screening v0.1928 CDCA7 Zornitza Stark Gene: cdca7 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1928 CDCA7 Zornitza Stark Classified gene: CDCA7 as Green List (high evidence)
BabyScreen+ newborn screening v0.1928 CDCA7 Zornitza Stark Gene: cdca7 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1927 CDCA7 Zornitza Stark Tag treatable tag was added to gene: CDCA7.
Tag immunological tag was added to gene: CDCA7.
BabyScreen+ newborn screening v0.1927 CDCA7 Zornitza Stark gene: CDCA7 was added
gene: CDCA7 was added to gNBS. Sources: Expert Review
Mode of inheritance for gene: CDCA7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CDCA7 were set to 26216346
Phenotypes for gene: CDCA7 were set to Immunodeficiency-centromeric instability-facial anomalies syndrome 3, MIM# 616910
Review for gene: CDCA7 was set to GREEN
Added comment: Congenital onset, severe disorder. At least 4 unrelated families reported.

Treatment: replacement immunoglobulins, bone marrow transplant

Non-genetic confirmatory testing: immunoglobulin levels, cytogenetic analysis for centromeric instability, DNA methylation studies
Sources: Expert Review
Intellectual disability syndromic and non-syndromic v0.5184 RRAS2 Elena Savva Classified gene: RRAS2 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.5184 RRAS2 Elena Savva Gene: rras2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5183 RRAS2 Elena Savva Marked gene: RRAS2 as ready
Intellectual disability syndromic and non-syndromic v0.5183 RRAS2 Elena Savva Gene: rras2 has been classified as Red List (Low Evidence).
Intellectual disability syndromic and non-syndromic v0.5183 RRAS2 Elena Savva gene: RRAS2 was added
gene: RRAS2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: RRAS2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RRAS2 were set to PMID: 31130282; 31130285
Phenotypes for gene: RRAS2 were set to Noonan syndrome 12 MIM#618624
Mode of pathogenicity for gene: RRAS2 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: RRAS2 was set to AMBER
Added comment: Gene has an established GOF mechanism

PMID: 31130282 - 3/9 individuals had mild learning difficulties or mild GDD

PMID: 31130285 - 1/3 individuals had mild ID, 1/3 had severe ID, 1/3 normal
Sources: Literature
BabyScreen+ newborn screening v0.1926 CD81 Zornitza Stark Marked gene: CD81 as ready
BabyScreen+ newborn screening v0.1926 CD81 Zornitza Stark Gene: cd81 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1926 CD81 Zornitza Stark Tag treatable tag was added to gene: CD81.
Tag immunological tag was added to gene: CD81.
BabyScreen+ newborn screening v0.1926 CD81 Zornitza Stark gene: CD81 was added
gene: CD81 was added to gNBS. Sources: Expert Review
Mode of inheritance for gene: CD81 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CD81 were set to 20237408
Phenotypes for gene: CD81 were set to Immunodeficiency, common variable, 6, MIM# 613496
Review for gene: CD81 was set to RED
Added comment: CVID, which would be congenital, severe and treatable with replacement immunoglobulins.

However, only a single individual reported.
Sources: Expert Review
BabyScreen+ newborn screening v0.1925 CD70 Zornitza Stark Marked gene: CD70 as ready
BabyScreen+ newborn screening v0.1925 CD70 Zornitza Stark Gene: cd70 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1925 CD70 Zornitza Stark Classified gene: CD70 as Green List (high evidence)
BabyScreen+ newborn screening v0.1925 CD70 Zornitza Stark Gene: cd70 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1924 CD70 Zornitza Stark gene: CD70 was added
gene: CD70 was added to gNBS. Sources: Expert Review
Mode of inheritance for gene: CD70 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CD70 were set to Lymphoproliferative syndrome 3, MIM# 618261
Review for gene: CD70 was set to GREEN
Added comment: Severe lymphoproliferation following EBV infection.

Treatment: bone marrow transplant.

Non-genetic confirmatory testing: immunoglobulin levels, T and B Lymphocyte and Natural Killer Cell Profile
Sources: Expert Review
BabyScreen+ newborn screening v0.1923 CD55 Zornitza Stark Marked gene: CD55 as ready
BabyScreen+ newborn screening v0.1923 CD55 Zornitza Stark Gene: cd55 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1923 CD55 Zornitza Stark Classified gene: CD55 as Green List (high evidence)
BabyScreen+ newborn screening v0.1923 CD55 Zornitza Stark Gene: cd55 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1922 CD55 Zornitza Stark Tag treatable tag was added to gene: CD55.
Tag immunological tag was added to gene: CD55.
BabyScreen+ newborn screening v0.1922 CD55 Zornitza Stark gene: CD55 was added
gene: CD55 was added to gNBS. Sources: Expert Review
Mode of inheritance for gene: CD55 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CD55 were set to 33398182
Phenotypes for gene: CD55 were set to Complement hyperactivation, angiopathic thrombosis, and protein-losing enteropathy, MIM# 226300
Review for gene: CD55 was set to GREEN
Added comment: Severe congenital disorder, high mortality.

Treatment: Eculizumab

Non-genetic confirmatory testing: albumin level, immunoglobulin level
Sources: Expert Review
BabyScreen+ newborn screening v0.1921 CD40 Zornitza Stark Marked gene: CD40 as ready
BabyScreen+ newborn screening v0.1921 CD40 Zornitza Stark Gene: cd40 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1921 CD40 Zornitza Stark Marked gene: CD40 as ready
BabyScreen+ newborn screening v0.1921 CD40 Zornitza Stark Gene: cd40 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1921 CD40 Zornitza Stark Classified gene: CD40 as Green List (high evidence)
BabyScreen+ newborn screening v0.1921 CD40 Zornitza Stark Gene: cd40 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1920 CD40 Zornitza Stark gene: CD40 was added
gene: CD40 was added to gNBS. Sources: Expert list
Mode of inheritance for gene: CD40 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CD40 were set to 29884852
Phenotypes for gene: CD40 were set to Immunodeficiency with hyper-IgM, type 3, MIM# 606843
Review for gene: CD40 was set to GREEN
Added comment: Severity can be variable but generally congenital onset, and predisposition to severe infections. Note CD40L already included.

Treatment: bone marrow transplantation.

Non-genetic confirmatory testing: immunoglobulin levels, flow cytometric analysis
Sources: Expert list
Paroxysmal Dyskinesia v0.106 SHQ1 Shekeeb Mohammad changed review comment from: Sources: Literature; to: Sources: Literature: PMID: 36847845
Paroxysmal Dyskinesia v0.106 SHQ1 Shekeeb Mohammad gene: SHQ1 was added
gene: SHQ1 was added to Paroxysmal Dyskinesia. Sources: Literature
Mode of inheritance for gene: SHQ1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SHQ1 were set to PAROXYSMAL DYSTONIA; INTELLECTUAL DISABILITY; HYPOTONIA; CHOREOATHETOSIS; EPILEPSY
Review for gene: SHQ1 was set to GREEN
gene: SHQ1 was marked as current diagnostic
Added comment: Sources: Literature
Dystonia - isolated/combined v1.30 ATP5B Shekeeb Mohammad gene: ATP5B was added
gene: ATP5B was added to Dystonia - isolated/combined. Sources: Literature
Mode of inheritance for gene: ATP5B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ATP5B were set to 36860166
Phenotypes for gene: ATP5B were set to DYSTONIA; PROGRESSIVE DYSTONIA
Penetrance for gene: ATP5B were set to Incomplete
Review for gene: ATP5B was set to GREEN
Added comment: Sources: Literature
Bone Marrow Failure v1.27 SRP19 Pasquale Barbaro gene: SRP19 was added
gene: SRP19 was added to Bone Marrow Failure. Sources: Literature
Mode of inheritance for gene: SRP19 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SRP19 were set to PMID: 36223592
Phenotypes for gene: SRP19 were set to neutropenia; myeloid maturation arrest; growth deficiency
Penetrance for gene: SRP19 were set to unknown
Review for gene: SRP19 was set to RED
Added comment: One kindred reported
Sources: Literature
Bone Marrow Failure v1.27 SRPRA Pasquale Barbaro gene: SRPRA was added
gene: SRPRA was added to Bone Marrow Failure. Sources: Literature
Mode of inheritance for gene: SRPRA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SRPRA were set to PMID: 36223592
Phenotypes for gene: SRPRA were set to neutropenia; myeloid maturation arrest; exocrine pancreatic insufficiency; growth deficiency
Penetrance for gene: SRPRA were set to unknown
Review for gene: SRPRA was set to RED
Added comment: One patient reported with functional data
Sources: Literature
Phagocyte Defects v1.10 SRPRA Pasquale Barbaro gene: SRPRA was added
gene: SRPRA was added to Phagocyte Defects. Sources: Literature
Mode of inheritance for gene: SRPRA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SRPRA were set to PMID: 36223592
Phenotypes for gene: SRPRA were set to neutropenia; myeloid maturation arrest; exocrine pancreatic insufficiency; growth deficiency
Penetrance for gene: SRPRA were set to unknown
Review for gene: SRPRA was set to RED
Added comment: One denovo variant identified in one patient
Sources: Literature
Phagocyte Defects v1.10 SRP19 Pasquale Barbaro gene: SRP19 was added
gene: SRP19 was added to Phagocyte Defects. Sources: Literature
Mode of inheritance for gene: SRP19 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SRP19 were set to PMID: 36223592
Phenotypes for gene: SRP19 were set to neutropenia; myeloid maturation arrest; growth deficiency
Penetrance for gene: SRP19 were set to unknown
Review for gene: SRP19 was set to RED
Added comment: Reported in 5 patients from one kindred
Sources: Literature
BabyScreen+ newborn screening v0.1919 CD3G Zornitza Stark Marked gene: CD3G as ready
BabyScreen+ newborn screening v0.1919 CD3G Zornitza Stark Gene: cd3g has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1919 CD3G Zornitza Stark Classified gene: CD3G as Green List (high evidence)
BabyScreen+ newborn screening v0.1919 CD3G Zornitza Stark Gene: cd3g has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1918 CD3G Zornitza Stark edited their review of gene: CD3G: Changed rating: GREEN
BabyScreen+ newborn screening v0.1918 CD3G Zornitza Stark Tag treatable tag was added to gene: CD3G.
Tag immunological tag was added to gene: CD3G.
BabyScreen+ newborn screening v0.1918 CD3G Zornitza Stark gene: CD3G was added
gene: CD3G was added to gNBS. Sources: Expert list
Mode of inheritance for gene: CD3G was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CD3G were set to 31921117
Phenotypes for gene: CD3G were set to Immunodeficiency 17; CD3 gamma deficient MIM# 615607
Added comment: 10 affected individuals from 5 unrelated families; homozygous and compound heterozygous variants (splicing, missense and small deletion variants) identified resulting in premature stop codons and truncated protein; multiple mouse models.

All individuals displayed immune deficiency and autoimmunity of variable severity. Some individuals presented at birth with failure to thrive due to lethal SCID features. The most common immunologic profile includes partial T lymphocytopenia and low CD3, with normal B cells, NK cells, and immunoglobulins.

Congenital onset.

Treatment: replacement immunoglobulin

Non-genetic confirmatory testing: immunoglobulin levels
Sources: Expert list
BabyScreen+ newborn screening v0.1917 CD27 Zornitza Stark Marked gene: CD27 as ready
BabyScreen+ newborn screening v0.1917 CD27 Zornitza Stark Gene: cd27 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1917 CD27 Zornitza Stark Classified gene: CD27 as Green List (high evidence)
BabyScreen+ newborn screening v0.1917 CD27 Zornitza Stark Gene: cd27 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1916 CD27 Zornitza Stark Tag treatable tag was added to gene: CD27.
Tag immunological tag was added to gene: CD27.
BabyScreen+ newborn screening v0.1916 CD27 Zornitza Stark gene: CD27 was added
gene: CD27 was added to gNBS. Sources: Expert list
Mode of inheritance for gene: CD27 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CD27 were set to 22197273; 22801960; 22365582; 25843314; 11062504
Phenotypes for gene: CD27 were set to CD27-deficiency MIM# 615122
Review for gene: CD27 was set to GREEN
Added comment: 17 affected individuals from 9 unrelated families; homozygous (missense) and compound heterozygous (missense/ nonsense) variants identified in CD27; one mouse model. Affected individuals present with varied phenotypes (even within the same families); most commonly with lymphadenopathy, fever, hepatosplenomegaly, EBV-related infections, and immunodeficiency associated with hypogammaglobulinaemia. However, some CD27-deficient individuals are asymptomatic or display borderline-low hypogammaglobulinaemia.

Treatment: replacement immunoglobulin treatment, rituximab, Bone marrow transplant.

Non-genetic confirmatory testing: immunoglobulin levels
Sources: Expert list
BabyScreen+ newborn screening v0.1915 CD247 Zornitza Stark Marked gene: CD247 as ready
BabyScreen+ newborn screening v0.1915 CD247 Zornitza Stark Gene: cd247 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1915 CD247 Zornitza Stark Classified gene: CD247 as Green List (high evidence)
BabyScreen+ newborn screening v0.1915 CD247 Zornitza Stark Gene: cd247 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1914 CD247 Zornitza Stark Tag treatable tag was added to gene: CD247.
Tag immunological tag was added to gene: CD247.
BabyScreen+ newborn screening v0.1914 CD247 Zornitza Stark gene: CD247 was added
gene: CD247 was added to gNBS. Sources: Expert Review
Mode of inheritance for gene: CD247 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CD247 were set to 16672702; 17170122
Phenotypes for gene: CD247 were set to Immunodeficiency 25, MIM# 610163
Review for gene: CD247 was set to GREEN
Added comment: Two reports in the literature, note additional two reports in ClinVar; functional data.

Congenital onset. Absent T cells, resulting in severe immunodeficiency.

Treatment: bone marrow transplant.

Non-genetic confirmatory testing: T, B and NK cell counts
Sources: Expert Review
BabyScreen+ newborn screening v0.1913 CD19 Zornitza Stark Marked gene: CD19 as ready
BabyScreen+ newborn screening v0.1913 CD19 Zornitza Stark Gene: cd19 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1913 CD19 Zornitza Stark Tag treatable tag was added to gene: CD19.
Tag immunological tag was added to gene: CD19.
BabyScreen+ newborn screening v0.1913 CD19 Zornitza Stark Classified gene: CD19 as Green List (high evidence)
BabyScreen+ newborn screening v0.1913 CD19 Zornitza Stark Gene: cd19 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1912 CD19 Zornitza Stark gene: CD19 was added
gene: CD19 was added to gNBS. Sources: Expert list
Mode of inheritance for gene: CD19 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CD19 were set to Immunodeficiency, common variable, 3, MIM# 613493
Review for gene: CD19 was set to GREEN
Added comment: More than 5 unrelated families reported. Clinical features include increased susceptibility to infection, hypogammaglobulinaemia, and normal numbers of mature B cells in blood, indicating a B-cell antibody-deficient immunodeficiency disorder.

Onset is congenital.

Treatment: IVIG

Non-genetic confirmatory testing: immunoglobulin levels
Sources: Expert list
BabyScreen+ newborn screening v0.1911 CAV1 Zornitza Stark Marked gene: CAV1 as ready
BabyScreen+ newborn screening v0.1911 CAV1 Zornitza Stark Gene: cav1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1911 CAV1 Zornitza Stark Classified gene: CAV1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1911 CAV1 Zornitza Stark Gene: cav1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1910 CAV1 Zornitza Stark Tag treatable tag was added to gene: CAV1.
Tag metabolic tag was added to gene: CAV1.
BabyScreen+ newborn screening v0.1910 CAV1 Zornitza Stark gene: CAV1 was added
gene: CAV1 was added to gNBS. Sources: Expert list
Mode of inheritance for gene: CAV1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAV1 were set to 29704234
Phenotypes for gene: CAV1 were set to Lipodystrophy, congenital generalized, type 3, MIM# 612526
Review for gene: CAV1 was set to GREEN
Added comment: Established gene-disease association.

Bi-allelic disease is more severe. Onset is congenital.

Treatment: metreleptin

Non-genetic confirmatory testing: leptin levels
Sources: Expert list
BabyScreen+ newborn screening v0.1908 PRDX1 Zornitza Stark Marked gene: PRDX1 as ready
BabyScreen+ newborn screening v0.1908 PRDX1 Zornitza Stark Gene: prdx1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1908 PRDX1 Zornitza Stark Classified gene: PRDX1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1908 PRDX1 Zornitza Stark Gene: prdx1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1907 PRDX1 Zornitza Stark Tag for review tag was added to gene: PRDX1.
BabyScreen+ newborn screening v0.1907 PNP Zornitza Stark Marked gene: PNP as ready
BabyScreen+ newborn screening v0.1907 PNP Zornitza Stark Gene: pnp has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1907 PNP Zornitza Stark Tag treatable tag was added to gene: PNP.
Tag immunological tag was added to gene: PNP.
BabyScreen+ newborn screening v0.1907 PNP Zornitza Stark Classified gene: PNP as Green List (high evidence)
BabyScreen+ newborn screening v0.1907 PNP Zornitza Stark Gene: pnp has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1906 MTHFR Zornitza Stark Marked gene: MTHFR as ready
BabyScreen+ newborn screening v0.1906 MTHFR Zornitza Stark Gene: mthfr has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1906 MTHFR Zornitza Stark Phenotypes for gene: MTHFR were changed from Homocystinuria due to MTHFR deficiency to Homocystinuria due to MTHFR deficiency MIM#236250
BabyScreen+ newborn screening v0.1905 MTHFR Zornitza Stark Publications for gene: MTHFR were set to
BabyScreen+ newborn screening v0.1904 MTHFR Zornitza Stark Classified gene: MTHFR as Red List (low evidence)
BabyScreen+ newborn screening v0.1904 MTHFR Zornitza Stark Gene: mthfr has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1903 MCCC2 Zornitza Stark Marked gene: MCCC2 as ready
BabyScreen+ newborn screening v0.1903 MCCC2 Zornitza Stark Gene: mccc2 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1903 MCCC2 Zornitza Stark Phenotypes for gene: MCCC2 were changed from 3-Methylcrotonyl-CoA carboxylase 2 deficiency; 3-Methylcrotonyl-CoA carboxylase 2 deficiency, MIM# 210210 to 3-Methylcrotonyl-CoA carboxylase 2 deficiency MIM#210210
BabyScreen+ newborn screening v0.1902 MCCC2 Zornitza Stark Publications for gene: MCCC2 were set to
BabyScreen+ newborn screening v0.1901 MCCC2 Zornitza Stark reviewed gene: MCCC2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: 3-Methylcrotonyl-CoA carboxylase 2 deficiency MIM#210210; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1901 MCCC1 Zornitza Stark Marked gene: MCCC1 as ready
BabyScreen+ newborn screening v0.1901 MCCC1 Zornitza Stark Gene: mccc1 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1901 MCCC1 Zornitza Stark Phenotypes for gene: MCCC1 were changed from 3-Methylcrotonyl-CoA carboxylase 1 deficiency; 3-Methylcrotonyl-CoA carboxylase 1 deficiency, MIM# 210200 to 3-Methylcrotonyl-CoA carboxylase 1 deficiency MIM#210200
BabyScreen+ newborn screening v0.1900 MCCC1 Zornitza Stark Publications for gene: MCCC1 were set to
BabyScreen+ newborn screening v0.1899 MCCC1 Zornitza Stark Classified gene: MCCC1 as Red List (low evidence)
BabyScreen+ newborn screening v0.1899 MCCC1 Zornitza Stark Gene: mccc1 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1898 MCCC1 Zornitza Stark reviewed gene: MCCC1: Rating: RED; Mode of pathogenicity: None; Publications: 31730530; Phenotypes: 3-Methylcrotonyl-CoA carboxylase 1 deficiency MIM#210200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1898 MAT1A Zornitza Stark Marked gene: MAT1A as ready
BabyScreen+ newborn screening v0.1898 MAT1A Zornitza Stark Gene: mat1a has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1898 MAT1A Zornitza Stark Mode of inheritance for gene: MAT1A was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1897 MAT1A Zornitza Stark Phenotypes for gene: MAT1A were changed from Methionine adenosyltransferase deficiency to Methionine adenosyltransferase deficiency MIM#250850
BabyScreen+ newborn screening v0.1896 LIAS Zornitza Stark Marked gene: LIAS as ready
BabyScreen+ newborn screening v0.1896 LIAS Zornitza Stark Gene: lias has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1896 LIAS Zornitza Stark Publications for gene: LIAS were set to PMID: 24334290, 24777537,
BabyScreen+ newborn screening v0.1895 LIAS Zornitza Stark Source Expert list was removed from LIAS.
Source Expert Review was added to LIAS.
Rating Changed from No List (delete) to Red List (low evidence)
BabyScreen+ newborn screening v0.1894 LIAS Zornitza Stark All sources for gene: LIAS were removed
BabyScreen+ newborn screening v0.1893 LIAS Zornitza Stark All sources for gene: LIAS were removed
BabyScreen+ newborn screening v0.1892 LIAS Zornitza Stark Classified gene: LIAS as Red List (low evidence)
BabyScreen+ newborn screening v0.1892 LIAS Zornitza Stark Gene: lias has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1891 HPD Zornitza Stark Marked gene: HPD as ready
BabyScreen+ newborn screening v0.1891 HPD Zornitza Stark Gene: hpd has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1891 HPD Zornitza Stark Publications for gene: HPD were set to
BabyScreen+ newborn screening v0.1890 HPD Zornitza Stark reviewed gene: HPD: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Tyrosinemia, type III MIM#276710; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1890 HIBCH Zornitza Stark Tag for review tag was added to gene: HIBCH.
BabyScreen+ newborn screening v0.1890 HMGCS2 Zornitza Stark Marked gene: HMGCS2 as ready
BabyScreen+ newborn screening v0.1890 HMGCS2 Zornitza Stark Gene: hmgcs2 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1890 HMGCS2 Zornitza Stark Classified gene: HMGCS2 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.1890 HMGCS2 Zornitza Stark Gene: hmgcs2 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1889 HMGCS2 Zornitza Stark Tag for review tag was added to gene: HMGCS2.
Tag treatable tag was added to gene: HMGCS2.
Tag metabolic tag was added to gene: HMGCS2.
BabyScreen+ newborn screening v0.1889 HMGCS2 Zornitza Stark reviewed gene: HMGCS2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: HMG-CoA synthase-2 deficiency MIM#605911; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1889 HIBCH Zornitza Stark Marked gene: HIBCH as ready
BabyScreen+ newborn screening v0.1889 HIBCH Zornitza Stark Gene: hibch has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1889 HIBCH Zornitza Stark Phenotypes for gene: HIBCH were changed from Neurodegeneration, progressive infantile to 3-hydroxyisobutryl-CoA hydrolase deficiency MIM#250620
BabyScreen+ newborn screening v0.1888 HIBCH Zornitza Stark Publications for gene: HIBCH were set to
BabyScreen+ newborn screening v0.1887 HIBCH Zornitza Stark Tag treatable tag was added to gene: HIBCH.
Tag metabolic tag was added to gene: HIBCH.
BabyScreen+ newborn screening v0.1887 HIBCH Zornitza Stark Classified gene: HIBCH as Green List (high evidence)
BabyScreen+ newborn screening v0.1887 HIBCH Zornitza Stark Gene: hibch has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1886 GLIS3 Zornitza Stark Marked gene: GLIS3 as ready
BabyScreen+ newborn screening v0.1886 GLIS3 Zornitza Stark Gene: glis3 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1886 GLIS3 Zornitza Stark Phenotypes for gene: GLIS3 were changed from Diabetes mellitus, neonatal, with congenital hypothyroidism; Diabetes mellitus, neonatal, with congenital hypothyroidism, MIM# 610199 to Diabetes mellitus, neonatal, with congenital hypothyroidism MIM#610199
BabyScreen+ newborn screening v0.1885 GLIS3 Zornitza Stark Publications for gene: GLIS3 were set to
BabyScreen+ newborn screening v0.1884 GLIS3 Zornitza Stark Classified gene: GLIS3 as Green List (high evidence)
BabyScreen+ newborn screening v0.1884 GLIS3 Zornitza Stark Gene: glis3 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1883 GLIS3 Zornitza Stark Tag treatable tag was added to gene: GLIS3.
Tag endocrine tag was added to gene: GLIS3.
BabyScreen+ newborn screening v0.1883 GLIS3 Zornitza Stark reviewed gene: GLIS3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Diabetes mellitus, neonatal, with congenital hypothyroidism MIM#610199; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1883 PRDX1 Lilian Downie gene: PRDX1 was added
gene: PRDX1 was added to gNBS. Sources: Expert list
Mode of inheritance for gene: PRDX1 was set to Other
Publications for gene: PRDX1 were set to PMID: 20301503, PMID: 29396438, PMID: 34215320, PMID: 33982424
Phenotypes for gene: PRDX1 were set to Methylmalonic aciduria and homocystinuria, cblC type, digenic MIM#277400
Review for gene: PRDX1 was set to GREEN
Added comment: Digenic inheritance with mutation in other allele of MMACHC
On GUARDIAN and Rx genes list

Recently, three individuals who are double heterozygous for pathogenic variants in MMACHC and PRDX1 have been identified. PRDX1 is a neighboring gene on chromosome 1 transcribed from the reverse strand. Variants identified in PRDX1 located at the intron 5 splice acceptor site caused skipping of exon 6, transcription of antisense MMACHC, and hypermethylation of the MMACHC promoter/exon 1, resulting in no gene expression from that allele [Guéant et al 2018].

Treatable with cobalamin, carnitine & diet. NB MMACHC is green on our list, on newborn screening.
Sources: Expert list
BabyScreen+ newborn screening v0.1883 PNP Lilian Downie gene: PNP was added
gene: PNP was added to gNBS. Sources: Expert list
Mode of inheritance for gene: PNP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PNP were set to PMID: 35968787, PMID: 35063692, PMID: 30885031, PMID: 1931007, PMID: 28674683
Phenotypes for gene: PNP were set to Immunodeficiency due to purine nucleoside phosphorylase deficiency MIM#613179
Review for gene: PNP was set to GREEN
Added comment: Decreased T cell function - SCID immunodeficiency
variable neurological phenotype
childhood onset
Treat bone marrow transplant
Sources: Expert list
BabyScreen+ newborn screening v0.1883 MTHFR Lilian Downie reviewed gene: MTHFR: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 34214447; Phenotypes: Homocystinuria due to MTHFR deficiency MIM#236250; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1883 MCCC2 Lilian Downie reviewed gene: MCCC2: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 22642865; Phenotypes: 3-Methylcrotonyl-CoA carboxylase 2 deficiency MIM#210210; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5182 RBSN Achchuthan Shanmugasundram gene: RBSN was added
gene: RBSN was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: RBSN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RBSN were set to 25233840; 29784638; 35652444
Phenotypes for gene: RBSN were set to intellectual disability, MONDO:0001071
Review for gene: RBSN was set to GREEN
Added comment: This gene should be rated GREEN as bi-allelic variants in RBSN has been associated with a phenotype encompassing developmental delay and intellectual disability from four unrelated families.

PMID:25233840 reported a 6.5 year old female patient with a homozygous missense variant c.1273G > A (p.Gly425Arg) and her clinical presentation included intractable seizures, developmental delay, microcephaly, dysostosis, osteopenia, craniofacial dysmorphism, macrocytosis and megaloblastoid erythropoiesis.

PMID:29784638 reported three siblings with homozygous variant c.289G>C (p.Gly97Arg) in RBSN. The proband presented global developmental delay, had complete 46,XY male-to-female sex reversal and died at age 20 months after multiple infections. The other 2 affected siblings underwent unrelated-donor bone marrow or stem cell transplantation at 8 and 6.5 months of age, respectively. Both have severe intellectual disability and are nonambulatory and nonverbal.

PMID:35652444 reported two unrelated families (three siblings from a family of Iranian descent identified with homozygous variant c.547G>A (p.Gly183Arg) and four members from a family of indigenous Cree descent identified with homozygous variant c.538C>G (p.Arg180Gly)) with overlapping phenotypes including developmental delay, intellectual disability, distal motor axonal neuropathy and facial dysmorphism.

This gene has not yet been associated with any phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5182 CTR9 Achchuthan Shanmugasundram changed review comment from: PMID:35717577 reported two additional unrelated cases with non-synonymous heterozygous CTR9 variants (p.Glu15Asp and p.Pro25Arg) and they presented with macrocephaly, motor delay, and intellectual disability. In addition, functional studies in also showed that knockout/ over-expression of CTR9 variants caused motor defects and enlargement of telencephalon (homologous to the mammalian cerebrum).; to: PMID:35717577 reported two additional unrelated cases with non-synonymous heterozygous CTR9 variants (p.Glu15Asp and p.Pro25Arg) and they presented with macrocephaly, motor delay, and intellectual disability. In addition, functional studies in zebrafish also showed that knockout/ over-expression of CTR9 variants caused motor defects and enlargement of telencephalon (homologous to the mammalian cerebrum).
Intellectual disability syndromic and non-syndromic v0.5182 DPYSL2 Achchuthan Shanmugasundram gene: DPYSL2 was added
gene: DPYSL2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: DPYSL2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DPYSL2 were set to 27249678; 35861646
Phenotypes for gene: DPYSL2 were set to intellectual disability, MONDO:0001071; Aplasia/Hypoplasia of the corpus callosum, HP:0007370
Review for gene: DPYSL2 was set to AMBER
Added comment: This gene should be rated AMBER, as it has been associated with intellectual disability (ID) from two unrelated cases displaying monoallelic variants in DPYSL2/ CRMP2, and supported by functional studies. However, the evidence is not sufficient for green rating as there are variants reported in other (but different) genes in the two patients.

PMID:35861646 reported two cases identified with heterozygous variants (patient1: c.1693C>T (p.Arg565Cys); patient 2: c.42C>A (p.Ser14Arg). These patients had overlapping phenotypes including dysmorphic features, severe global developmental delay and hypoplasia of the corpus callosum. In addition, patient 2 was bed-ridden and could not roll out and had a history of myoclonic seizures and status epilepticus.

It should be noted that patient 1 is compound heterozygous for 2 missense variants in the EFCAB5 gene and was hemizygous for a maternally inherited missense variant in the GPKOW gene and patient 2 had 1 de novo missense variant in the COBLL1 gene and was compound heterozygous for 2 missense variants in the POTEF gene. The severity of the phenotypes between the two cases differs significantly and the additional variants may have possibly contributed to this phenotype.

Brain-specific Crmp2 knockout mice display neuronal development deficits and behavioural impairments associated with hypoplasia of the corpus callosum. In addition, functional studies performed in zebrafish and cell lines that the CRMP2 variants lead to the loss-of-function of CRMP2 protein and can cause intellectual disability.

This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
BabyScreen+ newborn screening v0.1883 GATM Zornitza Stark Tag treatable tag was added to gene: GATM.
Tag metabolic tag was added to gene: GATM.
BabyScreen+ newborn screening v0.1883 GATM Zornitza Stark Marked gene: GATM as ready
BabyScreen+ newborn screening v0.1883 GATM Zornitza Stark Gene: gatm has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1883 GATM Zornitza Stark Classified gene: GATM as Green List (high evidence)
BabyScreen+ newborn screening v0.1883 GATM Zornitza Stark Gene: gatm has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1882 GATM Zornitza Stark reviewed gene: GATM: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301745; Phenotypes: Cerebral creatine deficiency syndrome 3, MIM#612718; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1882 FOXE1 Zornitza Stark Marked gene: FOXE1 as ready
BabyScreen+ newborn screening v0.1882 FOXE1 Zornitza Stark Gene: foxe1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1882 FOXE1 Zornitza Stark Phenotypes for gene: FOXE1 were changed from Bamforth-Lazarus syndrome to Bamforth-Lazarus syndrome MIM# 241850
BabyScreen+ newborn screening v0.1881 FOXE1 Zornitza Stark Publications for gene: FOXE1 were set to
BabyScreen+ newborn screening v0.1880 FOXE1 Zornitza Stark Classified gene: FOXE1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1880 FOXE1 Zornitza Stark Gene: foxe1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1879 FOXE1 Zornitza Stark Tag treatable tag was added to gene: FOXE1.
Tag endocrine tag was added to gene: FOXE1.
Tag deafness tag was added to gene: FOXE1.
BabyScreen+ newborn screening v0.1879 ALDH4A1 Zornitza Stark Marked gene: ALDH4A1 as ready
BabyScreen+ newborn screening v0.1879 ALDH4A1 Zornitza Stark Gene: aldh4a1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1879 ALDH4A1 Zornitza Stark Phenotypes for gene: ALDH4A1 were changed from Hyperprolinemia, type II to Hyperprolinemia, type II MIM#239510
BabyScreen+ newborn screening v0.1878 ALDH4A1 Zornitza Stark Publications for gene: ALDH4A1 were set to
BabyScreen+ newborn screening v0.1877 ALDH4A1 Zornitza Stark Classified gene: ALDH4A1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1877 ALDH4A1 Zornitza Stark Gene: aldh4a1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1876 ALDH4A1 Zornitza Stark Tag treatable tag was added to gene: ALDH4A1.
Tag metabolic tag was added to gene: ALDH4A1.
BabyScreen+ newborn screening v0.1876 ALDH4A1 Zornitza Stark reviewed gene: ALDH4A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hyperprolinemia, type II MIM#239510; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1876 ACADSB Zornitza Stark Marked gene: ACADSB as ready
BabyScreen+ newborn screening v0.1876 ACADSB Zornitza Stark Gene: acadsb has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1876 ACADSB Zornitza Stark Phenotypes for gene: ACADSB were changed from 2-Methylbutyryl-CoA dehydrogenase deficiency to 2-methylbutyrylglycinuria MIM#610006
BabyScreen+ newborn screening v0.1875 ACADS Zornitza Stark Marked gene: ACADS as ready
BabyScreen+ newborn screening v0.1875 ACADS Zornitza Stark Gene: acads has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1875 ABCD4 Zornitza Stark Marked gene: ABCD4 as ready
BabyScreen+ newborn screening v0.1875 ABCD4 Zornitza Stark Gene: abcd4 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1875 ABCD4 Zornitza Stark Phenotypes for gene: ABCD4 were changed from MAHCJ, MIM#614857; Methylmalonic aciduria and homocystinuria, cblJ TYPE; Methylmalonic aciduria and homocystinuria, cblJ type to Methylmalonic aciduria and homocystinuria, cblJ type MIM#614857
BabyScreen+ newborn screening v0.1874 ABCD4 Zornitza Stark Publications for gene: ABCD4 were set to
BabyScreen+ newborn screening v0.1873 ABCD4 Zornitza Stark Classified gene: ABCD4 as Green List (high evidence)
BabyScreen+ newborn screening v0.1873 ABCD4 Zornitza Stark Gene: abcd4 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1872 ABCD4 Zornitza Stark reviewed gene: ABCD4: Rating: GREEN; Mode of pathogenicity: None; Publications: 22922874, 30651581, 28572511, 31113616; Phenotypes: Methylmalonic aciduria and homocystinuria, cblJ type MIM#614857; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.700 TLN1 Achchuthan Shanmugasundram reviewed gene: TLN1: Rating: RED; Mode of pathogenicity: None; Publications: 35861643; Phenotypes: thrombocytopenia, MONDO:0002049, lymphopenia, MONDO:0003783; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Bleeding and Platelet Disorders v1.16 TLN1 Achchuthan Shanmugasundram gene: TLN1 was added
gene: TLN1 was added to Bleeding and Platelet Disorders. Sources: Literature
Mode of inheritance for gene: TLN1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TLN1 were set to 35861643
Phenotypes for gene: TLN1 were set to thrombocytopenia, MONDO:0002049
Review for gene: TLN1 was set to RED
Added comment: PMID:35861643 reported a 20-year old man of Mexican ancestry with a complex phenotype including thrombocytopenia, T lymphopenia, and low IgG levels. The patient generally had a platelet count of <20 000/mcL, but without significant bleeding. He was identified with a de novo heterozygous variant c.685C > T (p.Pro 229 Ser) that was not present in his parents.
Sources: Literature
Hereditary Neuropathy_CMT - isolated v1.28 PCK2 Bryony Thompson Marked gene: PCK2 as ready
Hereditary Neuropathy_CMT - isolated v1.28 PCK2 Bryony Thompson Gene: pck2 has been classified as Amber List (Moderate Evidence).
Hereditary Neuropathy_CMT - isolated v1.28 PCK2 Bryony Thompson Classified gene: PCK2 as Amber List (moderate evidence)
Hereditary Neuropathy_CMT - isolated v1.28 PCK2 Bryony Thompson Gene: pck2 has been classified as Amber List (Moderate Evidence).
Hereditary Neuropathy_CMT - isolated v1.26 PCK2 Bryony Thompson gene: PCK2 was added
gene: PCK2 was added to Hereditary Neuropathy_CMT - isolated. Sources: Literature
Mode of inheritance for gene: PCK2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCK2 were set to 36845668
Phenotypes for gene: PCK2 were set to Peripheral neuropathy (MONDO#0005244), PCK2-related
Mendeliome v1.700 PCK2 Bryony Thompson Classified gene: PCK2 as Amber List (moderate evidence)
Mendeliome v1.700 PCK2 Bryony Thompson Gene: pck2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.699 PCK2 Bryony Thompson reviewed gene: PCK2: Rating: AMBER; Mode of pathogenicity: None; Publications: 36845668; Phenotypes: Peripheral neuropathy (MONDO#0005244), PCK2-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1872 MCCC1 Lilian Downie reviewed gene: MCCC1: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 22642865; Phenotypes: 3-Methylcrotonyl-CoA carboxylase 1 deficiency MIM#210200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5182 CTR9 Achchuthan Shanmugasundram reviewed gene: CTR9: Rating: ; Mode of pathogenicity: None; Publications: 35717577; Phenotypes: ; Mode of inheritance: None
Regression v0.520 FTH1 Paul De Fazio gene: FTH1 was added
gene: FTH1 was added to Regression. Sources: Literature
Mode of inheritance for gene: FTH1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FTH1 were set to 36778397
Phenotypes for gene: FTH1 were set to Neuroferritinopathy (MONDO:0011638)
Mode of pathogenicity for gene: FTH1 was set to Other
Review for gene: FTH1 was set to AMBER
gene: FTH1 was marked as current diagnostic
Added comment: Note paper is pre-print hence Amber rating.

5 unrelated paediatric patients presented with developmental delay, epilepsy, and progressive neurologic decline. Heterozygous nonsense FTH1 variants were identified by WES in all patients, 4 of which were confirmed de novo. All variants are predicted to escape NMD and appear to act by a dominant toxic gain-of-function mechanism. p.F171* was recurrent in three unrelated individuals.

Patient fibroblasts show elevated ferritin protein levels, markers of oxidative stress, and increased susceptibility to iron accumulation. Targeted knock-down of mutant FTH1 transcript with rescues cellular phenotypes.

Note NMD-escape variants in gnomAD exist, upstream of the variants in patients.
Sources: Literature
Cerebellar and Pontocerebellar Hypoplasia v1.60 FTH1 Paul De Fazio changed review comment from: Note paper is pre-print hence Amber rating.

5 unrelated paediatric patients presented with developmental delay, epilepsy, and progressive neurologic decline. Heterozygous nonsense FTH1 variants were identified by WES in all patients, 4 of which were confirmed de novo. All variants are predicted to escape NMD and appear to act by a dominant toxic gain-of-function mechanism. p.F171* was recurrent in three unrelated individuals.

Patient fibroblasts show elevated ferritin protein levels, markers of oxidative stress, and increased susceptibility to iron accumulation. Targeted knock-down of mutant FTH1 transcript with rescues cellular phenotypes.

Note NMD-escape variants in gnomAD exist, upstream of the variants in patients.
Sources: Literature; to: Note paper is pre-print hence Amber rating.

5 unrelated paediatric patients presented with developmental delay, epilepsy, and progressive neurologic decline. All patients had pontocerebellar hypoplasia during infancy. Heterozygous nonsense FTH1 variants were identified by WES in all patients, 4 of which were confirmed de novo. All variants are predicted to escape NMD and appear to act by a dominant toxic gain-of-function mechanism. p.F171* was recurrent in three unrelated individuals.

Patient fibroblasts show elevated ferritin protein levels, markers of oxidative stress, and increased susceptibility to iron accumulation. Targeted knock-down of mutant FTH1 transcript with rescues cellular phenotypes.

Note NMD-escape variants in gnomAD exist, upstream of the variants in patients.
Sources: Literature
Cerebellar and Pontocerebellar Hypoplasia v1.60 FTH1 Seb Lunke Marked gene: FTH1 as ready
Cerebellar and Pontocerebellar Hypoplasia v1.60 FTH1 Seb Lunke Gene: fth1 has been classified as Amber List (Moderate Evidence).
Cerebellar and Pontocerebellar Hypoplasia v1.60 FTH1 Seb Lunke Classified gene: FTH1 as Amber List (moderate evidence)
Cerebellar and Pontocerebellar Hypoplasia v1.60 FTH1 Seb Lunke Gene: fth1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.699 FTH1 Paul De Fazio reviewed gene: FTH1: Rating: AMBER; Mode of pathogenicity: None; Publications: 36778397; Phenotypes: Neuroferritinopathy (MONDO:0011638); Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Cerebellar and Pontocerebellar Hypoplasia v1.59 FTH1 Paul De Fazio gene: FTH1 was added
gene: FTH1 was added to Cerebellar and Pontocerebellar Hypoplasia. Sources: Literature
Mode of inheritance for gene: FTH1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FTH1 were set to 36778397
Phenotypes for gene: FTH1 were set to Neuroferritinopathy (MONDO:0011638)
Mode of pathogenicity for gene: FTH1 was set to Other
Review for gene: FTH1 was set to AMBER
gene: FTH1 was marked as current diagnostic
Added comment: Note paper is pre-print hence Amber rating.

5 unrelated paediatric patients presented with developmental delay, epilepsy, and progressive neurologic decline. Heterozygous nonsense FTH1 variants were identified by WES in all patients, 4 of which were confirmed de novo. All variants are predicted to escape NMD and appear to act by a dominant toxic gain-of-function mechanism. p.F171* was recurrent in three unrelated individuals.

Patient fibroblasts show elevated ferritin protein levels, markers of oxidative stress, and increased susceptibility to iron accumulation. Targeted knock-down of mutant FTH1 transcript with rescues cellular phenotypes.

Note NMD-escape variants in gnomAD exist, upstream of the variants in patients.
Sources: Literature
Congenital Heart Defect v0.272 MCF2L Michelle Torres gene: MCF2L was added
gene: MCF2L was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: MCF2L was set to Unknown
Publications for gene: MCF2L were set to 36760094
Phenotypes for gene: MCF2L were set to vascular malformation MONDO:0024291, MCF2L-related
Review for gene: MCF2L was set to RED
Added comment: Three families with Systemic malformation (resulting in a left to right shunt instead of the right to left shunt seen in individuals with HHT) had missense variants in the MCF2L gene (families 1, 2 and 7).
Family 1 (Val875Met: v2 & v3: 113 hets) did no present PA (pulmonary artery).
Family 2 (Cys199Gly : v2 & v3: 260 hets, 1 hom) did no present PA (pulmonary artery).
Family 7: Leu130Pro (1 het, 0 hom), segregated in family 7 with SA-PA (systemic artery to the pulmonary artery), with 5x affected tested (Sanger or WES). Unaffected and other 6x individuals affected were not tested.
Sources: Literature
Neurodegeneration with brain iron accumulation v0.10 FTH1 Zornitza Stark Classified gene: FTH1 as Amber List (moderate evidence)
Neurodegeneration with brain iron accumulation v0.10 FTH1 Zornitza Stark Gene: fth1 has been classified as Amber List (Moderate Evidence).
Congenital Heart Defect v0.272 SMPD4 Elena Savva Classified gene: SMPD4 as Green List (high evidence)
Congenital Heart Defect v0.272 SMPD4 Elena Savva Gene: smpd4 has been classified as Green List (High Evidence).
Mendeliome v1.699 MCF2L Zornitza Stark Marked gene: MCF2L as ready
Mendeliome v1.699 MCF2L Zornitza Stark Gene: mcf2l has been classified as Red List (Low Evidence).
Congenital Heart Defect v0.272 SMPD4 Elena Savva Classified gene: SMPD4 as Green List (high evidence)
Congenital Heart Defect v0.272 SMPD4 Elena Savva Gene: smpd4 has been classified as Green List (High Evidence).
Mendeliome v1.699 MCF2L Zornitza Stark Classified gene: MCF2L as Red List (low evidence)
Mendeliome v1.699 MCF2L Zornitza Stark Gene: mcf2l has been classified as Red List (Low Evidence).
Congenital Heart Defect v0.271 SMPD4 Elena Savva Classified gene: SMPD4 as Green List (high evidence)
Congenital Heart Defect v0.271 SMPD4 Elena Savva Gene: smpd4 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.270 SMPD4 Elena Savva Marked gene: SMPD4 as ready
Congenital Heart Defect v0.270 SMPD4 Elena Savva Gene: smpd4 has been classified as Red List (Low Evidence).
Mendeliome v1.698 MCF2L Michelle Torres gene: MCF2L was added
gene: MCF2L was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MCF2L was set to Unknown
Publications for gene: MCF2L were set to 36760094
Phenotypes for gene: MCF2L were set to vascular malformation MONDO:0024291, MCF2L-related
Review for gene: MCF2L was set to RED
Added comment: Three families with Systemic malformation (resulting in a left to right shunt instead of the right to left shunt seen in individuals with HHT) had missense variants in the MCF2L gene (families 1, 2 and 7).
Family 1 (Val875Met: v2 & v3: 113 hets) did no present PA (pulmonary artery).
Family 2 (Cys199Gly : v2 & v3: 260 hets, 1 hom) did no present PA (pulmonary artery).
Family 7: Leu130Pro (1 het, 0 hom), segregated in family 7 with SA-PA (systemic artery to the pulmonary artery), with 5x affected tested (Sanger or WES). Unaffected and other 6x individuals affected were not tested.
Sources: Literature
Congenital Heart Defect v0.270 AMOTL1 Seb Lunke Marked gene: AMOTL1 as ready
Congenital Heart Defect v0.270 AMOTL1 Seb Lunke Gene: amotl1 has been classified as Green List (High Evidence).
Inflammatory bowel disease v0.90 PMM2 Zornitza Stark Marked gene: PMM2 as ready
Inflammatory bowel disease v0.90 PMM2 Zornitza Stark Gene: pmm2 has been classified as Red List (Low Evidence).
Inflammatory bowel disease v0.90 PMM2 Zornitza Stark Phenotypes for gene: PMM2 were changed from Inflammatory bowel disease, hyperinsulinism, polycystic kidney disease to Congenital disorder of glycosylation, type Ia, MIM# 212065; Inflammatory bowel disease, hyperinsulinism, polycystic kidney disease
Congenital Heart Defect v0.270 SMPD4 Elena Savva gene: SMPD4 was added
gene: SMPD4 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: SMPD4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SMPD4 were set to PMID: 36732302
Phenotypes for gene: SMPD4 were set to Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies MIM#618622
Review for gene: SMPD4 was set to GREEN
Added comment: PMID: 36732302 - 44% of patients have a type of congenital heart defect including ASD (16%), persistent ductus arteriosus (20%), long QT (4%), DCM (4%), VSD (8%) and transposition of the great arteries (4%)
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5182 AMOTL1 Seb Lunke Marked gene: AMOTL1 as ready
Intellectual disability syndromic and non-syndromic v0.5182 AMOTL1 Seb Lunke Gene: amotl1 has been classified as Green List (High Evidence).
Mendeliome v1.698 TRPV1 Krithika Murali reviewed gene: TRPV1: Rating: RED; Mode of pathogenicity: None; Publications: PMID: 36454632, PMID: 36472910; Phenotypes: Channelopathy-associated congenital insensitivity to pain, autosomal recessive - MONDO:0009459; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital Heart Defect v0.270 AMOTL1 Seb Lunke Classified gene: AMOTL1 as Green List (high evidence)
Congenital Heart Defect v0.270 AMOTL1 Seb Lunke Gene: amotl1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5182 AMOTL1 Seb Lunke Classified gene: AMOTL1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5182 AMOTL1 Seb Lunke Gene: amotl1 has been classified as Green List (High Evidence).
Inflammatory bowel disease v0.89 PMM2 Zornitza Stark Classified gene: PMM2 as Red List (low evidence)
Inflammatory bowel disease v0.89 PMM2 Zornitza Stark Gene: pmm2 has been classified as Red List (Low Evidence).
Mendeliome v1.698 TEFM Zornitza Stark Marked gene: TEFM as ready
Mendeliome v1.698 TEFM Zornitza Stark Gene: tefm has been classified as Green List (High Evidence).
Clefting disorders v0.194 AMOTL1 Seb Lunke Publications for gene: AMOTL1 were set to 33026150; 33026150
Intellectual disability syndromic and non-syndromic v0.5181 AMOTL1 Lucy Spencer gene: AMOTL1 was added
gene: AMOTL1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: AMOTL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AMOTL1 were set to 36751037
Phenotypes for gene: AMOTL1 were set to Orofacial clefting syndrome, MONDO:0015335, AMOTL1-related
Review for gene: AMOTL1 was set to GREEN
Added comment: PMID: 36751037- 16 individuals from 12 families with orofacial clefting syndrome and het variants in AMOTL1. Many in 1 hotspot: 5 individuals from 3 families have R157C, 6 individuals from another 4 families have R157H, 1 has P160L, and another has Q161R. Out of this hostpaot- 1 with P368A, 1 with E507K, 1 with E579K. 7 are de novo. All but 2 have clefting, 7 are dysmorphic, 5 have hearing loss, 9 have CHD, 7 have tall stature, 6 have dev delay. Other features include liver disease, myopia, scoliosis and immune involvement.

Another 2 families have been previously reported (described in the panelapp review in mendeliome) with variants in this hotspot 1 has 2 individuals with R157C, the other has 1 individual with P160L. All hotspot are absent from gnomad v2.
Sources: Literature
Monogenic Diabetes v0.37 SMPD4 Elena Savva Classified gene: SMPD4 as Green List (high evidence)
Monogenic Diabetes v0.37 SMPD4 Elena Savva Gene: smpd4 has been classified as Green List (High Evidence).
Mendeliome v1.698 TEFM Zornitza Stark Classified gene: TEFM as Green List (high evidence)
Mendeliome v1.698 TEFM Zornitza Stark Gene: tefm has been classified as Green List (High Evidence).
Monogenic Diabetes v0.36 SMPD4 Elena Savva Marked gene: SMPD4 as ready
Monogenic Diabetes v0.36 SMPD4 Elena Savva Gene: smpd4 has been classified as Red List (Low Evidence).
Mitochondrial disease v0.857 TEFM Zornitza Stark Marked gene: TEFM as ready
Mitochondrial disease v0.857 TEFM Zornitza Stark Gene: tefm has been classified as Green List (High Evidence).
Clefting disorders v0.193 AMOTL1 Seb Lunke Publications for gene: AMOTL1 were set to 33026150
Clefting disorders v0.192 AMOTL1 Seb Lunke Phenotypes for gene: AMOTL1 were changed from Cleft lip and palate; imperforate anus; dysmorphism to Orofacial clefting syndrome, MONDO:0015335, AMOTL1 -related
Clefting disorders v0.191 AMOTL1 Seb Lunke Classified gene: AMOTL1 as Green List (high evidence)
Clefting disorders v0.191 AMOTL1 Seb Lunke Gene: amotl1 has been classified as Green List (High Evidence).
Congenital Heart Defect v0.269 AMOTL1 Lucy Spencer gene: AMOTL1 was added
gene: AMOTL1 was added to Congenital Heart Defect. Sources: Literature
Mode of inheritance for gene: AMOTL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: AMOTL1 were set to 36751037
Phenotypes for gene: AMOTL1 were set to Orofacial clefting syndrome, MONDO:0015335, AMOTL1-related
Review for gene: AMOTL1 was set to GREEN
Added comment: PMID: 36751037- 16 individuals from 12 families with orofacial clefting syndrome and het variants in AMOTL1. Many in 1 hotspot: 5 individuals from 3 families have R157C, 6 individuals from another 4 families have R157H, 1 has P160L, and another has Q161R. Out of this hostpaot- 1 with P368A, 1 with E507K, 1 with E579K. 7 are de novo. All but 2 have clefting, 7 are dysmorphic, 5 have hearing loss, 9 have CHD, 7 have tall stature, 6 have dev delay. Other features include liver disease, myopia, scoliosis and immune involvement.

Another 2 families have been previously reported (described in the panelapp review below) with variants in this hotspot 1 has 2 individuals with R157C, the other has 1 individual with P160L. All hotspot are absent from gnomad v2.
Sources: Literature
Mendeliome v1.697 SLC25A36 Krithika Murali gene: SLC25A36 was added
gene: SLC25A36 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SLC25A36 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC25A36 were set to 34971397; 34576089; 31036718
Phenotypes for gene: SLC25A36 were set to Hyperinsulinemic hypoglycemia, familial, 8 - MIM#620211
Review for gene: SLC25A36 was set to GREEN
Added comment: Solute carrier family 25 members 33 (SLC25A33) and 36 (SLC25A36) are the only known mitochondrial pyrimidine nucleotide carriers in humans

PMID: 34971397 Sharoor et al 2022 report 2 siblings with hyperinsulinism, hypoglycemia and hyperammonemia from early infancy with homozygous SLC25A36 c.284 + 3 A > T variant identified through WES. Functional studies support LoF.

PMID: 34576089 report a 12-year-old patient with hypothyroidism, hyperinsulinism, hyperammonemia, chronical obstipation, short stature, along with language and general developmental delay. WES identified SLC25A36 gene homozygous c.803dupT, p.Ser269llefs*35 variant. Functional analysis of mutant SLC25A36 protein in proteoliposomes showed a virtually abolished transport activity. Immunoblotting results suggest that the mutant SLC25A36 protein in the patient undergoes fast degradation. Supplementation with uridine lead to some improvement in clinical course.

PMID: 31036718 deficiencies in SLC25A36 in mouse embryonic stem cells have been associated with mtDNA depletion as well as mitochondrial dysfunction
Sources: Literature
Mitochondrial disease v0.857 TEFM Zornitza Stark Classified gene: TEFM as Green List (high evidence)
Mitochondrial disease v0.857 TEFM Zornitza Stark Gene: tefm has been classified as Green List (High Evidence).
Mendeliome v1.697 AMOTL1 Seb Lunke Phenotypes for gene: AMOTL1 were changed from Cleft lip and palate; imperforate anus; dysmorphism to Orofacial clefting syndrome, MONDO:0015335, AMOTL1 -related
Monogenic Diabetes v0.36 SMPD4 Elena Savva gene: SMPD4 was added
gene: SMPD4 was added to Monogenic Diabetes. Sources: Literature
Mode of inheritance for gene: SMPD4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SMPD4 were set to PMID: 36732302
Phenotypes for gene: SMPD4 were set to Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies MIM#618622
Review for gene: SMPD4 was set to GREEN
Added comment: PMID: 36732302 - five individuals with microcephaly, brain anomalies and insulin-dependent diabetes in childhood. Reviews past reports, notes 27% of patients have insulin-dependent diabetes.
Sources: Literature
Mitochondrial disease v0.856 SLC25A36 Krithika Murali gene: SLC25A36 was added
gene: SLC25A36 was added to Mitochondrial disease. Sources: Literature
Mode of inheritance for gene: SLC25A36 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC25A36 were set to 34971397; 34576089; 31036718
Phenotypes for gene: SLC25A36 were set to Hyperinsulinemic hypoglycemia, familial, 8 - MIM#620211
Review for gene: SLC25A36 was set to GREEN
Added comment: Solute carrier family 25 members 33 (SLC25A33) and 36 (SLC25A36) are the only known mitochondrial pyrimidine nucleotide carriers in humans

PMID: 34971397 Sharoor et al 2022 report 2 siblings with hyperinsulinism, hypoglycemia and hyperammonemia from early infancy with homozygous SLC25A36 c.284 + 3 A > T variant identified through WES. Functional studies support LoF.

PMID: 34576089 report a 12-year-old patient with hypothyroidism, hyperinsulinism, hyperammonemia, chronical obstipation, short stature, along with language and general developmental delay. WES identified SLC25A36 gene homozygous c.803dupT, p.Ser269llefs*35 variant. Functional analysis of mutant SLC25A36 protein in proteoliposomes showed a virtually abolished transport activity. Immunoblotting results suggest that the mutant SLC25A36 protein in the patient undergoes fast degradation. Supplementation with uridine lead to some improvement in clinical course.

PMID: 31036718 deficiencies in SLC25A36 in mouse embryonic stem cells have been associated with mtDNA depletion as well as mitochondrial dysfunction
Sources: Literature
Inflammatory bowel disease v0.88 PMM2 Sarah Pantaleo gene: PMM2 was added
gene: PMM2 was added to Inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: PMM2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PMM2 were set to 36773065
Phenotypes for gene: PMM2 were set to Inflammatory bowel disease, hyperinsulinism, polycystic kidney disease
Penetrance for gene: PMM2 were set to Incomplete
Review for gene: PMM2 was set to RED
Added comment: “A specific pattern of variation in PMM2 as a novel association of early-onset IBD with distinctive gastric pathology.”

Cohort of patients affected by hyperinsulinaemic hypoglycaemia and ARPKD with a specific underlying variant in the PMM2 promoter. Three of these patients additionally developed IBD in childhood and manifest a distinctive pattern of gastric antral disease involvement.

The authors describe the development of IBD in three patients with PMM2-HIPKD, with onset of IBD at 0, 6 and 10 years of age. IBD was of variable severity at onset. The organ level pattern of disease manifestations in PMM2-HIPKD-IBD may reflect a loss of cis-acting regulatory control by hepatocyte nuclear factor 4 alpha (HNF4A).

All three patients have the same genotype, two pathogenic variants (ClinVar): A promoter variant, c.-167G>T, in trans with c.422G>A; p.(Arg141His). The promoter region is not covered in gnomAD. c.422G>A is in gnomAD v2 891 hets, v3 557 hets.

Functional studies: Protein expression of PMM2 and HNF4A assessed by immunohistochemistry for two patients. Patient 1 there appeared to be reduced protein expression compared to the control, especially in the gastric antrum and colon, but for patient 2, the expression profile closely matched the control.

Observation of intestinal inflammation and gastric antral foveolar hyperplasia in three patients with identical pathogenic genetic variants in the PMM2 locus, from independent kindreds, extends the previously reported spectrum of PMM2-related HI/ARPKD disease. It identifies PMM2 as a potential novel Mendelian association of early-onset IBD. Estimate low penetrance of IBD of 10% based on 30 patients in the literature.
Sources: Literature
Mendeliome v1.696 AMOTL1 Seb Lunke Publications for gene: AMOTL1 were set to 33026150
Hyperammonaemia v0.10 SLC25A36 Zornitza Stark Marked gene: SLC25A36 as ready
Hyperammonaemia v0.10 SLC25A36 Zornitza Stark Gene: slc25a36 has been classified as Green List (High Evidence).
Hyperammonaemia v0.10 SLC25A36 Zornitza Stark Classified gene: SLC25A36 as Green List (high evidence)
Hyperammonaemia v0.10 SLC25A36 Zornitza Stark Gene: slc25a36 has been classified as Green List (High Evidence).
Hyperinsulinism v1.8 SLC25A36 Zornitza Stark Marked gene: SLC25A36 as ready
Hyperinsulinism v1.8 SLC25A36 Zornitza Stark Gene: slc25a36 has been classified as Green List (High Evidence).
Hyperinsulinism v1.8 SLC25A36 Zornitza Stark Classified gene: SLC25A36 as Green List (high evidence)
Hyperinsulinism v1.8 SLC25A36 Zornitza Stark Gene: slc25a36 has been classified as Green List (High Evidence).
Mendeliome v1.695 TEFM Ee Ming Wong gene: TEFM was added
gene: TEFM was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TEFM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TEFM were set to 36823193
Phenotypes for gene: TEFM were set to Mitochondrial disease (MONDO#0044970), TEFM-related
Review for gene: TEFM was set to GREEN
gene: TEFM was marked as current diagnostic
Added comment: - Seven TEFM variants (4 missense, 2 fs, 1 in-frame del) in seven individuals across five unrelated families
- Muscle and primary fibroblast from the affected individuals have reduced levels of promoter distal mitochondrial RNA transcripts
- TEFM knockdown in zebrafish embryos resulted in neuromuscular junction abnormalities and abnormal mitochondrial function
Sources: Literature
Mendeliome v1.695 AMOTL1 Seb Lunke Classified gene: AMOTL1 as Green List (high evidence)
Mendeliome v1.695 AMOTL1 Seb Lunke Gene: amotl1 has been classified as Green List (High Evidence).
Hereditary Neuropathy - complex v0.142 COQ7 Zornitza Stark Publications for gene: COQ7 were set to PMID: 36454683
Hyperammonaemia v0.9 SLC25A36 Krithika Murali gene: SLC25A36 was added
gene: SLC25A36 was added to Hyperammonaemia. Sources: Literature
Mode of inheritance for gene: SLC25A36 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC25A36 were set to 34971397; 34576089; 31036718
Phenotypes for gene: SLC25A36 were set to Hyperinsulinemic hypoglycemia, familial, 8 - MIM#620211
Review for gene: SLC25A36 was set to GREEN
Added comment: Solute carrier family 25 members 33 (SLC25A33) and 36 (SLC25A36) are the only known mitochondrial pyrimidine nucleotide carriers in humans

PMID: 34971397 Sharoor et al 2022 report 2 siblings with hyperinsulinism, hypoglycemia and hyperammonemia from early infancy with homozygous SLC25A36 c.284 + 3 A > T variant identified through WES. Functional studies support LoF.

PMID: 34576089 report a 12-year-old patient with hypothyroidism, hyperinsulinism, hyperammonemia, chronical obstipation, short stature, along with language and general developmental delay. WES identified SLC25A36 gene homozygous c.803dupT, p.Ser269llefs*35 variant. Functional analysis of mutant SLC25A36 protein in proteoliposomes showed a virtually abolished transport activity. Immunoblotting results suggest that the mutant SLC25A36 protein in the patient undergoes fast degradation. Supplementation with uridine lead to some improvement in clinical course.

PMID: 31036718 deficiencies in SLC25A36 in mouse embryonic stem cells have been associated with mtDNA depletion as well as mitochondrial dysfunction
Sources: Literature
Hereditary Neuropathy - complex v0.141 COQ7 Zornitza Stark Classified gene: COQ7 as Green List (high evidence)
Hereditary Neuropathy - complex v0.141 COQ7 Zornitza Stark Gene: coq7 has been classified as Green List (High Evidence).
Clefting disorders v0.190 AMOTL1 Lucy Spencer reviewed gene: AMOTL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 33026150; Phenotypes: Orofacial clefting syndrome, MONDO:0015335, AMOTL1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mitochondrial disease v0.856 TEFM Ee Ming Wong gene: TEFM was added
gene: TEFM was added to Mitochondrial disease. Sources: Literature
Mode of inheritance for gene: TEFM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TEFM were set to 36823193
Phenotypes for gene: TEFM were set to Mitochondrial disease (MONDO#0044970), TEFM-related
Review for gene: TEFM was set to GREEN
gene: TEFM was marked as current diagnostic
Added comment: - Seven TEFM variants (4 missense, 2 fs, 1 in-frame del) in seven individuals across five unrelated families
- Muscle and primary fibroblast from the affected individuals have reduced levels of promoter distal mitochondrial RNA transcripts
- TEFM knockdown in zebrafish embryos resulted in neuromuscular junction abnormalities and abnormal mitochondrial function
Sources: Literature
Hyperinsulinism v1.7 SLC25A36 Krithika Murali gene: SLC25A36 was added
gene: SLC25A36 was added to Hyperinsulinism. Sources: Literature
Mode of inheritance for gene: SLC25A36 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC25A36 were set to 34971397; 34576089; 31036718
Phenotypes for gene: SLC25A36 were set to Hyperinsulinemic hypoglycemia, familial, 8 - MIM#620211
Review for gene: SLC25A36 was set to GREEN
Added comment: Solute carrier family 25 members 33 (SLC25A33) and 36 (SLC25A36) are the only known mitochondrial pyrimidine nucleotide carriers in humans

PMID: 34971397 Sharoor et al 2022 report 2 siblings with hyperinsulinism, hypoglycemia and hyperammonemia from early infancy with homozygous SLC25A36 c.284 + 3 A > T variant identified through WES. Functional studies support LoF.

PMID: 34576089 report a 12-year-old patient with hypothyroidism, hyperinsulinism, hyperammonemia, chronical obstipation, short stature, along with language and general developmental delay. WES identified SLC25A36 gene homozygous c.803dupT, p.Ser269llefs*35 variant. Functional analysis of mutant SLC25A36 protein in proteoliposomes showed a virtually abolished transport activity. Immunoblotting results suggest that the mutant SLC25A36 protein in the patient undergoes fast degradation. Supplementation with uridine lead to some improvement in clinical course.

PMID: 31036718 deficiencies in SLC25A36 in mouse embryonic stem cells have been associated with mtDNA depletion as well as mitochondrial dysfunction
Sources: Literature
Hereditary Neuropathy - complex v0.140 COQ7 Chern Lim reviewed gene: COQ7: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID:36758993, 36759155; Phenotypes: Distal hereditary motor neuropathy (MONDO#0018894), COQ7-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.694 AMOTL1 Lucy Spencer reviewed gene: AMOTL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36751037; Phenotypes: Orofacial clefting syndrome, MONDO:0015335, AMOTL1 -related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Polydactyly v0.266 HMGB1 Ain Roesley Phenotypes for gene: HMGB1 were changed from brachyphalangy, polydactyly, and tibial aplasia/hypoplasia MIM#163905 to brachyphalangy, polydactyly, and tibial aplasia/hypoplasia MIM#163905
Polydactyly v0.265 HMGB1 Ain Roesley Phenotypes for gene: HMGB1 were changed from Mirror image foot polydactyly to brachyphalangy, polydactyly, and tibial aplasia/hypoplasia MIM#163905
Polydactyly v0.265 HMGB1 Ain Roesley Publications for gene: HMGB1 were set to 34159400
Fetal anomalies v1.89 HMGB1 Ain Roesley Phenotypes for gene: HMGB1 were changed from Neurodevelopmental disorder MONDO:0700092, HMGB1-related; microcephaly; intellectual disability to Neurodevelopmental disorder MONDO:0700092, HMGB1-related; microcephaly; intellectual disability; brachyphalangy, polydactyly, and tibial aplasia/hypoplasia MIM#163905
Fetal anomalies v1.89 HMGB1 Ain Roesley Publications for gene: HMGB1 were set to 34164801
Mendeliome v1.694 HMGB1 Ain Roesley Phenotypes for gene: HMGB1 were changed from Mirror image foot polydactyly; Neurodevelopmental disorder MONDO:0700092, HMGB1-related to brachyphalangy, polydactyly, and tibial aplasia/hypoplasia MIM#163905; Neurodevelopmental disorder MONDO:0700092, HMGB1-related
Mendeliome v1.694 HMGB1 Ain Roesley Publications for gene: HMGB1 were set to 34159400; 34164801
Mendeliome v1.693 LGR4 Elena Savva Phenotypes for gene: LGR4 were changed from {Bone mineral density, low, susceptibility to} MIM#615311; Delayed puberty, self-limited MIM#619613; Syndromic disease, LGR4-related (MONDO#0002254) to {Bone mineral density, low, susceptibility to} MIM#615311; Delayed puberty, self-limited MIM#619613; Syndromic disease, LGR4-related (MONDO#0002254)
Polydactyly v0.265 HMGB1 Ain Roesley Classified gene: HMGB1 as Green List (high evidence)
Polydactyly v0.265 HMGB1 Ain Roesley Gene: hmgb1 has been classified as Green List (High Evidence).
Mendeliome v1.692 LGR4 Elena Savva Phenotypes for gene: LGR4 were changed from Delayed puberty to {Bone mineral density, low, susceptibility to} MIM#615311; Delayed puberty, self-limited MIM#619613; Syndromic disease, LGR4-related (MONDO#0002254)
Mendeliome v1.691 HMGB1 Ain Roesley edited their review of gene: HMGB1: Added comment: PMID:36755093
4 new families with de novo protein truncating variants.

In addition with PMID 34159400 ( all de novos)

c.556_559delGAAG;p.(Glu186Argfs*42) - 1 family
c.551_554delAGAA;p.(Lys184Argfs*44) - 4 families; Changed rating: GREEN; Changed publications: 34159400, 36755093; Changed phenotypes: brachyphalangy, polydactyly, and tibial aplasia/hypoplasia MIM#163905; Set current diagnostic: yes
Fetal anomalies v1.88 HMGB1 Ain Roesley reviewed gene: HMGB1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36755093, 34159400; Phenotypes: brachyphalangy, polydactyly, and tibial aplasia/hypoplasia MIM#163905; Mode of inheritance: None; Current diagnostic: yes
Mendeliome v1.691 LGR4 Elena Savva Publications for gene: LGR4 were set to 32493844
Mendeliome v1.690 LGR4 Elena Savva Mode of inheritance for gene: LGR4 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Polydactyly v0.264 HMGB1 Ain Roesley edited their review of gene: HMGB1: Added comment: PMID:36755093
4 new families with de novo protein truncating variants.

In addition with PMID 34159400,

c.556_559delGAAG;p.(Glu186Argfs*42) - 1 family
c.551_554delAGAA;p.(Lys184Argfs*44) - 4 families; Changed rating: GREEN; Changed publications: 34159400, 36755093; Changed phenotypes: brachyphalangy, polydactyly, and tibial aplasia/hypoplasia MIM#163905
Neurodegeneration with brain iron accumulation v0.9 FTH1 Paul De Fazio gene: FTH1 was added
gene: FTH1 was added to Neuroferritinopathies. Sources: Literature
Mode of inheritance for gene: FTH1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FTH1 were set to 36778397
Phenotypes for gene: FTH1 were set to Neuroferritinopathy (MONDO:0011638)
Mode of pathogenicity for gene: FTH1 was set to Other
Review for gene: FTH1 was set to AMBER
gene: FTH1 was marked as current diagnostic
Added comment: Note paper is pre-print hence Amber rating.

5 unrelated paediatric patients presented with developmental delay, epilepsy, and progressive neurologic decline. Heterozygous nonsense FTH1 variants were identified by WES in all patients, 4 of which were confirmed de novo. All variants are predicted to escape NMD and appear to act by a dominant toxic gain-of-function mechanism. p.F171* was recurrent in three unrelated individuals.

Patient fibroblasts show elevated ferritin protein levels, markers of oxidative stress, and increased susceptibility to iron accumulation. Targeted knock-down of mutant FTH1 transcript with rescues cellular phenotypes.

Note NMD-escape variants in gnomAD exist, upstream of the variants in patients.
Sources: Literature
Pain syndromes v0.34 TRPV1 Zornitza Stark Marked gene: TRPV1 as ready
Pain syndromes v0.34 TRPV1 Zornitza Stark Gene: trpv1 has been classified as Red List (Low Evidence).
Pain syndromes v0.34 TRPV1 Zornitza Stark Classified gene: TRPV1 as Red List (low evidence)
Pain syndromes v0.34 TRPV1 Zornitza Stark Gene: trpv1 has been classified as Red List (Low Evidence).
Mendeliome v1.689 LGR4 Elena Savva changed review comment from: PMID: 36538378 - hom canonical splice variant in an infant with failure to thrive, severe salt-wasting crises associated with isolated hypoaldosteronism, nail anomalies, short stature, and deafness. Multiple affected siblings but all deceased, two normal siblings found to be het or wildtype. Functional studies proved INFRAME exon 6 skipping, patients cell shad minimal protein.
Conditional K/O mouse model showed reduced expression of Wnt target genes, adrenal hypoplasia and aberrant zonal differentiation

gnomAD: no hom PTCs

PMID: 32493844 - 6 patients with delayed puberty, supported by functional studies on mice displaying impaired Wnt/β-catenin signaling. Recurring missense p.G363C present in 4/6 families, but super common in the population (67 homozygotes).; to: PMID: 36538378 - hom canonical splice variant in an infant with failure to thrive, severe salt-wasting crises associated with isolated hypoaldosteronism, nail anomalies, short stature, and deafness. Multiple affected siblings but all deceased, two normal siblings found to be het or wildtype. Functional studies proved INFRAME exon 6 skipping, patients cell shad minimal protein.
Conditional K/O mouse model showed reduced expression of Wnt target genes, adrenal hypoplasia and aberrant zonal differentiation

gnomAD: no hom PTCs

PMID: 32493844 - 6 patients with delayed puberty, supported by functional studies on mice displaying impaired Wnt/β-catenin signaling. Recurring missense p.G363C present in 4/6 families, but super common in the population (67 homozygotes).
Mendeliome v1.689 LGR4 Elena Savva edited their review of gene: LGR4: Added comment: PMID: 36538378 - hom canonical splice variant in an infant with failure to thrive, severe salt-wasting crises associated with isolated hypoaldosteronism, nail anomalies, short stature, and deafness. Multiple affected siblings but all deceased, two normal siblings found to be het or wildtype. Functional studies proved INFRAME exon 6 skipping, patients cell shad minimal protein.
Conditional K/O mouse model showed reduced expression of Wnt target genes, adrenal hypoplasia and aberrant zonal differentiation

gnomAD: no hom PTCs

PMID: 32493844 - 6 patients with delayed puberty, supported by functional studies on mice displaying impaired Wnt/β-catenin signaling. Recurring missense p.G363C present in 4/6 families, but super common in the population (67 homozygotes).; Changed publications: PMID: 32493844, 36538378; Changed phenotypes: {Bone mineral density, low, susceptibility to} MIM#615311; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Pain syndromes v0.33 TRPV1 Krithika Murali changed review comment from: PMID: 36454632 Katz et al 2023 describe two individuals from a consanguineous Palestinian Arab family with elevated heat pain and cold pain threshold with insensitivity to application of capsaicin to mouth and skin. No obvious associated health issues reported in this 11 year old and 1 year old individual secondary to this. Homozygous TPRV1 c.993C>G; p.N331K variant identified in both individuals (absent from gnomAD, highly conserved). Variant cell lines demonstrated loss of channel function with normal expression. In addition, homozygous PROKR1 variant identified in both affected individuals with potential for contribution to phenotype.

PMID: 36472910 - knockin mouse models with missense TRPV1 variant (K710N) also showed reduced capsaicin-induced calcium influx in dorsal root ganglion neurons.
Sources: Literature; to: PMID: 36454632 Katz et al 2023 describe two individuals from a consanguineous Palestinian Arab family with elevated heat pain and cold pain threshold with insensitivity to application of capsaicin to mouth and skin. No obvious associated health issues reported in this 11 year old and 1 year old individual secondary to this. Homozygous TPRV1 c.993C>G; p.N331K variant identified in both individuals (absent from gnomAD, highly conserved). Variant cell lines demonstrated loss of channel function with normal expression. In addition, homozygous PROKR1 gene variant identified in both affected individuals with potential for contribution to phenotype.

PMID: 36472910 - knockin mouse models with missense TRPV1 variant (K710N) also showed reduced capsaicin-induced calcium influx in dorsal root ganglion neurons.
Sources: Literature
Pain syndromes v0.33 TRPV1 Krithika Murali gene: TRPV1 was added
gene: TRPV1 was added to Pain syndromes. Sources: Literature
Mode of inheritance for gene: TRPV1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRPV1 were set to PMID: 36454632; PMID: 36472910
Phenotypes for gene: TRPV1 were set to Channelopathy-associated congenital insensitivity to pain, autosomal recessive - MONDO:0009459
Review for gene: TRPV1 was set to RED
Added comment: PMID: 36454632 Katz et al 2023 describe two individuals from a consanguineous Palestinian Arab family with elevated heat pain and cold pain threshold with insensitivity to application of capsaicin to mouth and skin. No obvious associated health issues reported in this 11 year old and 1 year old individual secondary to this. Homozygous TPRV1 c.993C>G; p.N331K variant identified in both individuals (absent from gnomAD, highly conserved). Variant cell lines demonstrated loss of channel function with normal expression. In addition, homozygous PROKR1 variant identified in both affected individuals with potential for contribution to phenotype.

PMID: 36472910 - knockin mouse models with missense TRPV1 variant (K710N) also showed reduced capsaicin-induced calcium influx in dorsal root ganglion neurons.
Sources: Literature
Mendeliome v1.689 USMG5 Bryony Thompson Marked gene: USMG5 as ready
Mendeliome v1.689 USMG5 Bryony Thompson Gene: usmg5 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.689 USMG5 Bryony Thompson Classified gene: USMG5 as Amber List (moderate evidence)
Mendeliome v1.689 USMG5 Bryony Thompson Gene: usmg5 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.688 USMG5 Bryony Thompson gene: USMG5 was added
gene: USMG5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: USMG5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: USMG5 were set to 29917077; 30240627
Phenotypes for gene: USMG5 were set to Mitochondrial complex V (ATP synthase) deficiency, nuclear type 6 MIM#618683
Review for gene: USMG5 was set to AMBER
Added comment: A homozygous splice site mutation in 4 patients from 3 unrelated families of Ashkenazi Jewish descent. Experimental analyses demonstrated that the splice variant leads to loss of protein expression and haplotype analysis suggested a founder effect. In situ cryo-ET analysis of the mitochondria of a homozygous affected case showed profound disturbances of mitochondrial crista ultrastructure.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5181 SLC35B2 Zornitza Stark Marked gene: SLC35B2 as ready
Intellectual disability syndromic and non-syndromic v0.5181 SLC35B2 Zornitza Stark Gene: slc35b2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5181 SLC35B2 Zornitza Stark Classified gene: SLC35B2 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.5181 SLC35B2 Zornitza Stark Gene: slc35b2 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5180 SLC35B2 Zornitza Stark gene: SLC35B2 was added
gene: SLC35B2 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: SLC35B2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC35B2 were set to 35325049
Phenotypes for gene: SLC35B2 were set to Leukodystrophy, hypomyelinating, 26, with chondrodysplasia, MIM# 620269
Review for gene: SLC35B2 was set to AMBER
Added comment: 2 x individuals with homozygous variants (c.1218_1220del and c.1224_1225del) in SLC35B2. Phenotypes included pre- and postnatal growth retardation, scoliosis, severe motor and intellectual disabilities and hypomyelinating leukodystrophy. Functional analysis on patient cells showed that the variants result in a decreased expression of mRNA and affect protein subcellular localization leading to functional impairment of the protein.
Sources: Literature
Leukodystrophy - paediatric v0.282 SLC35B2 Zornitza Stark edited their review of gene: SLC35B2: Changed phenotypes: Leukodystrophy, hypomyelinating, 26, with chondrodysplasia, MIM# 620269
Mendeliome v1.687 SLC35B2 Zornitza Stark Phenotypes for gene: SLC35B2 were changed from Leukodystrophy, MONDO:0019046, SLC35B2-related to Leukodystrophy, hypomyelinating, 26, with chondrodysplasia, MIM# 620269
Mendeliome v1.686 SLC35B2 Zornitza Stark reviewed gene: SLC35B2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Leukodystrophy, hypomyelinating, 26, with chondrodysplasia, MIM# 620269; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5179 EMC1 Achchuthan Shanmugasundram reviewed gene: EMC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35234901; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5179 ATG4D Zornitza Stark Marked gene: ATG4D as ready
Intellectual disability syndromic and non-syndromic v0.5179 ATG4D Zornitza Stark Gene: atg4d has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5179 ATG4D Zornitza Stark Phenotypes for gene: ATG4D were changed from neurodevelopmental disorder; Abnormal facial shape to Neurodevelopmental disorder, MONDO:0700092, ATG4D-related
Intellectual disability syndromic and non-syndromic v0.5178 ATG4D Zornitza Stark Classified gene: ATG4D as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5178 ATG4D Zornitza Stark Gene: atg4d has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5177 ATG4D Zornitza Stark reviewed gene: ATG4D: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, ATG4D-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.686 ATG4D Zornitza Stark Marked gene: ATG4D as ready
Mendeliome v1.686 ATG4D Zornitza Stark Gene: atg4d has been classified as Green List (High Evidence).
Mendeliome v1.686 ATG4D Zornitza Stark Phenotypes for gene: ATG4D were changed from neurodevelopmental disorder; Abnormal facial shape to Neurodevelopmental disorder, MONDO:0700092, ATG4D-related
Mendeliome v1.685 ATG4D Zornitza Stark Classified gene: ATG4D as Green List (high evidence)
Mendeliome v1.685 ATG4D Zornitza Stark Gene: atg4d has been classified as Green List (High Evidence).
Mendeliome v1.684 ATG4D Zornitza Stark reviewed gene: ATG4D: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, ATG4D-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.684 NLGN4X Elena Savva reviewed gene: NLGN4X: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 36747195; Phenotypes: Intellectual developmental disorder, X-linked MIM#300495; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Proteinuria v0.215 GLA Ain Roesley Phenotypes for gene: GLA were changed from Fairy disease, MIM# 301500 to Fabry disease, MIM# 301500
Disorders of immune dysregulation v0.166 DOCK2 Peter McNaughton gene: DOCK2 was added
gene: DOCK2 was added to Disorders of immune dysregulation. Sources: Literature
Mode of inheritance for gene: DOCK2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DOCK2 were set to PMID: 36836791
Phenotypes for gene: DOCK2 were set to HLH
Review for gene: DOCK2 was set to AMBER
Added comment: Patient with recurrent HLH. Heterozygous c.1334A>G (p.Asn445Ser) variant. Functional studies showing lower CD107a expression and diminished NK degranulation and cytotoxicity. ? partial dominant negative.
Sources: Literature
Hyperammonaemia v0.9 Bryony Thompson Panel types changed to Victorian Clinical Genetics Services; Royal Melbourne Hospital; Rare Disease
BabyScreen+ newborn screening v0.1872 MAT1A Lilian Downie reviewed gene: MAT1A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Methionine adenosyltransferase deficiency MIM#250850; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1872 LIAS Lilian Downie gene: LIAS was added
gene: LIAS was added to gNBS. Sources: Expert list
Mode of inheritance for gene: LIAS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LIAS were set to PMID: 24334290, 24777537,
Phenotypes for gene: LIAS were set to Hyperglycinemia, lactic acidosis, and seizures MIM#614462
Review for gene: LIAS was set to RED
Added comment: pyruvate dehydrogenase lipoic acid synthetase deficiency (PDHLD)
increased serum glycine and lactate in the first days of life, hypotonia, seizures, early death
No treatment
Sources: Expert list
BabyScreen+ newborn screening v0.1872 HPD Lilian Downie reviewed gene: HPD: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 9343288, PMID: 11916315, PMID: 32520295; Phenotypes: Tyrosinemia, type III MIM#276710; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1872 HMGCS2 Lilian Downie gene: HMGCS2 was added
gene: HMGCS2 was added to gNBS. Sources: Expert list
Mode of inheritance for gene: HMGCS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HMGCS2 were set to PMID: 32259399, 32470406
Phenotypes for gene: HMGCS2 were set to HMG-CoA synthase-2 deficiency MIM#605911
Penetrance for gene: HMGCS2 were set to Incomplete
Review for gene: HMGCS2 was set to AMBER
Added comment: Metabolic disorder; patients present with hypoketotic hypoglycemia, encephalopathy, and hepatomegaly, usually precipitated by an intercurrent infection or prolonged fasting. Recover completely between illnesses, do develop fatty liver.
?incomplete penetrance or variable age of onset
On GUARDIAN and Rx Genes
Rx IV glucose during acute episodes, avoid prolonged fasting
Metabolic parameters are normal in between episodes, so no ability to do a confirmatory biochemical test.
Pros: readily treatable if child has an episode Cons: unncessary worry as child may never have episode
Super rare ?30 cases
Discuss with JC?
Sources: Expert list
BabyScreen+ newborn screening v0.1872 HIBCH Lilian Downie reviewed gene: HIBCH: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32642440, PMID: 17160907, PMID: 27400804; Phenotypes: 3-hydroxyisobutryl-CoA hydrolase deficiency MIM#250620; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v0.229 DDRGK1 Achchuthan Shanmugasundram gene: DDRGK1 was added
gene: DDRGK1 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: DDRGK1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DDRGK1 were set to 28263186; 35377455; 35670300; 36243336
Phenotypes for gene: DDRGK1 were set to Spondyloepimetaphyseal dysplasia, Shohat type, OMIM:602557
Review for gene: DDRGK1 was set to GREEN
Added comment: Comment on gene classification: This gene should be rated GREEN as it has been associated with Spondyloepimetaphyseal dysplasia, Shohat type from seven unrelated cases from multiple ethnicities and supported by functional studies.

PMID:28263186 reported six individuals from three different families of Iraqi Jewish descent (three patients from family 1 and one individual each from families 2-4) identified with homozygous c.408+1G>A donor splice site loss-of-function mutation in DDRGK1 and presented with Shohat-type spondyloepimetaphyseal dysplasia (SEMD). It is a skeletal dysplasia that affects cartilage development.

PMID: 35670300 reported two unrelated cases of Moroccan descent identified with homozygous missense variant c.406G>A and presented with SEMD. PMID:36243336 reported an Omani female patient identified with the same homozygous variant as the Iraqi cases and was reported with SEMD.

In addition, studies on both zebrafish and mouse models confirms the physiological role of DDRGK1 in the development and maintenance of the growth plate cartilage and deficiency of DDRGK1 recapitulate the clinical phenotype of short stature and joint abnormalities observed in patients with Shohat type SEMD (PMID:28263186; PMID:35377455).

This gene has been associated with relevant phenotype in OMIM (MIM #602557), but not in Gene2Phenotype.
Sources: Literature
BabyScreen+ newborn screening v0.1872 GLIS3 Lilian Downie reviewed gene: GLIS3: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 29406006, 29992946, 27899417, PMID: 26259131; Phenotypes: Diabetes mellitus, neonatal, with congenital hypothyroidism MIM#610199; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1872 GATM Lilian Downie gene: GATM was added
gene: GATM was added to gNBS. Sources: Expert list
Mode of inheritance for gene: GATM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GATM were set to PMID: 20301745, 34972654
Phenotypes for gene: GATM were set to Cerebral creatine deficiency syndrome 3 MIM#612718
Review for gene: GATM was set to GREEN
Added comment: GUARDIAN gene list (not on babyseq or rxgenes)
ID and myopathy, early onset
Rx creatine
Seems like a good fit? I'm not clear from the literature how effective the treatment is. check with JC
Sources: Expert list
BabyScreen+ newborn screening v0.1872 FOXE1 Lilian Downie reviewed gene: FOXE1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 33272083, 2918525, 20453517, 35963604; Phenotypes: Bamforth-Lazarus syndrome MIM# 241850; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1872 ALDH4A1 Lilian Downie reviewed gene: ALDH4A1: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31884946, 34037900, 30930802, 34302426; Phenotypes: Hyperprolinemia, type II MIM#239510; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1872 ACADSB Lilian Downie reviewed gene: ACADSB: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: 2-methylbutyrylglycinuria MIM#610006; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Dystonia - isolated/combined v1.30 CACNA1B Bryony Thompson Marked gene: CACNA1B as ready
Dystonia - isolated/combined v1.30 CACNA1B Bryony Thompson Gene: cacna1b has been classified as Red List (Low Evidence).
Dystonia - isolated/combined v1.30 CACNA1B Bryony Thompson gene: CACNA1B was added
gene: CACNA1B was added to Dystonia - isolated/combined. Sources: Other
Mode of inheritance for gene: CACNA1B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CACNA1B were set to 25296916; 26157024; 35698023; 33051750; 35041927
Phenotypes for gene: CACNA1B were set to Myoclonus-dystonia syndrome MONDO:0000903
Review for gene: CACNA1B was set to RED
Added comment: The original report of the association of the gene with dystonia was a variant with a higher allele frequency than expected for a variant. There have been no compelling reports since.
PMID: 25296916 - c.4166G>A:p.R1389H was identified segregating in a family with myoclonus dystonia (M-D) and in vitro assays of the variant demonstrated an effect on protein function. However, the variant is present in 122 hets in gnomAD v2.1 (AF 0.04%) which is higher than expected for a dominant disease.
PMID: 26157024 - study with a case-control analysis that does not support a causal association for c.4166G>A:p.R1389H with M-D
PMID: 35698023 - c.2681A > T; p.K894M was identified in 2 siblings with generalised dystonia. Both parents were unaffected and did not undergo testing for the variant. However, this variant is present in 25 hets in gnomAD v3.1 (AF 0.02%) which is higher than expected for a dominant disease.
PMID: 33051750 - reports 2 CACNA1B variants in an isolated focal dystonia cohort, but the quality of the study is questionable. They report a supposed 2 bp deletion, but the screenshot of the reads is an apparent 1 bp deletion and the frequency in the cohort is questionable. They also report a missense c.6834T>G pLeu2215Arg, which is actually a common benign synonymous variant NM_000718.4(CACNA1B):c.6831T>G (p.Thr2277=)
PMID: 35041927 - Taiwanese dystonia cohort - c.6506A>T(p.N2169I - 1 het in gnomAD v3.1) was identified in case with childhood-onset of segmental dystonia involving the face, neck, and shoulder, associated with myoclonus. FH present, but segregation not possible. c.6694C>G (p.L2232V - absent in gnomAD) and c.6928G>A (p.V2310M - 3 hets in gnomAD v3.1) were identified each in a case with sporadic cervical dystonia. All VUS.
Sources: Other
Dystonia - isolated/combined v1.29 RELN Bryony Thompson Marked gene: RELN as ready
Dystonia - isolated/combined v1.29 RELN Bryony Thompson Gene: reln has been classified as Red List (Low Evidence).
Dystonia - isolated/combined v1.29 RELN Bryony Thompson gene: RELN was added
gene: RELN was added to Dystonia - isolated/combined. Sources: Other
Mode of inheritance for gene: RELN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RELN were set to 32334381; 25648840
Phenotypes for gene: RELN were set to Myoclonus-dystonia syndrome MONDO:0000903
Review for gene: RELN was set to RED
Added comment: Only identified a single proband with a rare de novo variant with a complex myoclonus-dystonia syndrome phenotype. Other study with segregation evidence, were missense variants that are too common in gnomAD v2.1
PMID: 32334381 - de novo c.6259T > C; W2087R. Male proband age of onset 26 yrs, with non progressive right upper limb dystonia, myoclonus, epilepsy, pyramidal syndrome, mild ID
PMID: 25648840 - 2 myoclonus-dystonia (MD) families segregating p.Thr1904Met (fam 1: 5 affected carriers & 5 unaffected non-carriers; fam 2: 5 affected carriers including obligates, 3 unaffected carriers, & 4 unaffected non-carriers). But, variant has 82 hets in gnomAD v2.1 (AF 0.03%) which is a bit high for a dominant condition. Another family segregating p.Ile1217Met with MD (3 affected carriers & 3 unaffected non carriers). However, there are 713 alleles in gnomAD v2.1 including 2 homozygotes (0.25% AF) which is too high for a dominant condition. 2 other missense reported in 2 MD probands, but both present in gnomAD v2.1 at frequencies not consistent with dominant disease.
Sources: Other
Mendeliome v1.684 CRIPT Suliman Khan reviewed gene: CRIPT: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36630262; Phenotypes: Short stature with microcephaly and distinctive facies; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.88 CRIPT Suliman Khan reviewed gene: CRIPT: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36630262; Phenotypes: Short stature with microcephaly and distinctive facies; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Growth failure v1.59 CRIPT Suliman Khan reviewed gene: CRIPT: Rating: ; Mode of pathogenicity: None; Publications: PMID: 36630262; Phenotypes: Short stature with microcephaly and distinctive facies; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Microcephalic Primordial Dwarfism and Slender bone dysplasias v0.24 CRIPT Suliman Khan reviewed gene: CRIPT: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36630262; Phenotypes: Short stature with microcephaly and distinctive facies; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Microcephaly v1.194 CRIPT Suliman Khan changed review comment from: PMID: 36630262 reported a patient with profound prenatal/postnatal growth restriction, developmental delay, dysmorphic facial features, and skin lesions along with the findings of bicytopenia and extensive retinal pigmentation defect. A novel truncating homozygous variant c.7_8delTG; p.(Cys3Argfs*4) was detected in CRIPT gene.; to: PMID: 36630262 reported a patient with profound prenatal/postnatal growth restriction, developmental delay, dysmorphic facial features, and skin lesions along with the findings of bicytopenia and extensive retinal pigmentation defect. A novel truncating homozygous variant was detected in CRIPT gene.
Microcephaly v1.194 CRIPT Suliman Khan reviewed gene: CRIPT: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36630262; Phenotypes: short stature, microcephaly, distinctive facies; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1872 ACADS Lilian Downie reviewed gene: ACADS: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Acyl-CoA dehydrogenase, short-chain, deficiency of MIM#201470; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1872 ABCD4 Lilian Downie reviewed gene: ABCD4: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 22922874, PMID: 33729671; Phenotypes: Methylmalonic aciduria and homocystinuria, cblJ type MIM#614857; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital nystagmus v1.17 ROBO1 Achchuthan Shanmugasundram gene: ROBO1 was added
gene: ROBO1 was added to Congenital nystagmus. Sources: Literature
Mode of inheritance for gene: ROBO1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ROBO1 were set to 35348658
Phenotypes for gene: ROBO1 were set to nystagmus, congenital, autosomal recessive, MONDO:0009762
Review for gene: ROBO1 was set to RED
Added comment: Comment on classification of gene: This gene should be rated RED as this gene has been associated with nystagmus from only one family.

PMID:35348658 reported three male siblings from the same family with nystagmus and they were identified with a homozygous missense variant p.Ser1522Leu.

This gene has not yet been associated with any phenotypes either in OMIM or Gene2Phenotype.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5177 ROBO1 Achchuthan Shanmugasundram gene: ROBO1 was added
gene: ROBO1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ROBO1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ROBO1 were set to 28286008; 30692597; 35227688; 35348658
Phenotypes for gene: ROBO1 were set to intellectual disability, MONDO:0001071
Review for gene: ROBO1 was set to GREEN
Added comment: Comment on gene classification: This gene should be rated green as this gene has been associated with intellectual disability from six unrelated cases. However, the MOI should be set as "BIALLELIC, autosomal or pseudoautosomal" as five of these cases were reported with biallelic variants and only one case was reported with monoallelic variant.

PMID:28286008 reported a boy with compound heterozygous variants that was presented with developmental delay in 13 months and had severe intellectual disability and hyperactivity at nine years of age. He was nonverbal and wheelchair dependent because of spastic diplegia and ataxia.

PMID:30692597 reported a five year old boy identified with a homozygous ROBO1 variant who had combined pituitary hormone deficiency, psychomotor developmental delay, severe intellectual disability, sensorineural hearing loss, strabismus and characteristic facial features.

PMID:35227688 reported eight patients including the boy reported in PMID:30692597. Of the other seven patients, three were presented with intellectual disability. Of these three patients, two harboured compound heterozygous and one harboured homozygous variants.

PMID:35348658 reported a patient identified with monoallelic de novo variant (p.D422G) who presented with early-onset epileptic encephalopathy and had severe developmental delay.

This gene has not yet been associated with any phenotypes in OMIM or Gene2Phenotype.
Sources: Literature
Mendeliome v1.684 ELOC Achchuthan Shanmugasundram gene: ELOC was added
gene: ELOC was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ELOC was set to Unknown
Publications for gene: ELOC were set to 35323939
Phenotypes for gene: ELOC were set to von Hippel-Lindau disease, MONDO:0008667; renal cell carcinoma, MONDO:0005086; retinal hemangioblastoma, MONDO:0003343
Review for gene: ELOC was set to RED
Added comment: Comment on gene classification: This gene should be rated red as there is only one case with germline variant found so far.

A female patient was identified with a germline de novo missense variant in ELOC gene (c.236A>G/ p.Tyr79Cys) and satisfied the clinical diagnostic criteria for von Hippel-Lindau (VHL) disease. The patient had left retinal haemangioblastomas, renal cell carcinomas, cyst of the right kidney, spinal haemangioblastoma, a haemangioblastoma at the cervicomedullary junction and Henoch-Schonlein purpura (PMID:35323939).

This is the only germline variant detected in ELOC gene and was associated with VHL so far. However, ~20 somatic ELOC variants have been reported to be associated with renal cell carcinomas so far.

This gene has not yet been associated with relevant phenotypes in OMIM or Gene2Phenotype.
Sources: Literature
Ectodermal Dysplasia v0.80 RIPK4 Achchuthan Shanmugasundram gene: RIPK4 was added
gene: RIPK4 was added to Ectodermal Dysplasia. Sources: Literature
Mode of inheritance for gene: RIPK4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RIPK4 were set to 26129644; 28940926; 33713555; 35220430
Phenotypes for gene: RIPK4 were set to CHAND syndrome, OMIM:214350; Popliteal pterygium syndrome, Bartsocas-Papas type 1, OMIM:263650; ectodermal dysplasia syndrome, MONDO:0019287
Review for gene: RIPK4 was set to GREEN
Added comment: Comment on classification of gene: RIPK4 should be rated green as biallelic variants in this gene has been implicated in ectodermal dysplasias (ED) of varying severity in multiple (>3) unrelated patients and supported by functional studies.

This gene has already been associated with relevant phenotypes in both OMIM and Gene2Phenotype.

The clinically distinct ED syndromes reported with RIPK4 variants include early lethal BPS (MIM #263650) and milder forms such as PPS and CHAND syndrome (MIM #214350). BPS1 is characterized by multiple popliteal pterygia, ankyloblepharon, filiform bands between the jaws, cleft lip and palate, and syndactyly and CHAND is characterized by ankyloblepharon, sparse, curly, and woolly hair, nail dysplasia, and oral frenula.

PMID:35220430 reported two siblings with novel biallelic (compound heterozygous) variants presented with cutaneous syndactyly associated to hair defects, alopecia, nail dysplasia and hyperkeratosis. This phenotype expands the clinical spectrum of the disorder further and is intermediary between BPS and CHAND syndrome.
Sources: Literature
Mendeliome v1.684 ATG4D Suliman Khan gene: ATG4D was added
gene: ATG4D was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ATG4D was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATG4D were set to PMID: 36765070
Phenotypes for gene: ATG4D were set to neurodevelopmental disorder; Abnormal facial shape
Penetrance for gene: ATG4D were set to unknown
Review for gene: ATG4D was set to GREEN
Added comment: PMID: 36765070 reported three individuals from two unrelated families with a neurodevelopmental disorder characterized by speech and motor impairment with a similar facial gestalt comprising almond-shaped eyes, depressed nasal bridge, and a prominent Cupid’s bow with variable disease severity and progression. NGS analysis revealed bi-allelic loss-of-function variants in ATG4D gene. Based on the clinical, bioinformatic, and functional data, the author concluded that bi-allelic loss-of-function variants in ATG4D contribute to the pathogenesis of syndromic neurodevelopmental disorder.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5177 ATG4D Suliman Khan gene: ATG4D was added
gene: ATG4D was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: ATG4D was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATG4D were set to PMID: 36765070
Phenotypes for gene: ATG4D were set to neurodevelopmental disorder; Abnormal facial shape
Penetrance for gene: ATG4D were set to unknown
Review for gene: ATG4D was set to GREEN
Added comment: PMID: 36765070 reported three individuals from two unrelated families with a neurodevelopmental disorder characterized by speech and motor impairment with a similar facial gestalt comprising almond-shaped eyes, depressed nasal bridge, and a prominent Cupid’s bow with variable disease severity and progression. NGS analysis revealed bi-allelic loss-of-function variants in ATG4D gene. Based on the clinical, bioinformatic, and functional data, the author concluded that bi-allelic loss-of-function variants in ATG4D contribute to the pathogenesis of syndromic neurodevelopmental disorder.
Sources: Literature
Mendeliome v1.684 TRPM3 Zornitza Stark Phenotypes for gene: TRPM3 were changed from Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures, MIM# 620224 to Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures, MIM# 620224; Cataract 50 with or without glaucoma, MIM#620253
Mendeliome v1.683 TRPM3 Zornitza Stark Publications for gene: TRPM3 were set to 31278393
Mendeliome v1.682 TRPM3 Zornitza Stark edited their review of gene: TRPM3: Added comment: Publications 25090642; 33484482: Single multi-generational family reported with a missense variant in this gene and cataract. Mouse model of same variant supports association. Amber for this association.; Changed publications: 31278393, 25090642, 33484482; Changed phenotypes: Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures, MIM# 620224, Cataract 50 with or without glaucoma, MIM#620253
Cataract v0.350 TRPM3 Zornitza Stark Marked gene: TRPM3 as ready
Cataract v0.350 TRPM3 Zornitza Stark Gene: trpm3 has been classified as Amber List (Moderate Evidence).
Cataract v0.350 TRPM3 Zornitza Stark Classified gene: TRPM3 as Amber List (moderate evidence)
Cataract v0.350 TRPM3 Zornitza Stark Gene: trpm3 has been classified as Amber List (Moderate Evidence).
Cataract v0.349 TRPM3 Zornitza Stark gene: TRPM3 was added
gene: TRPM3 was added to Cataract. Sources: Expert list
Mode of inheritance for gene: TRPM3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TRPM3 were set to 25090642; 33484482
Phenotypes for gene: TRPM3 were set to Cataract 50 with or without glaucoma, MIM#620253
Review for gene: TRPM3 was set to AMBER
Added comment: Single multi-generational family reported with a missense variant in this gene and cataract. Mouse model of same variant.
Sources: Expert list
Intellectual disability syndromic and non-syndromic v0.5177 PPM1K Zornitza Stark Publications for gene: PPM1K were set to 23086801
Intellectual disability syndromic and non-syndromic v0.5176 PPM1K Zornitza Stark Classified gene: PPM1K as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.5176 PPM1K Zornitza Stark Gene: ppm1k has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5175 PPM1K Zornitza Stark edited their review of gene: PPM1K: Added comment: PMID: 36706222 reported a patient with MSUD with mild findings and elevated BCAA levels carrying a novel homozygous start-loss variant in PPM1K.; Changed rating: AMBER; Changed publications: 23086801, 36706222
Mendeliome v1.682 PPM1K Zornitza Stark Publications for gene: PPM1K were set to 23086801
Mendeliome v1.681 PPM1K Zornitza Stark Classified gene: PPM1K as Amber List (moderate evidence)
Mendeliome v1.681 PPM1K Zornitza Stark Gene: ppm1k has been classified as Amber List (Moderate Evidence).
Mendeliome v1.680 PPM1K Zornitza Stark edited their review of gene: PPM1K: Added comment: PMID: 36706222 reported a patient with MSUD with mild findings and elevated BCAA levels carrying a novel homozygous start-loss variant in PPM1K; Changed rating: AMBER; Changed publications: 23086801, 36706222
Aminoacidopathy v1.4 PPM1K Zornitza Stark Phenotypes for gene: PPM1K were changed from maple syrup urine disease, mild variant MONDO:0014057 to Maple syrup urine disease, mild variant MONDO:0014057
Aminoacidopathy v1.3 PPM1K Zornitza Stark Publications for gene: PPM1K were set to 29152456; 23086801
Aminoacidopathy v1.2 PPM1K Zornitza Stark Classified gene: PPM1K as Amber List (moderate evidence)
Aminoacidopathy v1.2 PPM1K Zornitza Stark Gene: ppm1k has been classified as Amber List (Moderate Evidence).
Arrhythmogenic Cardiomyopathy v0.68 KBTBD13 Zornitza Stark Marked gene: KBTBD13 as ready
Arrhythmogenic Cardiomyopathy v0.68 KBTBD13 Zornitza Stark Gene: kbtbd13 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.680 ARHGAP35 Zornitza Stark Phenotypes for gene: ARHGAP35 were changed from neurodevelopmental disorder, ARHGAP35-related MONDO#0700092; Developmental defect of the eye (MONDO:0020145), ARHGAP35-related to Hypogonadotropic hypogonadism, MONDO:0015770, ARHGAP35-related; neurodevelopmental disorder, ARHGAP35-related MONDO#0700092; Developmental defect of the eye (MONDO:0020145), ARHGAP35-related
Mendeliome v1.679 ARHGAP35 Zornitza Stark Publications for gene: ARHGAP35 were set to 33057194; 36450800
Mendeliome v1.678 ARHGAP35 Zornitza Stark reviewed gene: ARHGAP35: Rating: GREEN; Mode of pathogenicity: None; Publications: 36178483; Phenotypes: Hypogonadotropic hypogonadism, MONDO:0015770, ARHGAP35-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v1.88 EFCAB1 Zornitza Stark Marked gene: EFCAB1 as ready
Fetal anomalies v1.88 EFCAB1 Zornitza Stark Gene: efcab1 has been classified as Green List (High Evidence).
Differences of Sex Development v0.272 ARHGAP35 Zornitza Stark Marked gene: ARHGAP35 as ready
Differences of Sex Development v0.272 ARHGAP35 Zornitza Stark Gene: arhgap35 has been classified as Green List (High Evidence).
Differences of Sex Development v0.272 ARHGAP35 Zornitza Stark Phenotypes for gene: ARHGAP35 were changed from Idiopathic hypogonadotropic hypogonadism, no OMIM # to Hypogonadotropic hypogonadism, MONDO:0015770, ARHGAP35-related
Differences of Sex Development v0.271 ARHGAP35 Zornitza Stark reviewed gene: ARHGAP35: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Hypogonadotropic hypogonadism, MONDO:0015770, ARHGAP35-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v1.88 EFCAB1 Zornitza Stark Classified gene: EFCAB1 as Green List (high evidence)
Fetal anomalies v1.88 EFCAB1 Zornitza Stark Gene: efcab1 has been classified as Green List (High Evidence).
Fetal anomalies v1.87 EFCAB1 Zornitza Stark gene: EFCAB1 was added
gene: EFCAB1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: EFCAB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EFCAB1 were set to 36727596
Phenotypes for gene: EFCAB1 were set to Primary ciliary dyskinesia, MONDO:0016575, EFCAB1-related
Review for gene: EFCAB1 was set to GREEN
Added comment: WES in 3 individuals with laterality defects and respiratory symptoms, identified homozygous pathogenic variants in CLXN (EFCAB1). They found Clxn expressed in mice left-right organizer. Transmission electron microscopy depicted outer dynein arm (ODA) defects in distal ciliary axonemes. Immunofluorescence microscopy revealed absence of CLXN from the ciliary axonemes, absence of the ODA components DNAH5, DNAI1 and DNAI2 from the distal axonemes, as well as mislocalization or absence of DNAH9. Additionally, CLXN is undetectable in ciliary axonemes of individuals with defects in the outer dynein arm docking (ODA-DC) machinery: ODAD1, ODAD2, ODAD3 and ODAD4. Moreover, SMED-EFCAB1-deficient planaria displayed ciliary dysmotility.
Sources: Literature
Heterotaxy v1.29 EFCAB1 Zornitza Stark Marked gene: EFCAB1 as ready
Heterotaxy v1.29 EFCAB1 Zornitza Stark Gene: efcab1 has been classified as Green List (High Evidence).
Heterotaxy v1.29 EFCAB1 Zornitza Stark Phenotypes for gene: EFCAB1 were changed from Primary ciliary dyskinesia and heterotaxy, no OMIM # to Primary ciliary dyskinesia, MONDO:0016575, EFCAB1-related
Ciliary Dyskinesia v1.28 EFCAB1 Zornitza Stark Marked gene: EFCAB1 as ready
Ciliary Dyskinesia v1.28 EFCAB1 Zornitza Stark Gene: efcab1 has been classified as Green List (High Evidence).
Ciliary Dyskinesia v1.28 EFCAB1 Zornitza Stark Phenotypes for gene: EFCAB1 were changed from Primary ciliary dyskinesia and heterotaxy, no OMIM # to Primary ciliary dyskinesia, MONDO:0016575, EFCAB1-related
Mendeliome v1.678 EFCAB1 Zornitza Stark Marked gene: EFCAB1 as ready
Mendeliome v1.678 EFCAB1 Zornitza Stark Gene: efcab1 has been classified as Green List (High Evidence).
Mendeliome v1.678 EFCAB1 Zornitza Stark Phenotypes for gene: EFCAB1 were changed from Primary ciliary dyskinesia and heterotaxy, no OMIM # to Primary ciliary dyskinesia, MONDO:0016575, EFCAB1-related
Mendeliome v1.677 EFCAB1 Zornitza Stark reviewed gene: EFCAB1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary ciliary dyskinesia, MONDO:0016575, EFCAB1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.677 CST6 Zornitza Stark Marked gene: CST6 as ready
Mendeliome v1.677 CST6 Zornitza Stark Gene: cst6 has been classified as Green List (High Evidence).
Mendeliome v1.677 CST6 Zornitza Stark Classified gene: CST6 as Green List (high evidence)
Mendeliome v1.677 CST6 Zornitza Stark Gene: cst6 has been classified as Green List (High Evidence).
Mendeliome v1.676 CST6 Zornitza Stark gene: CST6 was added
gene: CST6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CST6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CST6 were set to 30425301; 36371786
Phenotypes for gene: CST6 were set to Ectodermal dysplasia 15, hypohidrotic/hair type MIM#618535
Review for gene: CST6 was set to GREEN
Added comment: Two families reported and functional data.
Sources: Literature
Hair disorders v0.68 CST6 Zornitza Stark Publications for gene: CST6 were set to 30425301; 12393798
Hair disorders v0.67 CST6 Zornitza Stark reviewed gene: CST6: Rating: AMBER; Mode of pathogenicity: None; Publications: 36371786; Phenotypes: Ectodermal dysplasia 15, hypohidrotic/hair type, 618535; Mode of inheritance: None
Ectodermal Dysplasia v0.80 CST6 Zornitza Stark Marked gene: CST6 as ready
Ectodermal Dysplasia v0.80 CST6 Zornitza Stark Gene: cst6 has been classified as Green List (High Evidence).
Ectodermal Dysplasia v0.80 CST6 Zornitza Stark Phenotypes for gene: CST6 were changed from ?Ectodermal dysplasia 15, hypohidrotic/hair type, 618535 to Ectodermal dysplasia 15, hypohidrotic/hair type, 618535
Ectodermal Dysplasia v0.79 CST6 Zornitza Stark Publications for gene: CST6 were set to 30425301
Cone-rod Dystrophy v0.49 KCNV2 Zornitza Stark Publications for gene: KCNV2 were set to 30679166; 16909397; 18235024; 21882291
Palmoplantar Keratoderma and Erythrokeratoderma v0.128 KDSR Zornitza Stark Publications for gene: KDSR were set to 28774589; 30467204; 28575652
Intellectual disability syndromic and non-syndromic v0.5175 RAB39B Zornitza Stark Marked gene: RAB39B as ready
Intellectual disability syndromic and non-syndromic v0.5175 RAB39B Zornitza Stark Gene: rab39b has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5175 RAB39B Zornitza Stark Phenotypes for gene: RAB39B were changed from to Intellectual developmental disorder, X-linked 72, OMIM:300271; Waisman syndrome, OMIM:311510
Intellectual disability syndromic and non-syndromic v0.5174 RAB39B Zornitza Stark Publications for gene: RAB39B were set to
Intellectual disability syndromic and non-syndromic v0.5173 RAB39B Zornitza Stark Mode of inheritance for gene: RAB39B was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Intellectual disability syndromic and non-syndromic v0.5172 JPH3 Zornitza Stark Phenotypes for gene: JPH3 were changed from Intellectual disability; dystonia to Neurodevelopmental disorder, MONDO:0700092, JPH3-related; Intellectual disability; dystonia
Intellectual disability syndromic and non-syndromic v0.5171 JPH3 Zornitza Stark Publications for gene: JPH3 were set to 33824468
Intellectual disability syndromic and non-syndromic v0.5170 JPH3 Zornitza Stark Mode of inheritance for gene: JPH3 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5169 JPH3 Zornitza Stark Classified gene: JPH3 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.5169 JPH3 Zornitza Stark Gene: jph3 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5168 JPH3 Zornitza Stark reviewed gene: JPH3: Rating: AMBER; Mode of pathogenicity: None; Publications: 36273396; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, JPH3-related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.675 JPH3 Zornitza Stark Phenotypes for gene: JPH3 were changed from Intellectual disability; dystonia to Neurodevelopmental disorder, MONDO:0700092, JPH3-related; Intellectual disability; dystonia
Mendeliome v1.674 JPH3 Zornitza Stark Publications for gene: JPH3 were set to 33824468
Mendeliome v1.673 JPH3 Zornitza Stark Mode of inheritance for gene: JPH3 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.672 JPH3 Zornitza Stark Classified gene: JPH3 as Amber List (moderate evidence)
Mendeliome v1.672 JPH3 Zornitza Stark Gene: jph3 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.671 JPH3 Zornitza Stark reviewed gene: JPH3: Rating: AMBER; Mode of pathogenicity: None; Publications: 36273396; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, JPH3-related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Paroxysmal Dyskinesia v0.106 JPH3 Zornitza Stark Marked gene: JPH3 as ready
Paroxysmal Dyskinesia v0.106 JPH3 Zornitza Stark Gene: jph3 has been classified as Amber List (Moderate Evidence).
Paroxysmal Dyskinesia v0.106 JPH3 Zornitza Stark Mode of pathogenicity for gene: JPH3 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to None
Paroxysmal Dyskinesia v0.105 JPH3 Zornitza Stark Classified gene: JPH3 as Amber List (moderate evidence)
Paroxysmal Dyskinesia v0.105 JPH3 Zornitza Stark Gene: jph3 has been classified as Amber List (Moderate Evidence).
Paroxysmal Dyskinesia v0.104 JPH3 Zornitza Stark changed review comment from: Two families reported with bi-allelic variants and neurodevelopmental disorder involving paroxysmal dystonia. One family with mono-allelic variant, milder.; to: Two families reported with bi-allelic variants and neurodevelopmental disorder involving paroxysmal dystonia. One family with mono-allelic variant, milder.

Note STRs in this gene cause a separate disorder.
Paroxysmal Dyskinesia v0.104 JPH3 Zornitza Stark reviewed gene: JPH3: Rating: AMBER; Mode of pathogenicity: None; Publications: 36273396; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, JPH3-related; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Osteogenesis Imperfecta and Osteoporosis v0.90 WNT11 Zornitza Stark Marked gene: WNT11 as ready
Osteogenesis Imperfecta and Osteoporosis v0.90 WNT11 Zornitza Stark Gene: wnt11 has been classified as Green List (High Evidence).
Osteogenesis Imperfecta and Osteoporosis v0.90 WNT11 Zornitza Stark Classified gene: WNT11 as Green List (high evidence)
Osteogenesis Imperfecta and Osteoporosis v0.90 WNT11 Zornitza Stark Gene: wnt11 has been classified as Green List (High Evidence).
Osteogenesis Imperfecta and Osteoporosis v0.89 WNT11 Zornitza Stark gene: WNT11 was added
gene: WNT11 was added to Osteogenesis Imperfecta. Sources: Literature
Mode of inheritance for gene: WNT11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: WNT11 were set to 34875064
Phenotypes for gene: WNT11 were set to Osteoporosis, MONDO:0005298, WNT11-related
Review for gene: WNT11 was set to GREEN
Added comment: This gene has been implicated in early-onset osteoporosis from three unrelated cases and was supported by evidence from functional studies. All three patients harboured heterozygous variants in WNT11 gene.

Three unrelated cases are reported in PMID: 34875064. A four year-old boy harbouring de novo heterozygous loss-of-function variant c.677_678dupGG (p.Leu227Glyfs*22) was reported with low BMD, osteopenia and several fractures.

A 51 year-old woman and her 69 year-old mother were identified with a heterozygous missense variant c.217G>A (p.Ala73Thr). The woman was reported with bone fragility, several fractures, osteoarthritis and osteoporosis, while her mother also had several osteoporotic fractures.

A 61 year-old woman that was reported with lumbar spine osteoarthritis had several fractures since 55 years of age was identified with a heterozygous missense variant c.865G>A (p.Val289Met).

This was also supported by results from functional studies, where cell lines with the loss-of-function variant generated by CRISPR-Cas9 showed reduced cell proliferation and osteoblast differentiation in comparison to wild-type. The expression of genes in the Wnt canonical and non-canonical pathways was inhibited in these mutant cells.
Sources: Literature
Mendeliome v1.671 WNT11 Zornitza Stark Marked gene: WNT11 as ready
Mendeliome v1.671 WNT11 Zornitza Stark Gene: wnt11 has been classified as Green List (High Evidence).
Mendeliome v1.671 WNT11 Zornitza Stark Classified gene: WNT11 as Green List (high evidence)
Mendeliome v1.671 WNT11 Zornitza Stark Gene: wnt11 has been classified as Green List (High Evidence).
Mendeliome v1.670 MRPS7 Zornitza Stark Publications for gene: MRPS7 were set to 25556185
Mendeliome v1.669 MRPS7 Zornitza Stark Classified gene: MRPS7 as Amber List (moderate evidence)
Mendeliome v1.669 MRPS7 Zornitza Stark Gene: mrps7 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.668 MRPS7 Zornitza Stark edited their review of gene: MRPS7: Added comment: Now second publication (PMID: 36421788) describes sisters with an overlapping phenotype including sensorineural deafness and premature ovarian insufficiency. They both had compound heterozygous (one missense, one nonsense) MRPS7 variants.; Changed rating: AMBER; Changed publications: 25556185, 36421788
Mitochondrial disease v0.856 MRPS7 Zornitza Stark Publications for gene: MRPS7 were set to 25556185
Mitochondrial disease v0.855 MRPS7 Zornitza Stark Classified gene: MRPS7 as Amber List (moderate evidence)
Mitochondrial disease v0.855 MRPS7 Zornitza Stark Gene: mrps7 has been classified as Amber List (Moderate Evidence).
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.309 MRPS7 Zornitza Stark Marked gene: MRPS7 as ready
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.309 MRPS7 Zornitza Stark Gene: mrps7 has been classified as Amber List (Moderate Evidence).
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.309 MRPS7 Zornitza Stark Phenotypes for gene: MRPS7 were changed from sensorineural deafness; renal failure; liver failure; primary ovarian insufficiency to Combined oxidative phosphorylation deficiency 34, MIM# 617872; sensorineural deafness; renal failure; liver failure; primary ovarian insufficiency
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.308 MRPS7 Zornitza Stark Classified gene: MRPS7 as Amber List (moderate evidence)
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.308 MRPS7 Zornitza Stark Gene: mrps7 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.668 STAT6 Zornitza Stark Marked gene: STAT6 as ready
Mendeliome v1.668 STAT6 Zornitza Stark Gene: stat6 has been classified as Green List (High Evidence).
Mendeliome v1.668 STAT6 Zornitza Stark Classified gene: STAT6 as Green List (high evidence)
Mendeliome v1.668 STAT6 Zornitza Stark Gene: stat6 has been classified as Green List (High Evidence).
Mendeliome v1.667 STAT6 Zornitza Stark gene: STAT6 was added
gene: STAT6 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: STAT6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: STAT6 were set to 36216080; 36758835
Phenotypes for gene: STAT6 were set to Allergic disease, MONDO:0005271, STAT6-related; early-onset multiorgan allergies
Review for gene: STAT6 was set to GREEN
Added comment: Two families reported with GoF variants and extensive functional data.
Sources: Literature
Disorders of immune dysregulation v0.166 STAT6 Zornitza Stark Marked gene: STAT6 as ready
Disorders of immune dysregulation v0.166 STAT6 Zornitza Stark Gene: stat6 has been classified as Green List (High Evidence).
Disorders of immune dysregulation v0.166 STAT6 Zornitza Stark Phenotypes for gene: STAT6 were changed from early-onset multiorgan allergies to Allergic disease, MONDO:0005271, STAT6-related; early-onset multiorgan allergies
Disorders of immune dysregulation v0.165 STAT6 Zornitza Stark Classified gene: STAT6 as Green List (high evidence)
Disorders of immune dysregulation v0.165 STAT6 Zornitza Stark Gene: stat6 has been classified as Green List (High Evidence).
Mendeliome v1.666 LTV1 Zornitza Stark Marked gene: LTV1 as ready
Mendeliome v1.666 LTV1 Zornitza Stark Gene: ltv1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.666 LTV1 Zornitza Stark Classified gene: LTV1 as Amber List (moderate evidence)
Mendeliome v1.666 LTV1 Zornitza Stark Gene: ltv1 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1872 TANGO2 Zornitza Stark Marked gene: TANGO2 as ready
BabyScreen+ newborn screening v0.1872 TANGO2 Zornitza Stark Gene: tango2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1872 TANGO2 Zornitza Stark Phenotypes for gene: TANGO2 were changed from Cardiomyopathy; Metabolic Crises; Arrhythmia; Neurodevelopmental to Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration, MIM# 616878
BabyScreen+ newborn screening v0.1871 TANGO2 Zornitza Stark Classified gene: TANGO2 as Green List (high evidence)
BabyScreen+ newborn screening v0.1871 TANGO2 Zornitza Stark Gene: tango2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1870 TANGO2 Zornitza Stark Tag treatable tag was added to gene: TANGO2.
Tag metabolic tag was added to gene: TANGO2.
BabyScreen+ newborn screening v0.1870 LAMP2 Zornitza Stark Phenotypes for gene: LAMP2 were changed from Danon disease, MIM# 300257 to Danon disease, MIM# 300257
BabyScreen+ newborn screening v0.1869 LAMP2 Zornitza Stark Classified gene: LAMP2 as Green List (high evidence)
BabyScreen+ newborn screening v0.1869 LAMP2 Zornitza Stark Gene: lamp2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1868 NKX2-5 Zornitza Stark Marked gene: NKX2-5 as ready
BabyScreen+ newborn screening v0.1868 NKX2-5 Zornitza Stark Gene: nkx2-5 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1868 NKX2-5 Zornitza Stark Phenotypes for gene: NKX2-5 were changed from Congenital heart disease to Atrial septal defect 7, with or without AV conduction defects, MIM# 108900
BabyScreen+ newborn screening v0.1867 NKX2-5 Zornitza Stark Tag cardiac tag was added to gene: NKX2-5.
BabyScreen+ newborn screening v0.1867 NKX2-5 Zornitza Stark Classified gene: NKX2-5 as Green List (high evidence)
BabyScreen+ newborn screening v0.1867 NKX2-5 Zornitza Stark Gene: nkx2-5 has been classified as Green List (High Evidence).
Renal Tubulopathies and related disorders v1.8 AVP Zornitza Stark Marked gene: AVP as ready
Renal Tubulopathies and related disorders v1.8 AVP Zornitza Stark Gene: avp has been classified as Green List (High Evidence).
Renal Tubulopathies and related disorders v1.8 AVP Zornitza Stark Phenotypes for gene: AVP were changed from Diabetes insipidus, neurohypophyseal to Diabetes insipidus, neurohypophyseal MIM#125700
Renal Tubulopathies and related disorders v1.7 AVP Zornitza Stark Classified gene: AVP as Green List (high evidence)
Renal Tubulopathies and related disorders v1.7 AVP Zornitza Stark Gene: avp has been classified as Green List (High Evidence).
Renal Tubulopathies and related disorders v1.6 AVP Ella Wilkins gene: AVP was added
gene: AVP was added to Renal Tubulopathies and related disorders. Sources: Expert list
Mode of inheritance for gene: AVP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: AVP were set to Diabetes insipidus, neurohypophyseal
Review for gene: AVP was set to GREEN
Added comment: Included due to phenotypic overlap with nephrogenic DI.
Sources: Expert list
Mendeliome v1.665 LTV1 Achchuthan Shanmugasundram gene: LTV1 was added
gene: LTV1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: LTV1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LTV1 were set to 34999892
Phenotypes for gene: LTV1 were set to Inflammatory poikiloderma with hair abnormalities and acral keratoses, OMIM:620199
Review for gene: LTV1 was set to AMBER
Added comment: Comment on classification of gene: This gene should be rated amber as it has been implicated in inflammatory poikiloderma with hair abnormalities and acral keratoses as identified from two unrelated families harbouring the same biallelic variant and supported by functional studies.

PMID:34999892 reported four UK women of South Asian origin (three Pakistani sisters and an unrelated Indian woman) identified with homozygous variant c.503A>G, (p.Asn168Ser) and presented with poikiloderma, hair abnormalities, and acral keratoses, which the authors named as inflammatory poikiloderma with hair abnormalities and acral keratoses (IPHAK).

Both in silico modelling and splicing assays from a patient sample showed that this variant is responsible for splicing defects and defects in LTV1 alter the export of nascent ribosomal subunits to the cytoplasm in yeast.

This gene has already been associated with relevant phenotype (MIM #620199) in OMIM, but not in Gene2Phenotype.
Sources: Literature
Disorders of immune dysregulation v0.164 STAT6 Peter McNaughton edited their review of gene: STAT6: Added comment: Report of another child with severe atopic dermatitis, eosinophilia and elevated IgE with extensive functional data.; Changed rating: GREEN; Changed publications: PMID: 36216080, PMID: 36758835
Disorders of immune dysregulation v0.164 STAT6 Peter McNaughton changed review comment from: STAT6 gain-of-function variant associated with early-onset multiorgan allergies in a family with
3 affected members, extensive functional data to support mechanism of allergic disease.
Sources: Literature; to: STAT6 gain-of-function variant associated with early-onset multiorgan allergies in a family with
3 affected members, extensive functional data to support mechanism of allergic disease.
Sources: Literature
Primary Ovarian Insufficiency_Premature Ovarian Failure v0.307 MRPS7 Elena Tucker gene: MRPS7 was added
gene: MRPS7 was added to Primary Ovarian Insufficiency_Premature Ovarian Failure. Sources: Literature
Mode of inheritance for gene: MRPS7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPS7 were set to PMID: 25556185; 36421788
Phenotypes for gene: MRPS7 were set to sensorineural deafness; renal failure; liver failure; primary ovarian insufficiency
Review for gene: MRPS7 was set to AMBER
Added comment: The initial report (PMID: 25556185) describes a homozygous missense variant in two sisters with sensorineural deafness, progressive hepatic and renal failure and lactic acidemia. One sister died in early adolescence but the other survived beyond puberty and had primary ovarian insufficiency. Experimental evidence supported causation of the MRPS7 variant.

The second publication (PMID: 36421788) describes sisters with an overlapping phenotype including sensorineural deafness and premature ovarian insufficiency. They both had compound heterozygous (one missense, one nonsense) MRPS7 variants.
Sources: Literature
Mitochondrial disease v0.854 MRPS7 Elena Tucker reviewed gene: MRPS7: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 36421788, 25556185; Phenotypes: sensorineural deafness, renal failure, liver failure, primary ovarian insufficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.665 WNT11 Achchuthan Shanmugasundram gene: WNT11 was added
gene: WNT11 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: WNT11 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: WNT11 were set to 34875064
Phenotypes for gene: WNT11 were set to osteoporosis, MONDO:0005298; osteoarthritis, MONDO:0005178; recurrent fractures
Review for gene: WNT11 was set to GREEN
Added comment: Comment on gene classification: The rating of this gene can be added as green as this gene has been implicated in early-onset osteoporosis from three unrelated cases and was supported by evidence from functional studies. All three patients harboured heterozygous variants in WNT11 gene.

Three unrelated cases are reported in PMID: 34875064. A four year-old boy harbouring de novo heterozygous loss-of-function variant c.677_678dupGG (p.Leu227Glyfs*22) was reported with low BMD, osteopenia and several fractures.

A 51 year-old woman and her 69 year-old mother were identified with a heterozygous missense variant c.217G>A (p.Ala73Thr). The woman was reported with bone fragility, several fractures, osteoarthritis and osteoporosis, while her mother also had several osteoporotic fractures.

A 61 year-old woman that was reported with lumbar spine osteoarthritis had several fractures since 55 years of age was identified with a heterozygous missense variant c.865G>A (p.Val289Met).

This was also supported by results from functional studies, where cell lines with the loss-of-function variant generated by CRISPR-Cas9 showed reduced cell proliferation and osteoblast differentiation in comparison to wild-type. The expression of genes in the Wnt canonical and non-canonical pathways was inhibited in these mutant cells.

This gene has not yet been reported with any phenotypes either in OMIM or in G2P.
Sources: Literature
BabyScreen+ newborn screening v0.1866 ACTA2 Zornitza Stark Mode of inheritance for gene: ACTA2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1865 HADHA Ari Horton reviewed gene: HADHA: Rating: GREEN; Mode of pathogenicity: None; Publications: 31575911; Phenotypes: Cardiomyopathy, Metabolic Disorder; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1865 TANGO2 Ari Horton changed review comment from: Folate may assist with TANGO2
DOI: https://doi.org/10.21203/rs.3.rs-1778084/v1

While chronic symptoms are predominantly neurodevelopmental, metabolic stressors such as fasting, dehydration, illness, and excessive heat can trigger episodic metabolic crises characterized by encephalopathy, ataxia, muscle weakness, rhabdomyolysis, and hypoglycemia. During these events, patients can develop acute life-threatening cardiac arrhythmias. Arrhythmias typically initiate with isolated premature ventricular contractions (PVC) followed by recalcitrant ventricular tachycardia. Because these lethal arrhythmias usually do not respond to standard antiarrhythmic therapies, cardiac arrhythmias are the leading cause of death in TDD

Fasting and feeding recommendations to reduce crises and improve cardiac status and neurodev outcomes, reduce risk of cardiac arrhythmias and SCDY

Natural history study (ClinicalTrials.gov Identifier: NCT05374616) strongly suggests that subjects on a multivitamin or a Bcomplex vitamin supplement have a greatly reduced risk for metabolic crises and cardiac arrhythmias

Specific diet and fasting plans are recommended for all patients from the neonatal period
Sources: Expert Review; to: Folate may assist with TANGO2
DOI: https://doi.org/10.21203/rs.3.rs-1778084/v1

PMID: 35568137

While chronic symptoms are predominantly neurodevelopmental, metabolic stressors such as fasting, dehydration, illness, and excessive heat can trigger episodic metabolic crises characterized by encephalopathy, ataxia, muscle weakness, rhabdomyolysis, and hypoglycemia. During these events, patients can develop acute life-threatening cardiac arrhythmias. Arrhythmias typically initiate with isolated premature ventricular contractions (PVC) followed by recalcitrant ventricular tachycardia. Because these lethal arrhythmias usually do not respond to standard antiarrhythmic therapies, cardiac arrhythmias are the leading cause of death in TDD

Fasting and feeding recommendations to reduce crises and improve cardiac status and neurodev outcomes, reduce risk of cardiac arrhythmias and SCDY

Natural history study (ClinicalTrials.gov Identifier: NCT05374616) strongly suggests that subjects on a multivitamin or a Bcomplex vitamin supplement have a greatly reduced risk for metabolic crises and cardiac arrhythmias

Twenty-seven children were admitted for 43 cardiac crises (median age 6.4 years; interquartile range [IQR] 2.4–9.8 years) at 14 centers. During crisis, QTc prolongation occurred in all (median 547 ms; IQR 504–600 ms) and a type I Brugada pattern in 8 (26%). Arrhythmias included VT in 21 (78%), supraventricular tachycardia in 3 (11%), and heart block in 1 (4%). Nineteen patients (70%) developed cardiomyopathy, and 20 (74%) experienced a cardiac arrest. There were 10 deaths (37%), 6 related to arrhythmias. In 5 patients, recalcitrant VT occurred despite use of antiarrhythmic drugs. In 6 patients, arrhythmias were controlled after extracorporeal membrane oxygenation (ECMO) support; 5 of these patients survived. Among 10 patients who survived VT without ECMO, successful treatment included intravenous magnesium, isoproterenol, and atrial pacing in multiple cases and verapamil in 1 patient. Initiation of feeds seemed to decrease VT events.

Specific diet and fasting plans are recommended for all patients from the neonatal period
Sources: Expert Review
BabyScreen+ newborn screening v0.1865 TANGO2 Ari Horton gene: TANGO2 was added
gene: TANGO2 was added to gNBS. Sources: Expert Review
Mode of inheritance for gene: TANGO2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TANGO2 were set to Cardiomyopathy; Metabolic Crises; Arrhythmia; Neurodevelopmental
Penetrance for gene: TANGO2 were set to Complete
Review for gene: TANGO2 was set to GREEN
Added comment: Folate may assist with TANGO2
DOI: https://doi.org/10.21203/rs.3.rs-1778084/v1

While chronic symptoms are predominantly neurodevelopmental, metabolic stressors such as fasting, dehydration, illness, and excessive heat can trigger episodic metabolic crises characterized by encephalopathy, ataxia, muscle weakness, rhabdomyolysis, and hypoglycemia. During these events, patients can develop acute life-threatening cardiac arrhythmias. Arrhythmias typically initiate with isolated premature ventricular contractions (PVC) followed by recalcitrant ventricular tachycardia. Because these lethal arrhythmias usually do not respond to standard antiarrhythmic therapies, cardiac arrhythmias are the leading cause of death in TDD

Fasting and feeding recommendations to reduce crises and improve cardiac status and neurodev outcomes, reduce risk of cardiac arrhythmias and SCDY

Natural history study (ClinicalTrials.gov Identifier: NCT05374616) strongly suggests that subjects on a multivitamin or a Bcomplex vitamin supplement have a greatly reduced risk for metabolic crises and cardiac arrhythmias

Specific diet and fasting plans are recommended for all patients from the neonatal period
Sources: Expert Review
BabyScreen+ newborn screening v0.1865 LAMP2 Ari Horton reviewed gene: LAMP2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Childhood onset cardiomyopathy (Severe), Neuordevelopmental phenotype; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
BabyScreen+ newborn screening v0.1865 NKX2-5 Ari Horton reviewed gene: NKX2-5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neonatal onset cardiomyopathy, Congenital Heart Disease; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
BabyScreen+ newborn screening v0.1865 GATA4 Ari Horton reviewed gene: GATA4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cardiomyopathy, Congenital Heart Disease, Arrhythmia, Extra-cardiac Manifestations; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
BabyScreen+ newborn screening v0.1865 ACTA2 Ari Horton reviewed gene: ACTA2: Rating: GREEN; Mode of pathogenicity: Other; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Mendeliome v1.665 DEPDC5 Zornitza Stark Mode of inheritance for gene: DEPDC5 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v1.86 ATP9A Zornitza Stark Phenotypes for gene: ATP9A were changed from neurodevelopmental disorder, ATP9A-related MONDO#0700092 to Neurodevelopmental disorder with poor growth and behavioural abnormalities, MIM# 620242
Intellectual disability syndromic and non-syndromic v0.5168 ATP9A Zornitza Stark Phenotypes for gene: ATP9A were changed from Neurodevelopmental delay; Postnatal microcephaly; Failure to thrive; Gastrointestinal symptoms to Neurodevelopmental disorder with poor growth and behavioural abnormalities, MIM# 620242
Intellectual disability syndromic and non-syndromic v0.5167 ATP9A Zornitza Stark edited their review of gene: ATP9A: Changed phenotypes: Neurodevelopmental disorder with poor growth and behavioural abnormalities, MIM# 620242
Microcephaly v1.194 ATP9A Zornitza Stark Phenotypes for gene: ATP9A were changed from Neurodevelopmental delay; Postnatal microcephaly; Failure to thrive; Gastrointestinal symptoms to Neurodevelopmental disorder with poor growth and behavioural abnormalities, MIM# 620242
Microcephaly v1.193 ATP9A Zornitza Stark edited their review of gene: ATP9A: Changed phenotypes: Neurodevelopmental disorder with poor growth and behavioural abnormalities, MIM# 620242
Mendeliome v1.664 ATP9A Zornitza Stark Phenotypes for gene: ATP9A were changed from Neurodevelopmental delay; Postnatal microcephaly; Failure to thrive; Gastrointestinal symptoms to Neurodevelopmental disorder with poor growth and behavioural abnormalities, MIM# 620242
Mendeliome v1.663 ATP9A Zornitza Stark edited their review of gene: ATP9A: Changed phenotypes: Neurodevelopmental disorder with poor growth and behavioural abnormalities, MIM# 620242
Mendeliome v1.663 ATP9A Zornitza Stark edited their review of gene: ATP9A: Changed phenotypes: NeurodevNeurodevelopmental disorder with poor growth and behavioral abnormalities, MIM# 620242
Paroxysmal Dyskinesia v0.104 JPH3 SHEKEEB MOHAMMAD gene: JPH3 was added
gene: JPH3 was added to Paroxysmal Dyskinesia. Sources: Literature
Mode of inheritance for gene: JPH3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: JPH3 were set to PMID: 36273396
Phenotypes for gene: JPH3 were set to paroxysmal dystonia, intellectual disability
Penetrance for gene: JPH3 were set to unknown
Mode of pathogenicity for gene: JPH3 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: JPH3 was set to GREEN
Added comment: Sources: Literature
Fetal anomalies v1.85 GOLGA2 Zornitza Stark Phenotypes for gene: GOLGA2 were changed from neuromuscular disease, GOLGA2-related MONDO#0019056 to Developmental delay with hypotonia, myopathy, and brain abnormalities, MIM 620240
Fetal anomalies v1.84 GOLGA2 Zornitza Stark edited their review of gene: GOLGA2: Added comment: Third family reported but again hypoplasia of CC which may be difficult to detect. Onset of microcephaly uncertain.; Changed publications: 34424553; Changed phenotypes: Developmental delay with hypotonia, myopathy, and brain abnormalities, MIM 620240
Intellectual disability syndromic and non-syndromic v0.5167 GOLGA2 Zornitza Stark Phenotypes for gene: GOLGA2 were changed from Neuromuscular disorder to Developmental delay with hypotonia, myopathy, and brain abnormalities, MIM 620240
Intellectual disability syndromic and non-syndromic v0.5166 GOLGA2 Zornitza Stark Publications for gene: GOLGA2 were set to PMID: 30237576; 26742501
Intellectual disability syndromic and non-syndromic v0.5165 GOLGA2 Zornitza Stark edited their review of gene: GOLGA2: Added comment: Third family reported.; Changed publications: 34424553; Changed phenotypes: Developmental delay with hypotonia, myopathy, and brain abnormalities, MIM 620240; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Muscular dystrophy and myopathy_Paediatric v0.126 GOLGA2 Zornitza Stark Phenotypes for gene: GOLGA2 were changed from Neuromuscular disorder to Developmental delay with hypotonia, myopathy, and brain abnormalities, MIM 620240
Muscular dystrophy and myopathy_Paediatric v0.125 GOLGA2 Zornitza Stark Publications for gene: GOLGA2 were set to PMID: 30237576; 26742501
Muscular dystrophy and myopathy_Paediatric v0.124 GOLGA2 Zornitza Stark edited their review of gene: GOLGA2: Added comment: Third family reported.; Changed publications: 34424553
Muscular dystrophy and myopathy_Paediatric v0.124 GOLGA2 Zornitza Stark edited their review of gene: GOLGA2: Changed phenotypes: Developmental delay with hypotonia, myopathy, and brain abnormalities, MIM 620240; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Microcephaly v1.193 GOLGA2 Zornitza Stark Phenotypes for gene: GOLGA2 were changed from Neuromuscular disorder to Developmental delay with hypotonia, myopathy, and brain abnormalities, MIM 620240
Microcephaly v1.192 GOLGA2 Zornitza Stark Publications for gene: GOLGA2 were set to PMID: 30237576; 26742501
Microcephaly v1.191 GOLGA2 Zornitza Stark reviewed gene: GOLGA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34424553; Phenotypes: Developmental delay with hypotonia, myopathy, and brain abnormalities, MIM 620240; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.663 GOLGA2 Zornitza Stark Phenotypes for gene: GOLGA2 were changed from Neuromuscular disorder to Developmental delay with hypotonia, myopathy, and brain abnormalities, MIM 620240
Mendeliome v1.662 GOLGA2 Zornitza Stark Publications for gene: GOLGA2 were set to PMID: 30237576; 26742501
Mendeliome v1.661 GOLGA2 Zornitza Stark reviewed gene: GOLGA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 34424553; Phenotypes: Developmental delay with hypotonia, myopathy, and brain abnormalities, MIM 620240; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.661 THSD1 Zornitza Stark Phenotypes for gene: THSD1 were changed from Aneurysm, intracranial berry, 12 , MIM# 618734; Hydrops fetalis MONDO:0015193, THSD1-related to Aneurysm, intracranial berry, 12 , MIM# 618734; Lymphatic malformation 13, MIM# 620244
Mendeliome v1.660 THSD1 Zornitza Stark Mode of inheritance for gene: THSD1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hydrops fetalis v0.295 THSD1 Zornitza Stark Phenotypes for gene: THSD1 were changed from Hydrops fetalis MONDO:0015193, THSD1-related to Lymphatic malformation 13, MIM# 620244
Hydrops fetalis v0.294 THSD1 Zornitza Stark reviewed gene: THSD1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Lymphatic malformation 13, MIM# 620244; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5165 RAB39B Achchuthan Shanmugasundram reviewed gene: RAB39B: Rating: GREEN; Mode of pathogenicity: None; Publications: 20159109, 25434005, 11050621, 29152164, 32873259, 34761259; Phenotypes: Intellectual developmental disorder, X-linked 72, OMIM:300271, Waisman syndrome, OMIM:311510; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Palmoplantar Keratoderma and Erythrokeratoderma v0.127 KDSR Achchuthan Shanmugasundram reviewed gene: KDSR: Rating: GREEN; Mode of pathogenicity: None; Publications: 34686882; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1865 MCFD2 Zornitza Stark Classified gene: MCFD2 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.1865 MCFD2 Zornitza Stark Gene: mcfd2 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1864 MCFD2 Zornitza Stark changed review comment from: Reviewed with Meg Wall, haematologist.
Treatable, including with prophylactic DDAVP, include.; to: Reviewed with Meg Wall, haematologist.
Treatable, including with prophylactic DDAVP; however, generally mild, therefore exclude.
BabyScreen+ newborn screening v0.1864 MCFD2 Zornitza Stark edited their review of gene: MCFD2: Changed rating: AMBER
BabyScreen+ newborn screening v0.1864 HBB Zornitza Stark Phenotypes for gene: HBB were changed from Sickle cell anaemia, MIM# 603903; Thalassaemia, beta, MIM# 613985 to Sickle cell anaemia, MIM# 603903
BabyScreen+ newborn screening v0.1863 HBB Zornitza Stark edited their review of gene: HBB: Changed phenotypes: Sickle cell anaemia, MIM# 603903
Intellectual disability syndromic and non-syndromic v0.5165 WDR11 Zornitza Stark reviewed gene: WDR11: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Intellectual developmental disorder, autosomal recessive 78, MIM# 620237; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Microcephaly v1.191 WDR11 Zornitza Stark Phenotypes for gene: WDR11 were changed from Intellectual disability; Microcephaly; Short stature to Intellectual developmental disorder, autosomal recessive 78, MIM# 620237; Intellectual disability; Microcephaly; Short stature
Microcephaly v1.190 WDR11 Zornitza Stark edited their review of gene: WDR11: Changed phenotypes: Intellectual developmental disorder, autosomal recessive 78, MIM# 620237, Intellectual disability, Microcephaly, Short stature
Mendeliome v1.659 WDR11 Zornitza Stark Phenotypes for gene: WDR11 were changed from Intellectual disability; Hypogonadotropic hypogonadism 14 with or without anosmia MIM #614858 to Intellectual developmental disorder, autosomal recessive 78, MIM# 620237; Hypogonadotropic hypogonadism 14 with or without anosmia MIM #614858
Mendeliome v1.658 WDR11 Zornitza Stark edited their review of gene: WDR11: Changed phenotypes: Intellectual developmental disorder, autosomal recessive 78, MIM# 620237, Hypogonadotropic hypogonadism 14 with or without anosmia MIM #614858
Cone-rod Dystrophy v0.48 KCNV2 Achchuthan Shanmugasundram changed review comment from: Seven cases are identified with homozygous variants in KCNV2 gene and reported with cone dystrophy with supernormal rod responses (CDSRR) in PMID:23221069. Similarly, 15 unrelated patients were identified with three different homozygous KCNV2 variants and reported with CDSRR in PMID:31960170. PMID:34535971 reports a Chinese family with compound heterozygous variants and implicated in CDSRR. KCNV2 knockout mouse exhibits aberrant retinal activities that phenocopies CDSRR patients (PMID:34652420).; to: Additional cases: Seven cases are identified with homozygous variants in KCNV2 gene and reported with cone dystrophy with supernormal rod responses (CDSRR) in PMID:23221069. Similarly, 15 unrelated patients were identified with three different homozygous KCNV2 variants and reported with CDSRR in PMID:31960170. PMID:34535971 reports a Chinese family with compound heterozygous variants and implicated in CDSRR.

Functional studies: KCNV2 knockout mouse exhibits aberrant retinal activities that phenocopies CDSRR patients (PMID:34652420).
Cone-rod Dystrophy v0.48 KCNV2 Achchuthan Shanmugasundram reviewed gene: KCNV2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23221069, 31960170, 34535971, 34652420; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1863 RUNX1 Zornitza Stark Classified gene: RUNX1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1863 RUNX1 Zornitza Stark Gene: runx1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1862 RUNX1 Zornitza Stark edited their review of gene: RUNX1: Changed rating: GREEN
BabyScreen+ newborn screening v0.1862 MCFD2 Zornitza Stark Marked gene: MCFD2 as ready
BabyScreen+ newborn screening v0.1862 MCFD2 Zornitza Stark Gene: mcfd2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1862 MCFD2 Zornitza Stark Tag for review was removed from gene: MCFD2.
Tag treatable tag was added to gene: MCFD2.
BabyScreen+ newborn screening v0.1862 MCFD2 Zornitza Stark reviewed gene: MCFD2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Factor V and factor VIII, combined deficiency of, MIM# 613625; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1862 HBB Zornitza Stark Tag for review was removed from gene: HBB.
BabyScreen+ newborn screening v0.1862 HBB Zornitza Stark changed review comment from: Well established gene-disease associations.

Congenital onset.

Both sickle cell anaemia and beta thalassaemia are treatable disorders.

Beta thal: gene therapy (betibeglogene autotemcel - clinical trial), red cell transfusions, bone marrow transplantation (Hematopoietic Stem Cell Transplantation (HSCT)), Luspatercept

Sickle cell: glutamine, voxelotor, crizanlizumab, hydroxyurea, ,red cell transfusions, bone marrow transplantation (Hematopoietic Stem Cell Transplantation (HSCT)), gene therapy (BCH-BB694 BCL11A shmiR lentiviral vector - clinical trial and autologous CRISPR-Cas9-edited CD34+ hematopoietic stem and progenitor cells) - clinical trial)

Some of the beta-that variants are structural -- ability to detect reliably? For review.; to: Well established gene-disease associations.

Congenital onset.

Both sickle cell anaemia and beta thalassaemia are treatable disorders.

Beta thal: gene therapy (betibeglogene autotemcel - clinical trial), red cell transfusions, bone marrow transplantation (Hematopoietic Stem Cell Transplantation (HSCT)), Luspatercept

Sickle cell: glutamine, voxelotor, crizanlizumab, hydroxyurea, ,red cell transfusions, bone marrow transplantation (Hematopoietic Stem Cell Transplantation (HSCT)), gene therapy (BCH-BB694 BCL11A shmiR lentiviral vector - clinical trial and autologous CRISPR-Cas9-edited CD34+ hematopoietic stem and progenitor cells) - clinical trial)

Some of the beta-that variants are structural -- ability to detect reliably? For review.

We are only able to reliably screen for the HbS association.
BabyScreen+ newborn screening v0.1862 HBA2 Zornitza Stark Classified gene: HBA2 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.1862 HBA2 Zornitza Stark Gene: hba2 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1861 HBA2 Zornitza Stark edited their review of gene: HBA2: Changed rating: AMBER
BabyScreen+ newborn screening v0.1861 HBA1 Zornitza Stark Classified gene: HBA1 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.1861 HBA1 Zornitza Stark Gene: hba1 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1860 HBA1 Zornitza Stark changed review comment from: Well established gene-disease association.

Congenital onset.

Treatable: transfusions, bone marrow transplant.

However, there is widespread screening in pregnancy. Also note mutational spectrum includes SVs/CNVs: can we reliably diagnose? For review.; to: Well established gene-disease association.

Congenital onset.

Treatable: transfusions, bone marrow transplant.

However, there is widespread screening in pregnancy. Also note mutational spectrum includes SVs/CNVs: can we reliably diagnose?

Exclude for now due to technical concerns.
BabyScreen+ newborn screening v0.1860 HBA1 Zornitza Stark edited their review of gene: HBA1: Changed rating: AMBER
BabyScreen+ newborn screening v0.1860 F8 Zornitza Stark Classified gene: F8 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.1860 F8 Zornitza Stark Gene: f8 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1859 F8 Zornitza Stark changed review comment from: Well established gene-disease association.

Variable severity.

Treatment: recombinant factor VIII. Gene therapy trial.

Non-genetic confirmatory testing: factor VIII levels.

Note: excluded from other screening tests due to concerns regarding ability to detect the intron 22 inversion (Inv22) mutation of F8 which causes about 45% of severe HA cases. For review.; to: Well established gene-disease association.

Variable severity.

Treatment: recombinant factor VIII. Gene therapy trial.

Non-genetic confirmatory testing: factor VIII levels.

Note: excluded from other screening tests due to concerns regarding ability to detect the intron 22 inversion (Inv22) mutation of F8 which causes about 45% of severe HA cases. Intron 1 inversion also common.

Excluded for now until we can confirm we can detect inversion.
BabyScreen+ newborn screening v0.1859 F8 Zornitza Stark edited their review of gene: F8: Changed rating: AMBER
Intellectual disability syndromic and non-syndromic v0.5165 TRPM3 Zornitza Stark Phenotypes for gene: TRPM3 were changed from Neurodevelopmental disorder, MONDO:0700092, TRPM3-related to Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures, MIM# 620224
Intellectual disability syndromic and non-syndromic v0.5164 TRPM3 Zornitza Stark edited their review of gene: TRPM3: Changed phenotypes: Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures, MIM# 620224
Genetic Epilepsy v0.1833 TRPM3 Zornitza Stark Phenotypes for gene: TRPM3 were changed from Neurodevelopmental disorder, MONDO:0700092, TRPM3-related to Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures, MIM# 620224
Genetic Epilepsy v0.1832 TRPM3 Zornitza Stark edited their review of gene: TRPM3: Changed phenotypes: Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures, MIM# 620224
Mendeliome v1.658 TRPM3 Zornitza Stark Phenotypes for gene: TRPM3 were changed from Neurodevelopmental disorder, MONDO:0700092, TRPM3-related to Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures, MIM# 620224
Mendeliome v1.657 TRPM3 Zornitza Stark edited their review of gene: TRPM3: Changed phenotypes: Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures, MIM# 620224
Disorders of immune dysregulation v0.164 STAT6 Peter McNaughton gene: STAT6 was added
gene: STAT6 was added to Disorders of immune dysregulation. Sources: Literature
Mode of inheritance for gene: STAT6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: STAT6 were set to PMID: 36216080
Phenotypes for gene: STAT6 were set to early-onset multiorgan allergies
Mode of pathogenicity for gene: STAT6 was set to Other
Review for gene: STAT6 was set to AMBER
Added comment: STAT6 gain-of-function variant associated with early-onset multiorgan allergies in a family with
3 affected members, extensive functional data to support mechanism of allergic disease.
Sources: Literature
Ectodermal Dysplasia v0.78 CST6 Chirag Patel Classified gene: CST6 as Green List (high evidence)
Ectodermal Dysplasia v0.78 CST6 Chirag Patel Gene: cst6 has been classified as Green List (High Evidence).
Ectodermal Dysplasia v0.77 CST6 Chirag Patel reviewed gene: CST6: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36371786; Phenotypes: dry skin, desquamation and abnormal keratosis without hypotrichosis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.657 EFCAB1 Chirag Patel Classified gene: EFCAB1 as Green List (high evidence)
Mendeliome v1.657 EFCAB1 Chirag Patel Gene: efcab1 has been classified as Green List (High Evidence).
Heterotaxy v1.28 EFCAB1 Chirag Patel Classified gene: EFCAB1 as Green List (high evidence)
Heterotaxy v1.28 EFCAB1 Chirag Patel Gene: efcab1 has been classified as Green List (High Evidence).
Mendeliome v1.656 EFCAB1 Chirag Patel gene: EFCAB1 was added
gene: EFCAB1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: EFCAB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EFCAB1 were set to PMID: 36727596
Phenotypes for gene: EFCAB1 were set to Primary ciliary dyskinesia and heterotaxy, no OMIM #
Review for gene: EFCAB1 was set to GREEN
Added comment: WES in 3 individuals with laterality defects and respiratory symptoms, identified homozygous pathogenic variants in CLXN (EFCAB1). They found Clxn expressed in mice left-right organizer. Transmission electron microscopy depicted outer dynein arm (ODA) defects in distal ciliary axonemes. Immunofluorescence microscopy revealed absence of CLXN from the ciliary axonemes, absence of the ODA components DNAH5, DNAI1 and DNAI2 from the distal axonemes, as well as mislocalization or absence of DNAH9. Additionally, CLXN is undetectable in ciliary axonemes of individuals with defects in the outer dynein arm docking (ODA-DC) machinery: ODAD1, ODAD2, ODAD3 and ODAD4. Moreover, SMED-EFCAB1-deficient planaria displayed ciliary dysmotility.
Sources: Literature
Ciliary Dyskinesia v1.27 EFCAB1 Chirag Patel Classified gene: EFCAB1 as Green List (high evidence)
Ciliary Dyskinesia v1.27 EFCAB1 Chirag Patel Gene: efcab1 has been classified as Green List (High Evidence).
Heterotaxy v1.27 EFCAB1 Chirag Patel gene: EFCAB1 was added
gene: EFCAB1 was added to Heterotaxy. Sources: Literature
Mode of inheritance for gene: EFCAB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EFCAB1 were set to PMID: 36727596
Phenotypes for gene: EFCAB1 were set to Primary ciliary dyskinesia and heterotaxy, no OMIM #
Review for gene: EFCAB1 was set to GREEN
Added comment: WES in 3 individuals with laterality defects and respiratory symptoms, identified homozygous pathogenic variants in CLXN (EFCAB1). They found Clxn expressed in mice left-right organizer. Transmission electron microscopy depicted outer dynein arm (ODA) defects in distal ciliary axonemes. Immunofluorescence microscopy revealed absence of CLXN from the ciliary axonemes, absence of the ODA components DNAH5, DNAI1 and DNAI2 from the distal axonemes, as well as mislocalization or absence of DNAH9. Additionally, CLXN is undetectable in ciliary axonemes of individuals with defects in the outer dynein arm docking (ODA-DC) machinery: ODAD1, ODAD2, ODAD3 and ODAD4. Moreover, SMED-EFCAB1-deficient planaria displayed ciliary dysmotility.
Sources: Literature
Ciliary Dyskinesia v1.27 EFCAB1 Chirag Patel Classified gene: EFCAB1 as Green List (high evidence)
Ciliary Dyskinesia v1.27 EFCAB1 Chirag Patel Gene: efcab1 has been classified as Green List (High Evidence).
Ciliary Dyskinesia v1.26 EFCAB1 Chirag Patel gene: EFCAB1 was added
gene: EFCAB1 was added to Ciliary Dyskinesia. Sources: Literature
Mode of inheritance for gene: EFCAB1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EFCAB1 were set to PMID: 36727596
Phenotypes for gene: EFCAB1 were set to Primary ciliary dyskinesia and heterotaxy, no OMIM #
Review for gene: EFCAB1 was set to GREEN
Added comment: WES in 3 individuals with laterality defects and respiratory symptoms, identified homozygous pathogenic variants in CLXN (EFCAB1). They found Clxn expressed in mice left-right organizer. Transmission electron microscopy depicted outer dynein arm (ODA) defects in distal ciliary axonemes. Immunofluorescence microscopy revealed absence of CLXN from the ciliary axonemes, absence of the ODA components DNAH5, DNAI1 and DNAI2 from the distal axonemes, as well as mislocalization or absence of DNAH9. Additionally, CLXN is undetectable in ciliary axonemes of individuals with defects in the outer dynein arm docking (ODA-DC) machinery: ODAD1, ODAD2, ODAD3 and ODAD4. Moreover, SMED-EFCAB1-deficient planaria displayed ciliary dysmotility.
Sources: Literature
Differences of Sex Development v0.271 ARHGAP35 Chirag Patel Classified gene: ARHGAP35 as Green List (high evidence)
Differences of Sex Development v0.271 ARHGAP35 Chirag Patel Gene: arhgap35 has been classified as Green List (High Evidence).
Differences of Sex Development v0.270 ARHGAP35 Chirag Patel gene: ARHGAP35 was added
gene: ARHGAP35 was added to Differences of Sex Development. Sources: Literature
Mode of inheritance for gene: ARHGAP35 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARHGAP35 were set to PMID: 36178483
Phenotypes for gene: ARHGAP35 were set to Idiopathic hypogonadotropic hypogonadism, no OMIM #
Review for gene: ARHGAP35 was set to GREEN
Added comment: 12 patients with idiopathic hypogonadotropic hypogonadism. Rare protein-truncating variants (n = 5) and missense variants (n = 7) found in the RhoGAP domain of ARHGAP35 gene. Zebrafish modeling using gnrh3:egfp phenotype assessment showed that mutant larvae with deficient arhgap35a (predominant ARHGAP35 paralog in zebrafish brain), displayed decreased GnRH3-GFP+ neuronal area, a readout for IHH. In vitro GAP activity studies showed that 1 rare missense variant (Arg1284Trp) had decreased GAP activity.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5164 WDR5 Bryony Thompson Publications for gene: WDR5 were set to DOI:https://doi.org/10.1016/j.xhgg.2022.100157
Intellectual disability syndromic and non-syndromic v0.5163 WDR5 Bryony Thompson edited their review of gene: WDR5: Changed publications: 36408368
Mendeliome v1.655 WDR5 Bryony Thompson Publications for gene: WDR5 were set to DOI:https://doi.org/10.1016/j.xhgg.2022.100157
Mendeliome v1.654 WDR5 Bryony Thompson edited their review of gene: WDR5: Changed publications: 36408368
Arrhythmogenic Cardiomyopathy v0.68 KBTBD13 Bryony Thompson Classified gene: KBTBD13 as Amber List (moderate evidence)
Arrhythmogenic Cardiomyopathy v0.68 KBTBD13 Bryony Thompson Gene: kbtbd13 has been classified as Amber List (Moderate Evidence).
Arrhythmogenic Cardiomyopathy v0.67 KBTBD13 Bryony Thompson gene: KBTBD13 was added
gene: KBTBD13 was added to Arrhythmogenic Cardiomyopathy. Sources: Literature
Mode of inheritance for gene: KBTBD13 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KBTBD13 were set to 36335629
Phenotypes for gene: KBTBD13 were set to Intrinsic cardiomyopathy MONDO:0000591
Review for gene: KBTBD13 was set to AMBER
gene: KBTBD13 was marked as current diagnostic
Added comment: In 3 families with the Nemaline myopathy type 6 (NEM6) Dutch founder variant, c.1222C>T, p.Arg408Cys (KBTBD13 p.R408C), a cardiac phenotype was found to co-segregate with the variant (LOD score 6.02). In total, 65 NEM6 patients were evaluated of whom 12% presented with LV dilatation, 29% with LVEF < 50%, 8% with atrial fibrillation, 9% with ventricular tachycardia, and 20% with repolarization abnormalities. Although some patients meet criteria for dilated cardiomyopathy, others have normal LV dimensions and meet criteria for arrhythmogenic cardiomyopathy, or display arrhythmia in the absence of cardiomyopathy. Mouse studies demonstrated that mice harbouring the Kbtbd13 p.R408C variant displayed mild diastolic dysfunction and Kbtbd13-deficient mice have systolic dysfunction. Currently, a cardiac phenotype has not been identified in individuals with any other pathogenic variants in KBTBD13.
Sources: Literature
Mendeliome v1.654 KBTBD13 Bryony Thompson reviewed gene: KBTBD13: Rating: AMBER; Mode of pathogenicity: None; Publications: 36335629; Phenotypes: Cardiomyopathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.654 KLHL24 Zornitza Stark Phenotypes for gene: KLHL24 were changed from Epidermolysis bullosa simplex, generalized, with scarring and hair loss OMIM#617294; dilated cardiomyopathy; Hypertrophic cardiomyopathy to Epidermolysis bullosa simplex, generalized, with scarring and hair loss OMIM#617294; dilated cardiomyopathy; Cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies, MIM# 620236
Hypertrophic cardiomyopathy_HCM v0.172 KLHL24 Zornitza Stark Phenotypes for gene: KLHL24 were changed from Hypertrophic cardiomyopathy to Cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies, MIM# 620236
Mendeliome v1.653 ASNA1 Zornitza Stark Marked gene: ASNA1 as ready
Mendeliome v1.653 ASNA1 Zornitza Stark Gene: asna1 has been classified as Red List (Low Evidence).
Mendeliome v1.653 ASNA1 Zornitza Stark Classified gene: ASNA1 as Red List (low evidence)
Mendeliome v1.653 ASNA1 Zornitza Stark Gene: asna1 has been classified as Red List (Low Evidence).
Cardiomyopathy_Paediatric v0.157 ASNA1 Zornitza Stark Marked gene: ASNA1 as ready
Cardiomyopathy_Paediatric v0.157 ASNA1 Zornitza Stark Gene: asna1 has been classified as Red List (Low Evidence).
Cardiomyopathy_Paediatric v0.157 ASNA1 Zornitza Stark Classified gene: ASNA1 as Red List (low evidence)
Cardiomyopathy_Paediatric v0.157 ASNA1 Zornitza Stark Gene: asna1 has been classified as Red List (Low Evidence).
Cardiomyopathy_Paediatric v0.156 RRAGD Zornitza Stark Marked gene: RRAGD as ready
Cardiomyopathy_Paediatric v0.156 RRAGD Zornitza Stark Gene: rragd has been classified as Green List (High Evidence).
Cardiomyopathy_Paediatric v0.156 RRAGD Zornitza Stark Classified gene: RRAGD as Green List (high evidence)
Cardiomyopathy_Paediatric v0.156 RRAGD Zornitza Stark Gene: rragd has been classified as Green List (High Evidence).
Cardiomyopathy_Paediatric v0.155 RRAGD Zornitza Stark gene: RRAGD was added
gene: RRAGD was added to Cardiomyopathy_Paediatric. Sources: Literature
Mode of inheritance for gene: RRAGD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RRAGD were set to 34607910
Phenotypes for gene: RRAGD were set to Inherited renal tubular disease, MONDO:0015962, RRAGD-related; dilated cardiomyopathy; hypomagnesaemia; renal salt-wasting; nephrocalcinosis
Review for gene: RRAGD was set to GREEN
Added comment: PMID: 34607910; Schlingmann, KP. et al. (2021) J Am Soc Nephrol. 32(11):2885-2899. Six missense variants in RRAGD identified in eight children (some early infant onset) from unrelated families. The variants were recurrent or affecting the same amino acid, i.e., p.S76L, S76W, p.T97P, p.P119L, p.P119R and p.I221K note: these are absent in gnomAD v2.1.1, and are very highly conserved residues. All variants are located in the N-terminal G-domain and affect sequence motifs involved in nucleotide binding The children had a tubulopathy characterised by hypomagnesemia, hypokalaemia, salt wasting, and nephrocalcinosis, and six had dilated cardiomyopathy. Most occurred de novo. Two were familial. One family with two affected siblings showed low level mosaicism in the mother. In vitro studies using transfected HEK293 cells showed increased binding to RPTOR and MTOR.
Sources: Literature
Renal Tubulopathies and related disorders v1.6 RRAGD Zornitza Stark Marked gene: RRAGD as ready
Renal Tubulopathies and related disorders v1.6 RRAGD Zornitza Stark Gene: rragd has been classified as Green List (High Evidence).
Renal Tubulopathies and related disorders v1.6 RRAGD Zornitza Stark Classified gene: RRAGD as Green List (high evidence)
Renal Tubulopathies and related disorders v1.6 RRAGD Zornitza Stark Gene: rragd has been classified as Green List (High Evidence).
Renal Tubulopathies and related disorders v1.5 RRAGD Zornitza Stark gene: RRAGD was added
gene: RRAGD was added to Renal Tubulopathies and related disorders. Sources: Literature
Mode of inheritance for gene: RRAGD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RRAGD were set to 34607910
Phenotypes for gene: RRAGD were set to Inherited renal tubular disease, MONDO:0015962, RRAGD-related; dilated cardiomyopathy; hypomagnesaemia; renal salt-wasting; nephrocalcinosis
Review for gene: RRAGD was set to GREEN
Added comment: PMID: 34607910; Schlingmann, KP. et al. (2021) J Am Soc Nephrol. 32(11):2885-2899.
Six missense variants in RRAGD identified in eight children (some early infant onset) from unrelated families. The variants were recurrent or affecting the same amino acid, i.e., p.S76L, S76W, p.T97P, p.P119L, p.P119R and p.I221K note: these are absent in gnomAD v2.1.1, and are very highly conserved residues. All variants are located in the N-terminal G-domain and affect sequence motifs involved in nucleotide binding
The children had a tubulopathy characterised by hypomagnesemia, hypokalaemia, salt wasting, and nephrocalcinosis, and six had dilated cardiomyopathy.
Most occurred de novo. Two were familial. One family with two affected siblings showed low level mosaicism in the mother.
In vitro studies using transfected HEK293 cells showed increased binding to RPTOR and MTOR.
Sources: Literature
Mendeliome v1.652 RRAGD Zornitza Stark Classified gene: RRAGD as Green List (high evidence)
Mendeliome v1.652 RRAGD Zornitza Stark Gene: rragd has been classified as Green List (High Evidence).
Mendeliome v1.651 RRAGD Zornitza Stark Marked gene: RRAGD as ready
Mendeliome v1.651 RRAGD Zornitza Stark Gene: rragd has been removed from the panel.
Mendeliome v1.651 RRAGD Zornitza Stark Phenotypes for gene: RRAGD were changed from Kidney tubulopathy; dilated cardiomyopathy; hypomagnesaemia; renal salt-wasting; nephrocalcinosis to Inherited renal tubular disease, MONDO:0015962, RRAGD-related; dilated cardiomyopathy; hypomagnesaemia; renal salt-wasting; nephrocalcinosis
Mendeliome v1.650 PMEL Zornitza Stark Marked gene: PMEL as ready
Mendeliome v1.650 PMEL Zornitza Stark Gene: pmel has been classified as Red List (Low Evidence).
Mendeliome v1.650 PMEL Zornitza Stark Classified gene: PMEL as Red List (low evidence)
Mendeliome v1.650 PMEL Zornitza Stark Gene: pmel has been classified as Red List (Low Evidence).
Hirschsprung disease v0.24 PMEL Zornitza Stark Marked gene: PMEL as ready
Hirschsprung disease v0.24 PMEL Zornitza Stark Gene: pmel has been classified as Red List (Low Evidence).
Hirschsprung disease v0.24 PMEL Zornitza Stark Classified gene: PMEL as Red List (low evidence)
Hirschsprung disease v0.24 PMEL Zornitza Stark Gene: pmel has been classified as Red List (Low Evidence).
Ocular and Oculocutaneous Albinism v1.9 PMEL Zornitza Stark Marked gene: PMEL as ready
Ocular and Oculocutaneous Albinism v1.9 PMEL Zornitza Stark Gene: pmel has been classified as Red List (Low Evidence).
Ocular and Oculocutaneous Albinism v1.9 PMEL Zornitza Stark Classified gene: PMEL as Red List (low evidence)
Ocular and Oculocutaneous Albinism v1.9 PMEL Zornitza Stark Gene: pmel has been classified as Red List (Low Evidence).
Mendeliome v1.649 ASNA1 Naomi Baker gene: ASNA1 was added
gene: ASNA1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: ASNA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ASNA1 were set to 31461301; 16797549
Phenotypes for gene: ASNA1 were set to Dilated cardiomyopathy, MONDO:0001644, ASNA1-related
Review for gene: ASNA1 was set to RED
Added comment: Two siblings reported with biallelic variants - there were two variants on the paternal allele (c.867C>G p.(Cys289Trp) and c.913C>T p.(Gln305*)) and one variant on the maternal allele (c.488T>C p.(Val163Ala)). Unaffected sibling was heterozygous for maternal allele. Western blotting demonstrated reduced protein expression. Knockout of asna1 in zebrafish mode resulted in cardiac defects and early lethality. The Asna1 knockout mice displayed early embryonic lethality, consistent with a role of Asna1 in early embryonic development.
Sources: Literature
Cardiomyopathy_Paediatric v0.154 ASNA1 Naomi Baker gene: ASNA1 was added
gene: ASNA1 was added to Cardiomyopathy_Paediatric. Sources: Literature
Mode of inheritance for gene: ASNA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ASNA1 were set to 31461301; 16797549
Phenotypes for gene: ASNA1 were set to Dilated cardiomyopathy, MONDO:0001644, ASNA1-related
Review for gene: ASNA1 was set to RED
Added comment: Two siblings reported with biallelic variants - there were two variants on the paternal allele (c.867C>G p.(Cys289Trp) and c.913C>T p.(Gln305*)) and one variant on the maternal allele (c.488T>C p.(Val163Ala)). Unaffected sibling was heterozygous for maternal allele. Western blotting demonstrated reduced protein expression. Knockout of asna1 in zebrafish mode resulted in cardiac defects and early lethality. The Asna1 knockout mice displayed early embryonic lethality, consistent with a role of Asna1 in early embryonic development.
Sources: Literature
Mendeliome v1.649 RRAGD Hazel Phillimore changed review comment from: PMID: 34607910; Schlingmann, KP. et al. (2021) J Am Soc Nephrol. 32(11):2885-2899.
Five missense variants in RRAGD identified in eight children (some early infant onset) from unrelated families. The variants were recurrent or affecting the same amino acid, i.e., p.S76L, S76W, p.T97P, p.P119L, p.P119R and p.I221K note: these are absent in gnomAD v2.1.1, and are very highly conserved residues. All variants are located in the N-terminal G-domain and affect sequence motifs involved in nucleotide binding
The children had a tubulopathy characterised by hypomagnesemia, hypokalaemia, salt wasting, and nephrocalcinosis, and six had dilated cardiomyopathy.
Most occurred de novo. Two were familial. One family with two affected siblings showed low level mosaicism in the mother.
In vitro studies using transfected HEK293 cells showed increased binding to RPTOR and MTOR.
Sources: Literature; to: PMID: 34607910; Schlingmann, KP. et al. (2021) J Am Soc Nephrol. 32(11):2885-2899.
Six missense variants in RRAGD identified in eight children (some early infant onset) from unrelated families. The variants were recurrent or affecting the same amino acid, i.e., p.S76L, S76W, p.T97P, p.P119L, p.P119R and p.I221K note: these are absent in gnomAD v2.1.1, and are very highly conserved residues. All variants are located in the N-terminal G-domain and affect sequence motifs involved in nucleotide binding
The children had a tubulopathy characterised by hypomagnesemia, hypokalaemia, salt wasting, and nephrocalcinosis, and six had dilated cardiomyopathy.
Most occurred de novo. Two were familial. One family with two affected siblings showed low level mosaicism in the mother.
In vitro studies using transfected HEK293 cells showed increased binding to RPTOR and MTOR.
Sources: Literature
Mendeliome v1.649 RRAGD Hazel Phillimore gene: RRAGD was added
gene: RRAGD was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: RRAGD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RRAGD were set to PMID: 34607910
Phenotypes for gene: RRAGD were set to Kidney tubulopathy; dilated cardiomyopathy; hypomagnesaemia; renal salt-wasting; nephrocalcinosis
Review for gene: RRAGD was set to GREEN
Added comment: PMID: 34607910; Schlingmann, KP. et al. (2021) J Am Soc Nephrol. 32(11):2885-2899.
Five missense variants in RRAGD identified in eight children (some early infant onset) from unrelated families. The variants were recurrent or affecting the same amino acid, i.e., p.S76L, S76W, p.T97P, p.P119L, p.P119R and p.I221K note: these are absent in gnomAD v2.1.1, and are very highly conserved residues. All variants are located in the N-terminal G-domain and affect sequence motifs involved in nucleotide binding
The children had a tubulopathy characterised by hypomagnesemia, hypokalaemia, salt wasting, and nephrocalcinosis, and six had dilated cardiomyopathy.
Most occurred de novo. Two were familial. One family with two affected siblings showed low level mosaicism in the mother.
In vitro studies using transfected HEK293 cells showed increased binding to RPTOR and MTOR.
Sources: Literature
Ocular and Oculocutaneous Albinism v1.8 PMEL Paul De Fazio edited their review of gene: PMEL: Changed phenotypes: Oculocutaneous albinism, PMEL-related MONDO:0018910
Hirschsprung disease v0.23 PMEL Paul De Fazio edited their review of gene: PMEL: Changed phenotypes: Oculocutaneous albinism, PMEL-related MONDO:0018910
Mendeliome v1.649 PMEL Paul De Fazio gene: PMEL was added
gene: PMEL was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PMEL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PMEL were set to 36166100; 36207673
Phenotypes for gene: PMEL were set to Oculocutaneous albinism, PMEL-related MONDO:0018910
Review for gene: PMEL was set to RED
gene: PMEL was marked as current diagnostic
Added comment: A consanguineous family with oculocutaneous albinism and Hirschsprung disease was found to have a biallelic LoF variant in PMEL, which although NMD-predicted was found not to result in NMD by RT-PCR.

Some evidence that polymorphisms in this gene influence pigmentation in cattle.
Sources: Literature
Hirschsprung disease v0.23 PMEL Paul De Fazio gene: PMEL was added
gene: PMEL was added to Hirschsprung disease. Sources: Literature
Mode of inheritance for gene: PMEL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PMEL were set to 36166100
Phenotypes for gene: PMEL were set to Cculocutaneous albinism, PMEL-related MONDO:0018910
Review for gene: PMEL was set to RED
gene: PMEL was marked as current diagnostic
Added comment: A consanguineous family with oculocutaneous albinism and Hirschsprung disease was found to have a biallelic LoF variant in PMEL, which although NMD-predicted was found not to result in NMD by RT-PCR.
Sources: Literature
Gastrointestinal neuromuscular disease v1.20 MIR145 Zornitza Stark Marked gene: MIR145 as ready
Gastrointestinal neuromuscular disease v1.20 MIR145 Zornitza Stark Gene: mir145 has been classified as Red List (Low Evidence).
Mendeliome v1.649 SPTSSA Seb Lunke Marked gene: SPTSSA as ready
Mendeliome v1.649 SPTSSA Seb Lunke Gene: sptssa has been classified as Amber List (Moderate Evidence).
Mendeliome v1.649 SPTSSA Seb Lunke Classified gene: SPTSSA as Amber List (moderate evidence)
Mendeliome v1.649 SPTSSA Seb Lunke Added comment: Comment on list classification: Three individuals but only two variants with different inheritance. Amber despite functional data.
Mendeliome v1.649 SPTSSA Seb Lunke Gene: sptssa has been classified as Amber List (Moderate Evidence).
Ocular and Oculocutaneous Albinism v1.8 PMEL Paul De Fazio gene: PMEL was added
gene: PMEL was added to Ocular and Oculocutaneous Albinism. Sources: Literature
Mode of inheritance for gene: PMEL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PMEL were set to 36166100; 36207673
Phenotypes for gene: PMEL were set to Cculocutaneous albinism, PMEL-related MONDO:0018910
Review for gene: PMEL was set to RED
gene: PMEL was marked as current diagnostic
Added comment: A consanguineous family with oculocutaneous albinism and Hirschsprung disease was found to have a biallelic LoF variant in PMEL, which although NMD-predicted was found not to result in NMD by RT-PCR.

Some evidence that polymorphisms in this gene influence pigmentation in cattle.
Sources: Literature
Gastrointestinal neuromuscular disease v1.20 MIR145 Zornitza Stark Classified gene: MIR145 as Red List (low evidence)
Gastrointestinal neuromuscular disease v1.20 MIR145 Zornitza Stark Gene: mir145 has been classified as Red List (Low Evidence).
Mendeliome v1.648 SPTSSA Seb Lunke gene: SPTSSA was added
gene: SPTSSA was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SPTSSA was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: SPTSSA were set to 36718090
Phenotypes for gene: SPTSSA were set to complex hereditary spastic paraplegia, MONDO:0015150
Review for gene: SPTSSA was set to AMBER
Added comment: Three unrelated individuals with common neurological features of developmental delay, progressive motor impairment, progressive lower extremity spasticity, and epileptiform activity or seizures. Other additional features varied.

Two of the individuals had the same de-novo missense, Thr51Ile, while the third was homozygous for a late truncating variant, Gln58AlafsTer10. The patient with the hom variant was described as less severe.

Functional studies in fibroblasts showed dysregulation of the sphingolipid (SL) synthesis pathway, showing that both variants impair ORMDL regulation of the pathway leading to various levels of increased SL. Over expression of human SPTSSA was shown to lead to motor development in flies, rescued by expression of ORMDL for WT SPTSSA but not mutant SPTSSA.

The de-novo missense were shown to impact regulation more than the hom truncation, while the truncated region was shown to previously to be important for ORMDL regulation.

Mice with a hom KO of the functional equivalent sptssb had early onset ataxia and died prematurely, with evidence of axonic degeneration.
Sources: Literature
Mendeliome v1.647 MIR145 Zornitza Stark Marked gene: MIR145 as ready
Mendeliome v1.647 MIR145 Zornitza Stark Gene: mir145 has been classified as Red List (Low Evidence).
Mendeliome v1.647 MIR145 Zornitza Stark Classified gene: MIR145 as Red List (low evidence)
Mendeliome v1.647 MIR145 Zornitza Stark Gene: mir145 has been classified as Red List (Low Evidence).
Ocular and Oculocutaneous Albinism v1.8 TPCN2 Seb Lunke Marked gene: TPCN2 as ready
Ocular and Oculocutaneous Albinism v1.8 TPCN2 Seb Lunke Gene: tpcn2 has been classified as Amber List (Moderate Evidence).
Ocular and Oculocutaneous Albinism v1.8 TPCN2 Seb Lunke Classified gene: TPCN2 as Amber List (moderate evidence)
Ocular and Oculocutaneous Albinism v1.8 TPCN2 Seb Lunke Gene: tpcn2 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.646 TRU-TCA1-1 Zornitza Stark Marked gene: TRU-TCA1-1 as ready
Mendeliome v1.646 TRU-TCA1-1 Zornitza Stark Gene: tru-tca1-1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.646 TRU-TCA1-1 Zornitza Stark Phenotypes for gene: TRU-TCA1-1 were changed from Hyperthyroidism MONDO:0004425 to Inherited thyroid metabolism disease, MONDO:0045046, TRU-TCA1-1 related
Genetic Epilepsy v0.1832 CAMLG Seb Lunke Classified gene: CAMLG as Red List (low evidence)
Genetic Epilepsy v0.1832 CAMLG Seb Lunke Gene: camlg has been classified as Red List (Low Evidence).
Mendeliome v1.645 TRU-TCA1-1 Zornitza Stark Classified gene: TRU-TCA1-1 as Amber List (moderate evidence)
Mendeliome v1.645 TRU-TCA1-1 Zornitza Stark Gene: tru-tca1-1 has been classified as Amber List (Moderate Evidence).
Congenital Disorders of Glycosylation v1.33 CAMLG Seb Lunke Classified gene: CAMLG as Red List (low evidence)
Congenital Disorders of Glycosylation v1.33 CAMLG Seb Lunke Gene: camlg has been classified as Red List (Low Evidence).
Mendeliome v1.644 TRU-TCA1-1 Zornitza Stark Classified gene: TRU-TCA1-1 as Amber List (moderate evidence)
Mendeliome v1.644 TRU-TCA1-1 Zornitza Stark Gene: tru-tca1-1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.644 C1GALT1C1 Ain Roesley Phenotypes for gene: C1GALT1C1 were changed from Tn polyagglutination syndrome, somatic MIM#300622 to Tn polyagglutination syndrome, somatic MIM#300622; atypical haemolytic-uremic syndrome MONDO#0016244, C1GALT1C1-related
Genetic Epilepsy v0.1831 CAMLG Seb Lunke Marked gene: CAMLG as ready
Genetic Epilepsy v0.1831 CAMLG Seb Lunke Gene: camlg has been classified as Red List (Low Evidence).
Congenital Disorders of Glycosylation v1.32 CAMLG Seb Lunke Marked gene: CAMLG as ready
Congenital Disorders of Glycosylation v1.32 CAMLG Seb Lunke Gene: camlg has been classified as Red List (Low Evidence).
Mendeliome v1.643 C1GALT1C1 Ain Roesley Publications for gene: C1GALT1C1 were set to 18537974; 16251947
Genetic Epilepsy v0.1831 CAMLG Seb Lunke Classified gene: CAMLG as Red List (low evidence)
Genetic Epilepsy v0.1831 CAMLG Seb Lunke Gene: camlg has been classified as Red List (Low Evidence).
Congenital Disorders of Glycosylation v1.32 CAMLG Seb Lunke Classified gene: CAMLG as Red List (low evidence)
Congenital Disorders of Glycosylation v1.32 CAMLG Seb Lunke Gene: camlg has been classified as Red List (Low Evidence).
Arthrogryposis v0.359 CAMLG Seb Lunke Marked gene: CAMLG as ready
Arthrogryposis v0.359 CAMLG Seb Lunke Gene: camlg has been classified as Red List (Low Evidence).
Hyperthyroidism v0.23 TRU-TCA1-1 Zornitza Stark Marked gene: TRU-TCA1-1 as ready
Hyperthyroidism v0.23 TRU-TCA1-1 Zornitza Stark Gene: tru-tca1-1 has been classified as Amber List (Moderate Evidence).
Hyperthyroidism v0.23 TRU-TCA1-1 Zornitza Stark Phenotypes for gene: TRU-TCA1-1 were changed from Hyperthyroidism MONDO:0004425 to Inherited thyroid metabolism disease, MONDO:0045046, TRU-TCA1-1 related
Mendeliome v1.642 CAMLG Seb Lunke Marked gene: CAMLG as ready
Mendeliome v1.642 CAMLG Seb Lunke Gene: camlg has been classified as Red List (Low Evidence).
Mendeliome v1.642 C1GALT1C1 Ain Roesley edited their review of gene: C1GALT1C1: Added comment: Red association for aHUS

1x male with de novo p.(Thr89Ile) which is absent in gnomAD v2 and v3 and has very high conservation; Changed publications: 18537974, 16251947, 36599939; Changed phenotypes: Tn polyagglutination syndrome, somatic MIM#300622, atypical haemolytic-uremic syndrome MONDO#0016244, C1GALT1C1-related
Mendeliome v1.642 CAMLG Seb Lunke Phenotypes for gene: CAMLG were changed from Congenital disorder of glycosylation type IIz, 620201 to Congenital disorder of glycosylation type IIz, OMIM# 620201
Arthrogryposis v0.359 CAMLG Seb Lunke Classified gene: CAMLG as Red List (low evidence)
Arthrogryposis v0.359 CAMLG Seb Lunke Gene: camlg has been classified as Red List (Low Evidence).
Atypical Haemolytic Uraemic Syndrome_MPGN v0.49 C1GALT1C1 Ain Roesley edited their review of gene: C1GALT1C1: Changed phenotypes: atypical haemolytic-uremic syndrome MONDO#0016244, C1GALT1C1-related
Atypical Haemolytic Uraemic Syndrome_MPGN v0.49 C1GALT1C1 Ain Roesley Marked gene: C1GALT1C1 as ready
Atypical Haemolytic Uraemic Syndrome_MPGN v0.49 C1GALT1C1 Ain Roesley Gene: c1galt1c1 has been classified as Red List (Low Evidence).
Mendeliome v1.641 CAMLG Seb Lunke Classified gene: CAMLG as Red List (low evidence)
Mendeliome v1.641 CAMLG Seb Lunke Gene: camlg has been classified as Red List (Low Evidence).
Hyperthyroidism v0.22 TRU-TCA1-1 Zornitza Stark Classified gene: TRU-TCA1-1 as Amber List (moderate evidence)
Hyperthyroidism v0.22 TRU-TCA1-1 Zornitza Stark Gene: tru-tca1-1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.641 SPRY1 Elena Savva Phenotypes for gene: SPRY1 were changed from to Craniosynostosis, SPRY1-related, MONDO:0015469
Craniosynostosis v1.47 SPRY1 Elena Savva Phenotypes for gene: SPRY1 were changed from Craniosynostosis, SPRY1-related, MONDO:0015469 to Craniosynostosis, SPRY1-related, MONDO:0015469
Atypical Haemolytic Uraemic Syndrome_MPGN v0.49 C1GALT1C1 Ain Roesley gene: C1GALT1C1 was added
gene: C1GALT1C1 was added to Atypical Haemolytic Uraemic Syndrome_MPGN. Sources: Literature
Mode of inheritance for gene: C1GALT1C1 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: C1GALT1C1 were set to 36599939
Phenotypes for gene: C1GALT1C1 were set to atypical hemolytic-uremic syndrome MONDO#0016244, C1GALT1C1-related
Review for gene: C1GALT1C1 was set to RED
gene: C1GALT1C1 was marked as current diagnostic
Added comment: 1x male with de novo p.(Thr89Ile) which is absent in gnomAD v2 and v3 and has very high conservation
Sources: Literature
Mendeliome v1.640 SPRY1 Elena Savva Publications for gene: SPRY1 were set to
Gastrointestinal neuromuscular disease v1.19 MIR145 Lucy Spencer gene: MIR145 was added
gene: MIR145 was added to Gastrointestinal neuromuscular disease. Sources: Literature
Mode of inheritance for gene: MIR145 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MIR145 were set to 36649075
Phenotypes for gene: MIR145 were set to multisystemic smooth muscle dysfunction syndrome (MONDO:0013452)
Review for gene: MIR145 was set to RED
Added comment: PMID: 36649075- a patient whose fetal ultrasound revealed polyhydramnios, enlarged abdomenand bladder, and prune belly syndrome. During infancy/childhood profound gastrointestinal dysmotility, cerebrovascular disease, and multiple strokes. Described as a multisystemic smooth muscle dysfunction syndrome. Patient was found to have a de novo SNP in MIR145 NR_029686.1:n.18C>A. The MIR145transcript is processed into two microRNAs, with the variant position at nucleotide 3 of miR-145-5p.

Transfection of an siRNA against mutant miR145-5p induced a notable decrease in the expression of several cytoskeletal proteins including transgelin, calponin, and importantly, smooth muscle actin. Hybridization analysis and miR RNA-seq demonstrated a decrease in expression of miR145-5p in the presence of mutant miR145-5p. RNA-seq showed that the differentially expressed genes were substantially different between patient and control fibroblasts.
Sources: Literature
Mendeliome v1.639 SPRY1 Elena Savva Mode of inheritance for gene: SPRY1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.638 SPRY1 Elena Savva Classified gene: SPRY1 as Amber List (moderate evidence)
Mendeliome v1.638 SPRY1 Elena Savva Gene: spry1 has been classified as Amber List (Moderate Evidence).
Craniosynostosis v1.47 SPRY1 Elena Savva Classified gene: SPRY1 as Amber List (moderate evidence)
Craniosynostosis v1.47 SPRY1 Elena Savva Gene: spry1 has been classified as Amber List (Moderate Evidence).
Microcephaly v1.190 CCDC84 Zornitza Stark Marked gene: CCDC84 as ready
Microcephaly v1.190 CCDC84 Zornitza Stark Gene: ccdc84 has been classified as Amber List (Moderate Evidence).
Microcephaly v1.190 CCDC84 Zornitza Stark Classified gene: CCDC84 as Amber List (moderate evidence)
Microcephaly v1.190 CCDC84 Zornitza Stark Gene: ccdc84 has been classified as Amber List (Moderate Evidence).
Craniosynostosis v1.47 SPRY1 Elena Savva Phenotypes for gene: SPRY1 were changed from raniosynostosis MONDO:0015469 to Craniosynostosis, SPRY1-related, MONDO:0015469
Mendeliome v1.637 SPRY1 Elena Savva Classified gene: SPRY1 as Amber List (moderate evidence)
Mendeliome v1.637 SPRY1 Elena Savva Gene: spry1 has been classified as Amber List (Moderate Evidence).
Hereditary Spastic Paraplegia - paediatric v1.57 SPTSSA Seb Lunke Marked gene: SPTSSA as ready
Hereditary Spastic Paraplegia - paediatric v1.57 SPTSSA Seb Lunke Gene: sptssa has been classified as Amber List (Moderate Evidence).
Mendeliome v1.636 CCDC84 Zornitza Stark Marked gene: CCDC84 as ready
Mendeliome v1.636 CCDC84 Zornitza Stark Gene: ccdc84 has been classified as Amber List (Moderate Evidence).
Craniosynostosis v1.47 SPRY1 Elena Savva Classified gene: SPRY1 as Amber List (moderate evidence)
Craniosynostosis v1.47 SPRY1 Elena Savva Gene: spry1 has been classified as Amber List (Moderate Evidence).
Hereditary Spastic Paraplegia - paediatric v1.57 SPTSSA Seb Lunke Classified gene: SPTSSA as Amber List (moderate evidence)
Hereditary Spastic Paraplegia - paediatric v1.57 SPTSSA Seb Lunke Gene: sptssa has been classified as Amber List (Moderate Evidence).
Craniosynostosis v1.46 SPRY1 Elena Savva Marked gene: SPRY1 as ready
Craniosynostosis v1.46 SPRY1 Elena Savva Gene: spry1 has been classified as Red List (Low Evidence).
Mendeliome v1.636 CCDC84 Zornitza Stark Classified gene: CCDC84 as Amber List (moderate evidence)
Mendeliome v1.636 CCDC84 Zornitza Stark Gene: ccdc84 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.635 SPRY1 Elena Savva reviewed gene: SPRY1: Rating: AMBER; Mode of pathogenicity: None; Publications: 36543535; Phenotypes: Craniosynostosis, SPRY1-related, MONDO:0015469; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5163 CCDC84 Zornitza Stark Marked gene: CCDC84 as ready
Intellectual disability syndromic and non-syndromic v0.5163 CCDC84 Zornitza Stark Gene: ccdc84 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5163 CCDC84 Zornitza Stark Classified gene: CCDC84 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.5163 CCDC84 Zornitza Stark Gene: ccdc84 has been classified as Amber List (Moderate Evidence).
Craniosynostosis v1.46 SPRY1 Elena Savva gene: SPRY1 was added
gene: SPRY1 was added to Craniosynostosis. Sources: Literature
Mode of inheritance for gene: SPRY1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPRY1 were set to 36543535
Phenotypes for gene: SPRY1 were set to raniosynostosis MONDO:0015469
Review for gene: SPRY1 was set to AMBER
Added comment: no homozygous PTCs in gnomAD

PMID: 36543535:
- Hom null mutant mice display kidney/urinary tract abnormalities and altered size of the skull, het mice were normal
- 1 hom proband (3' NMD escape PTC) with sagittal craniosynostosis
- Functional studies proved NMD escape, but loss of full length protein
Sources: Literature
Mendeliome v1.635 TPCN2 Paul De Fazio reviewed gene: TPCN2: Rating: AMBER; Mode of pathogenicity: Other; Publications: 36641477; Phenotypes: Hypopigmentation of the skin, TPCN2-related MONDO:0019290; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v1.635 MIR145 Lucy Spencer gene: MIR145 was added
gene: MIR145 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: MIR145 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MIR145 were set to 36649075
Phenotypes for gene: MIR145 were set to multisystemic smooth muscle dysfunction syndrome (MONDO:0013452), MIR145-related
Review for gene: MIR145 was set to RED
Added comment: PMID: 36649075- a patient whose fetal ultrasound revealed polyhydramnios, enlarged abdomenand bladder, and prune belly syndrome. During infancy/childhood profound gastrointestinal dysmotility, cerebrovascular disease, and multiple strokes. Described as a multisystemic smooth muscle dysfunction syndrome. Patient was found to have a de novo SNP in MIR145 NR_029686.1:n.18C>A. The MIR145transcript is processed into two microRNAs, with the variant position at nucleotide 3 of miR-145-5p.

Transfection of an siRNA against mutant miR145-5p induced a notable decrease in the expression of several cytoskeletal proteins including transgelin, calponin, and importantly, smooth muscle actin. Hybridization analysis and miR RNA-seq demonstrated a decrease in expression of miR145-5p in the presence of mutant miR145-5p. RNA-seq showed that the differentially expressed genes were substantially different between patient and control fibroblasts.
Sources: Literature
Ataxia - paediatric v1.6 TTI1 Zornitza Stark Phenotypes for gene: TTI1 were changed from to Neurodevelopmental disorder, MONDO:0700092, TTI1-related
Hereditary Spastic Paraplegia - paediatric v1.56 SPTSSA Seb Lunke gene: SPTSSA was added
gene: SPTSSA was added to Hereditary Spastic Paraplegia - paediatric. Sources: Literature
Mode of inheritance for gene: SPTSSA was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: SPTSSA were set to 36718090
Phenotypes for gene: SPTSSA were set to complex hereditary spastic paraplegia, MONDO:0015150
Review for gene: SPTSSA was set to GREEN
Added comment: Three unrelated individuals with common neurological features of developmental delay, progressive motor impairment, progressive lower extremity spasticity, and epileptiform activity or seizures. Other additional features varied.

Two of the individuals had the same de-novo missense, Thr51Ile, while the third was homozygous for a late truncating variant, Gln58AlafsTer10. The patient with the hom variant was described as less severe.

Functional studies in fibroblasts showed dysregulation of the sphingolipid (SL) synthesis pathway, showing that both variants impair ORMDL regulation of the pathway leading to various levels of increased SL. Over expression of human SPTSSA was shown to lead to motor development in flies, rescued by expression of ORMDL for WT SPTSSA but not mutant SPTSSA.

The de-novo missense were shown to impact regulation more than the hom truncation, while the truncated region was shown to previously to be important for ORMDL regulation.

Mice with a hom KO of the functional equivalent sptssb had early onset ataxia and died prematurely, with evidence of axonic degeneration.
Sources: Literature
Ataxia - paediatric v1.5 TTI1 Zornitza Stark Mode of inheritance for gene: TTI1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Ataxia - paediatric v1.4 TTI1 Zornitza Stark Classified gene: TTI1 as Green List (high evidence)
Ataxia - paediatric v1.4 TTI1 Zornitza Stark Gene: tti1 has been classified as Green List (High Evidence).
Mendeliome v1.635 TTI1 Zornitza Stark Phenotypes for gene: TTI1 were changed from Intellectual disability to Neurodevelopmental disorder, MONDO:0700092, TTI1-related
Congenital Disorders of Glycosylation v1.31 CAMLG Manny Jacobs gene: CAMLG was added
gene: CAMLG was added to Congenital Disorders of Glycosylation. Sources: Literature
Mode of inheritance for gene: CAMLG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAMLG were set to PMID: 35262690
Phenotypes for gene: CAMLG were set to Congenital disorder of glycosylation type IIz, OMIM #: 620201
Penetrance for gene: CAMLG were set to unknown
Review for gene: CAMLG was set to RED
Added comment: PMID: 35262690 (2022)
Report one patient with hom splice variant. No other reported patients.
GDD, seizures, contractures, hypotonia and brain malformations.
Sources: Literature
Ocular and Oculocutaneous Albinism v1.7 TPCN2 Paul De Fazio edited their review of gene: TPCN2: Changed phenotypes: Hypopigmentation of the skin, TPCN2-related MONDO:0019290
Mendeliome v1.634 TTI1 Zornitza Stark Classified gene: TTI1 as Green List (high evidence)
Mendeliome v1.634 TTI1 Zornitza Stark Gene: tti1 has been classified as Green List (High Evidence).
Microcephaly v1.189 TTI1 Zornitza Stark Marked gene: TTI1 as ready
Microcephaly v1.189 TTI1 Zornitza Stark Gene: tti1 has been classified as Green List (High Evidence).
Microcephaly v1.189 TTI1 Zornitza Stark Classified gene: TTI1 as Green List (high evidence)
Microcephaly v1.189 TTI1 Zornitza Stark Gene: tti1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5162 TTI1 Zornitza Stark Phenotypes for gene: TTI1 were changed from Neurodevelopmental disorder, MONDO:0700092, TTI1-related to Neurodevelopmental disorder, MONDO:0700092, TTI1-related
Ocular and Oculocutaneous Albinism v1.7 TPCN2 Paul De Fazio gene: TPCN2 was added
gene: TPCN2 was added to Ocular and Oculocutaneous Albinism. Sources: Literature
Mode of inheritance for gene: TPCN2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TPCN2 were set to 36641477
Phenotypes for gene: TPCN2 were set to Hypopigmentation of the skin MONDO:0019290
Mode of pathogenicity for gene: TPCN2 was set to Other
Review for gene: TPCN2 was set to AMBER
gene: TPCN2 was marked as current diagnostic
Added comment: A de novo variant in TPCN2, R210C, was identified in a girl who exhibited white skin, blonde hair that darkened to brown with age, no apparent nystagmus and photophobia, and normal vision acuity. Color fundus photography and optical coherence tomography (OCT) showed normal and well-developed macula and fovea. The variant has 1 het in gnomad.

Mice harbouring the homologous variant recapitulate the phenotype. Functional testing indicates the variant has a gain of function effect.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5162 TTI1 Zornitza Stark Phenotypes for gene: TTI1 were changed from Intellectual disability to Neurodevelopmental disorder, MONDO:0700092, TTI1-related
Intellectual disability syndromic and non-syndromic v0.5161 OGDH Zornitza Stark Classified gene: OGDH as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5161 OGDH Zornitza Stark Gene: ogdh has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5162 OGDH Zornitza Stark Marked gene: OGDH as ready
Intellectual disability syndromic and non-syndromic v0.5162 OGDH Zornitza Stark Gene: ogdh has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5162 FICD Elena Savva Classified gene: FICD as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.5162 FICD Elena Savva Gene: ficd has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5161 FICD Elena Savva Classified gene: FICD as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.5161 FICD Elena Savva Gene: ficd has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5161 FICD Elena Savva Classified gene: FICD as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.5161 FICD Elena Savva Gene: ficd has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5161 TTI1 Zornitza Stark Classified gene: TTI1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5161 TTI1 Zornitza Stark Gene: tti1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5160 FICD Elena Savva Marked gene: FICD as ready
Intellectual disability syndromic and non-syndromic v0.5160 FICD Elena Savva Gene: ficd has been classified as Red List (Low Evidence).
Monogenic Diabetes v0.35 FICD Elena Savva Marked gene: FICD as ready
Monogenic Diabetes v0.35 FICD Elena Savva Gene: ficd has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5160 FICD Elena Savva gene: FICD was added
gene: FICD was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: FICD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FICD were set to 36704923
Phenotypes for gene: FICD were set to Neurodevelopmental disorder, FICD-related (MONDO#0700092)
Review for gene: FICD was set to AMBER
Added comment: PMID: 36704923:
- five individuals (3 families) w/ infancy onset diabetes mellitus (5/5) and severe neurodevelopmental delay (4/5)
- all homozygous for p.R371S
- variant expression in E. coli showed loss of affinity, deregulates BiP-AMP and affects secretion
Sources: Literature
Mendeliome v1.633 PCK2 Ain Roesley Phenotypes for gene: PCK2 were changed from PEPCK deficiency, mitochondrial - MIM#261650 to PEPCK deficiency, mitochondrial - MIM#261650; peripheral neuropathy (MONDO#0005244), PCK2-related
Intellectual disability syndromic and non-syndromic v0.5160 OGDH Zornitza Stark Classified gene: OGDH as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5160 OGDH Zornitza Stark Gene: ogdh has been classified as Green List (High Evidence).
Mendeliome v1.632 PCK2 Ain Roesley reviewed gene: PCK2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: peripheral neuropathy (MONDO#0005244), PCK2-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.5159 OGDH Zornitza Stark gene: OGDH was added
gene: OGDH was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: OGDH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OGDH were set to 36520152; 32383294
Phenotypes for gene: OGDH were set to Oxoglutarate dehydrogenase deficiency, MIM# 203740
Review for gene: OGDH was set to GREEN
Added comment: 6 individuals reported with bi-allelic variants in this gene and DD.
Sources: Literature
Arthrogryposis v0.358 CAMLG Manny Jacobs gene: CAMLG was added
gene: CAMLG was added to Arthrogryposis. Sources: Literature
Mode of inheritance for gene: CAMLG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAMLG were set to 35262690
Phenotypes for gene: CAMLG were set to Congenital disorder of glycosylation type IIz, OMIM #: 620201
Penetrance for gene: CAMLG were set to unknown
Review for gene: CAMLG was set to RED
Added comment: PMID: 35262690 (2022)
Report one patient with hom splice variant. No other reported patients.
GDD, seizures, contractures, hypotonia and brain malformations.
Sources: Literature
Monogenic Diabetes v0.35 FICD Elena Savva Classified gene: FICD as Amber List (moderate evidence)
Monogenic Diabetes v0.35 FICD Elena Savva Gene: ficd has been classified as Amber List (Moderate Evidence).
Monogenic Diabetes v0.34 FICD Elena Savva gene: FICD was added
gene: FICD was added to Monogenic Diabetes. Sources: Literature
Mode of inheritance for gene: FICD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FICD were set to 36704923; 36136088
Phenotypes for gene: FICD were set to Monogenic diabetes, MONDO:0015967, FICD-related
Review for gene: FICD was set to AMBER
Added comment: PMID: 36704923:
- five individuals (3 families) w/ infancy onset diabetes mellitus (5/5) and severe neurodevelopmental delay (4/5)
- all homozygous for p.R371S
- variant expression in E. coli showed loss of affinity, deregulates BiP-AMP and affects secretion

PMID: 36136088:
- 1/5 with diabetes mellitus, affect sibling has no diabetes
Sources: Literature
Genetic Epilepsy v0.1830 CAMLG Manny Jacobs gene: CAMLG was added
gene: CAMLG was added to Genetic Epilepsy. Sources: Literature
Mode of inheritance for gene: CAMLG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAMLG were set to 35262690
Phenotypes for gene: CAMLG were set to Congenital disorder of glycosylation type IIz, OMIM #: 620201
Penetrance for gene: CAMLG were set to unknown
Review for gene: CAMLG was set to RED
Added comment: PMID: 35262690 (2022)
Report one patient with hom splice variant. No other reported patients.
GDD, seizures, contractures, hypotonia and brain malformations.
Sources: Literature
Mitochondrial disease v0.854 OGDH Zornitza Stark Classified gene: OGDH as Green List (high evidence)
Mitochondrial disease v0.854 OGDH Zornitza Stark Gene: ogdh has been classified as Green List (High Evidence).
Mitochondrial disease v0.853 OGDH Zornitza Stark Classified gene: OGDH as Green List (high evidence)
Mitochondrial disease v0.853 OGDH Zornitza Stark Gene: ogdh has been classified as Green List (High Evidence).
Mendeliome v1.632 CAMLG Manny Jacobs gene: CAMLG was added
gene: CAMLG was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CAMLG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAMLG were set to PMID: 35262690
Phenotypes for gene: CAMLG were set to Congenital disorder of glycosylation type IIz, 620201
Penetrance for gene: CAMLG were set to unknown
Review for gene: CAMLG was set to RED
Added comment: PMID: 35262690 (2022)
Report one patient with hom splice variant. No other reported patients.
GDD, seizures, contractures, hypotonia and brain malformations.
Sources: Literature
Mendeliome v1.632 OGDH Zornitza Stark Publications for gene: OGDH were set to 32383294
Mendeliome v1.631 OGDH Zornitza Stark Classified gene: OGDH as Green List (high evidence)
Mendeliome v1.631 OGDH Zornitza Stark Gene: ogdh has been classified as Green List (High Evidence).
Ataxia - paediatric v1.3 TTI1 Ee Ming Wong reviewed gene: TTI1: Rating: GREEN; Mode of pathogenicity: None; Publications: DOI:https://doi.org/10.1016/j.ajhg.2023.01.006; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, TTI1-related to; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.630 HTR2C Zornitza Stark Marked gene: HTR2C as ready
Mendeliome v1.630 HTR2C Zornitza Stark Gene: htr2c has been classified as Green List (High Evidence).
Mendeliome v1.630 TRU-TCA1-1 Paul De Fazio gene: TRU-TCA1-1 was added
gene: TRU-TCA1-1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TRU-TCA1-1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRU-TCA1-1 were set to 26854926; 34956927
Phenotypes for gene: TRU-TCA1-1 were set to Hyperthyroidism MONDO:0004425
Review for gene: TRU-TCA1-1 was set to AMBER
gene: TRU-TCA1-1 was marked as current diagnostic
Added comment: PMID 26854926: male 8 year old proband investigated for abdominal pain, fatigue, muscle weakness, and thyroid dysfunction (raised T4, normal T3, raised reverse T3) suggestive of impaired deiodinase activity in combination with low plasma selenium levels. Homozygosity mapping led to identification of a a single nucleotide change, C65G, in TRU-TCA1-1, a tRNA in the selenocysteine incorporation pathway. This mutation resulted in reduction in expression of stress-related selenoproteins. A methylribosylation defect at uridine 34 of mutant tRNA observed in patient cells was restored by cellular complementation with normal tRNA.

PMID 34956927: a 10 year old originally investigated for Hashimoto's disease was found to be homozygous for the same C65G variant identified in the previous paper, inherited from the father in what was concluded to be paternal isodisomy.
Sources: Literature
Mendeliome v1.630 HTR2C Zornitza Stark Classified gene: HTR2C as Green List (high evidence)
Mendeliome v1.630 HTR2C Zornitza Stark Gene: htr2c has been classified as Green List (High Evidence).
Mendeliome v1.629 HTR2C Zornitza Stark gene: HTR2C was added
gene: HTR2C was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: HTR2C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HTR2C were set to 36536256
Phenotypes for gene: HTR2C were set to Obesity disorder, MONDO:0011122, HTR2C-related
Review for gene: HTR2C was set to GREEN
Added comment: Exome sequencing of 2,548 people with severe obesity and 1,117 control individuals without obesity identified 13 rare variants in the gene encoding 5-HT2CR (HTR2C) in 19 unrelated people (3 males and 16 females). Eleven variants caused a loss of function in HEK293 cells. All people who carried variants had hyperphagia and some degree of maladaptive behavior. Obesity was severe, childhood-onset. Knock-in male mice harboring a human loss-of-function HTR2C variant developed obesity and reduced social exploratory behavior; female mice heterozygous for the same variant showed similar deficits with reduced severity.
Sources: Literature
Hyperthyroidism v0.21 TRU-TCA1-1 Paul De Fazio gene: TRU-TCA1-1 was added
gene: TRU-TCA1-1 was added to Hyperthyroidism. Sources: Literature
Mode of inheritance for gene: TRU-TCA1-1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRU-TCA1-1 were set to 26854926; 34956927
Phenotypes for gene: TRU-TCA1-1 were set to Hyperthyroidism MONDO:0004425
Review for gene: TRU-TCA1-1 was set to AMBER
gene: TRU-TCA1-1 was marked as current diagnostic
Added comment: PMID 26854926: male 8 year old proband investigated for abdominal pain, fatigue, muscle weakness, and thyroid dysfunction (raised T4, normal T3, raised reverse T3) suggestive of impaired deiodinase activity in combination with low plasma selenium levels. Homozygosity mapping led to identification of a a single nucleotide change, C65G, in TRU-TCA1-1, a tRNA in the selenocysteine incorporation pathway. This mutation resulted in reduction in expression of stress-related selenoproteins. A methylribosylation defect at uridine 34 of mutant tRNA observed in patient cells was restored by cellular complementation with normal tRNA.

PMID 34956927: a 10 year old originally investigated for Hashimoto's disease was found to be homozygous for the same C65G variant identified in the previous paper, inherited from the father in what was concluded to be paternal isodisomy.
Sources: Literature
Mendeliome v1.628 TTI1 Ee Ming Wong reviewed gene: TTI1: Rating: GREEN; Mode of pathogenicity: None; Publications: DOI:https://doi.org/10.1016/j.ajhg.2023.01.006; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, TTI1-related to; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Severe early-onset obesity v1.8 HTR2C Zornitza Stark Marked gene: HTR2C as ready
Severe early-onset obesity v1.8 HTR2C Zornitza Stark Gene: htr2c has been classified as Green List (High Evidence).
Severe early-onset obesity v1.8 HTR2C Zornitza Stark Classified gene: HTR2C as Green List (high evidence)
Severe early-onset obesity v1.8 HTR2C Zornitza Stark Gene: htr2c has been classified as Green List (High Evidence).
Severe early-onset obesity v1.7 HTR2C Zornitza Stark gene: HTR2C was added
gene: HTR2C was added to Severe early-onset obesity. Sources: Literature
Mode of inheritance for gene: HTR2C was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HTR2C were set to 36536256
Phenotypes for gene: HTR2C were set to Obesity disorder, MONDO:0011122, HTR2C-related
Review for gene: HTR2C was set to GREEN
Added comment: Exome sequencing of 2,548 people with severe obesity and 1,117 control individuals without obesity identified 13 rare variants in the gene encoding 5-HT2CR (HTR2C) in 19 unrelated people (3 males and 16 females). Eleven variants caused a loss of function in HEK293 cells. All people who carried variants had hyperphagia and some degree of maladaptive behavior. Obesity was severe, childhood-onset.
Knock-in male mice harboring a human loss-of-function HTR2C variant developed obesity and reduced social exploratory behavior; female mice heterozygous for the same variant showed similar deficits with reduced severity.
Sources: Literature
Mendeliome v1.628 CCDC84 Lucy Spencer gene: CCDC84 was added
gene: CCDC84 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: CCDC84 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC84 were set to 34009673
Phenotypes for gene: CCDC84 were set to Mosaic variegated aneuploidy syndrome 4 (MIM#620153)
Review for gene: CCDC84 was set to AMBER
Added comment: PMID: 34009673- patients with constitutional mosaic aneuploidy were found to have biallelic mutations in CENATAC(CCDC84). 2 adult siblings with mosaic aneuploidies, microcephaly, dev delay, and maculopathy. Both chet for a missense and a splice site deletion- but the paper days these both result in the creation of a novel splice site that leads to frameshifts and loss of the c-terminal 64 amino acids.

Gene is shown to be part of a spliceosome. CENATAC depletion or expression of disease mutants resulted in retention of introns in ~100 genes enriched for nucleocytoplasmic transport and cell cycle regulation, and caused chromosome segregation errors.

Functional analysis in CENATAC-depleted HeLa cells demonstrated chromosome congression defects and subsequent mitotic arrest, which could be fully rescued by wildtype but not mutant CENATAC. Expression of the MVA-associated mutants exacerbated the phenotype, suggesting that the mutant proteins dominantly repress the function of any residual wildtype protein.
Sources: Literature
Microcephaly v1.188 CCDC84 Lucy Spencer gene: CCDC84 was added
gene: CCDC84 was added to Microcephaly. Sources: Literature
Mode of inheritance for gene: CCDC84 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC84 were set to 34009673
Phenotypes for gene: CCDC84 were set to Mosaic variegated aneuploidy syndrome 4 (MIM#620153)
Review for gene: CCDC84 was set to AMBER
Added comment: PMID: 34009673- patients with constitutional mosaic aneuploidy were found to have biallelic mutations in CENATAC(CCDC84). 2 adult siblings with mosaic aneuploidies, microcephaly, dev delay, and maculopathy. Both chet for a missense and a splice site deletion- but the paper days these both result in the creation of a novel splice site that leads to frameshifts and loss of the c-terminal 64 amino acids.

Gene is shown to be part of a spliceosome. CENATAC depletion or expression of disease mutants resulted in retention of introns in ~100 genes enriched for nucleocytoplasmic transport and cell cycle regulation, and caused chromosome segregation errors.

Functional analysis in CENATAC-depleted HeLa cells demonstrated chromosome congression defects and subsequent mitotic arrest, which could be fully rescued by wildtype but not mutant CENATAC. Expression of the MVA-associated mutants exacerbated the phenotype, suggesting that the mutant proteins dominantly repress the function of any residual wildtype protein.
Sources: Literature
Microcephaly v1.188 TTI1 Ee Ming Wong gene: TTI1 was added
gene: TTI1 was added to Microcephaly. Sources: Literature
Mode of inheritance for gene: TTI1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TTI1 were set to DOI:https://doi.org/10.1016/j.ajhg.2023.01.006
Phenotypes for gene: TTI1 were set to Neurodevelopmental disorder, MONDO:0700092, TTI1-related to
Review for gene: TTI1 was set to GREEN
gene: TTI1 was marked as current diagnostic
Added comment: - Eleven individuals from nine unrelated families with biallelic variants in TTI1 (10x missense, 2x canonical splice, 2x nonsense and 1x frameshift)
- All present with ID, and most with microcephaly, short stature, and a movement disorder
- Missense mutant constructs transfected into HEK293T cells demonstrated impairment of the TTT complex and of mTOR pathway activity which is improved by treatment with Rapamycin
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5158 CCDC84 Lucy Spencer gene: CCDC84 was added
gene: CCDC84 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: CCDC84 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC84 were set to 34009673
Phenotypes for gene: CCDC84 were set to Mosaic variegated aneuploidy syndrome 4 (MIM#620153)
Review for gene: CCDC84 was set to AMBER
Added comment: PMID: 34009673- patients with constitutional mosaic aneuploidy were found to have biallelic mutations in CENATAC(CCDC84). 2 adult siblings with mosaic aneuploidies, microcephaly, dev delay, and maculopathy. Both chet for a missense and a splice site deletion- but the paper days these both result in the creation of a novel splice site that leads to frameshifts and loss of the c-terminal 64 amino acids.

Gene is shown to be part of a spliceosome. CENATAC depletion or expression of disease mutants resulted in retention of introns in ~100 genes enriched for nucleocytoplasmic transport and cell cycle regulation, and caused chromosome segregation errors.

Functional analysis in CENATAC-depleted HeLa cells demonstrated chromosome congression defects and subsequent mitotic arrest, which could be fully rescued by wildtype but not mutant CENATAC. Expression of the MVA-associated mutants exacerbated the phenotype, suggesting that the mutant proteins dominantly repress the function of any residual wildtype protein.
Sources: Literature
Mendeliome v1.628 THBS1 Zornitza Stark Marked gene: THBS1 as ready
Mendeliome v1.628 THBS1 Zornitza Stark Gene: thbs1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5158 TTI1 Ee Ming Wong reviewed gene: TTI1: Rating: GREEN; Mode of pathogenicity: None; Publications: DOI:https://doi.org/10.1016/j.ajhg.2023.01.006; Phenotypes: Neurodevelopmental disorder, MONDO:0700092, TTI1-related to; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v1.628 THBS1 Zornitza Stark Classified gene: THBS1 as Green List (high evidence)
Mendeliome v1.628 THBS1 Zornitza Stark Gene: thbs1 has been classified as Green List (High Evidence).
Mitochondrial disease v0.852 OGDH Sarah Pantaleo reviewed gene: OGDH: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36520152; Phenotypes: Oxoglutarate dehydrogenase deficiency, MIM# 203740; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.627 OGDH Sarah Pantaleo reviewed gene: OGDH: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36520152; Phenotypes: Oxoglutarate dehydrogenase deficiency, MIM# 203740; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Ataxia - adult onset v1.2 NPTX1 Ain Roesley Marked gene: NPTX1 as ready
Ataxia - adult onset v1.2 NPTX1 Ain Roesley Gene: nptx1 has been classified as Green List (High Evidence).
Ataxia - adult onset v1.2 NPTX1 Ain Roesley Classified gene: NPTX1 as Green List (high evidence)
Ataxia - adult onset v1.2 NPTX1 Ain Roesley Gene: nptx1 has been classified as Green List (High Evidence).
Mendeliome v1.627 NPTX1 Ain Roesley Marked gene: NPTX1 as ready
Mendeliome v1.627 NPTX1 Ain Roesley Gene: nptx1 has been classified as Green List (High Evidence).
Mendeliome v1.627 NPTX1 Ain Roesley Classified gene: NPTX1 as Green List (high evidence)
Mendeliome v1.627 NPTX1 Ain Roesley Gene: nptx1 has been classified as Green List (High Evidence).
Ataxia - adult onset v1.1 NPTX1 Ain Roesley gene: NPTX1 was added
gene: NPTX1 was added to Ataxia - adult onset. Sources: Literature
Mode of inheritance for gene: NPTX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NPTX1 were set to 34788392; 35288776; 35285082; 35560436
Phenotypes for gene: NPTX1 were set to cerebellar ataxia MONDO#0000437, NPTX1-related
Review for gene: NPTX1 was set to GREEN
gene: NPTX1 was marked as current diagnostic
Added comment: PMID:34788392
5 families with multigenerational segregations - late onset ataxia
4 families with p.(Gly389Arg) + 1x p.(Glu327Gly)
functional studies done

Note: case report of a family member published elsewhere (PMID:35288776)

PMID:35285082
1x de novo in a male with late-onset, slowly progressive cerebellar ataxia, oculomotor apraxia, choreiform dyskinesias, and cerebellar cognitive affective syndrome
p.(Arg143Leu)

PMID:35560436
1x de novo in a female with early-onset ataxia and cerebellar atrophy since infancy
p.(Gln370Arg)
Sources: Literature
Mendeliome v1.626 THBS1 Zornitza Stark gene: THBS1 was added
gene: THBS1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: THBS1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: THBS1 were set to 36453543
Phenotypes for gene: THBS1 were set to Congenital glaucoma MONDO:0020366, THBS1-related
Review for gene: THBS1 was set to GREEN
Added comment: Missense alleles altering p.Arg1034, a highly evolutionarily conserved amino acid, in 3 unrelated and ethnically diverse families affected by congenital glaucoma.

Thbs1R1034C-mutant mice had elevated intraocular pressure (IOP), reduced ocular fluid outflow, and retinal ganglion cell loss. Histology revealed an abundant, abnormal extracellular accumulation of THBS1 with abnormal morphology of juxtacanalicular trabecular meshwork (TM), an ocular tissue critical for aqueous fluid outflow. Functional characterization showed that the THBS1 missense alleles found in affected individuals destabilized the THBS1 C-terminus, causing protein misfolding and extracellular aggregation. Analysis using a range of amino acid substitutions at position R1034 showed that the extent of aggregation was correlated with the change in protein-folding free energy caused by variations in amino acid structure.
Sources: Literature
Mendeliome v1.625 NPTX1 Ain Roesley gene: NPTX1 was added
gene: NPTX1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NPTX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NPTX1 were set to 34788392; 35288776; 35285082; 35560436
Phenotypes for gene: NPTX1 were set to cerebellar ataxia MONDO#0000437, NPTX1-related
Review for gene: NPTX1 was set to GREEN
gene: NPTX1 was marked as current diagnostic
Added comment: PMID:34788392
5 families with multigenerational segregations - late onset ataxia
4 families with p.(Gly389Arg) + 1x p.(Glu327Gly)
functional studies done

Note: case report of a family member published elsewhere (PMID:35288776)

PMID:35285082
1x de novo in a male with late-onset, slowly progressive cerebellar ataxia, oculomotor apraxia, choreiform dyskinesias, and cerebellar cognitive affective syndrome
p.(Arg143Leu)

PMID:35560436
1x de novo in a female with early-onset ataxia and cerebellar atrophy since infancy
p.(Gln370Arg)
Sources: Literature
Glaucoma congenital v1.8 THBS1 Zornitza Stark Marked gene: THBS1 as ready
Glaucoma congenital v1.8 THBS1 Zornitza Stark Gene: thbs1 has been classified as Green List (High Evidence).
Glaucoma congenital v1.8 THBS1 Zornitza Stark Classified gene: THBS1 as Green List (high evidence)
Glaucoma congenital v1.8 THBS1 Zornitza Stark Gene: thbs1 has been classified as Green List (High Evidence).
Glaucoma congenital v1.7 THBS1 Zornitza Stark gene: THBS1 was added
gene: THBS1 was added to Glaucoma congenital. Sources: Literature
Mode of inheritance for gene: THBS1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: THBS1 were set to 36453543
Phenotypes for gene: THBS1 were set to Congenital glaucoma MONDO:0020366, THBS1-related
Review for gene: THBS1 was set to GREEN
Added comment: Missense alleles altering p.Arg1034, a highly evolutionarily conserved amino acid, in 3 unrelated and ethnically diverse families affected by congenital glaucoma.

Thbs1R1034C-mutant mice had elevated intraocular pressure (IOP), reduced ocular fluid outflow, and retinal ganglion cell loss. Histology revealed an abundant, abnormal extracellular accumulation of THBS1 with abnormal morphology of juxtacanalicular trabecular meshwork (TM), an ocular tissue critical for aqueous fluid outflow. Functional characterization showed that the THBS1 missense alleles found in affected individuals destabilized the THBS1 C-terminus, causing protein misfolding and extracellular aggregation. Analysis using a range of amino acid substitutions at position R1034 showed that the extent of aggregation was correlated with the change in protein-folding free energy caused by variations in amino acid structure.
Sources: Literature
Mendeliome v1.624 GET4 Elena Savva Marked gene: GET4 as ready
Mendeliome v1.624 GET4 Elena Savva Gene: get4 has been classified as Red List (Low Evidence).
Mendeliome v1.624 GET4 Elena Savva gene: GET4 was added
gene: GET4 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: GET4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GET4 were set to 32395830
Phenotypes for gene: GET4 were set to ?Congenital disorder of glycosylation,, type IIy MIM#620200
Review for gene: GET4 was set to RED
Added comment: PMID: 32395830
- chet patient (missense x2), functionally shown to result in downregulation of three TRC proteins in patient cell lines.
- patient phenotype included ID, DD, seizures, dysmorphism and delayed bone age.
- functional studies on missense themselves not performed
Sources: Literature
Congenital Disorders of Glycosylation v1.31 GET4 Elena Savva Marked gene: GET4 as ready
Congenital Disorders of Glycosylation v1.31 GET4 Elena Savva Gene: get4 has been classified as Red List (Low Evidence).
Congenital Disorders of Glycosylation v1.31 GET4 Elena Savva gene: GET4 was added
gene: GET4 was added to Congenital Disorders of Glycosylation. Sources: Literature
Mode of inheritance for gene: GET4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GET4 were set to 32395830
Phenotypes for gene: GET4 were set to ?Congenital disorder of glycosylation,, type IIy MIM#620200
Review for gene: GET4 was set to RED
Added comment: PMID: 32395830
- chet patient (missense x2), functionally shown to result in downregulation of three TRC proteins in patient cell lines.
- patient phenotype included ID, DD, seizures, dysmorphism and delayed bone age.
- functional studies on missense themselves not performed
Sources: Literature
Pierre Robin Sequence v0.46 ARCN1 Zornitza Stark Marked gene: ARCN1 as ready
Pierre Robin Sequence v0.46 ARCN1 Zornitza Stark Gene: arcn1 has been classified as Green List (High Evidence).
Pierre Robin Sequence v0.46 ARCN1 Zornitza Stark Classified gene: ARCN1 as Green List (high evidence)
Pierre Robin Sequence v0.46 ARCN1 Zornitza Stark Gene: arcn1 has been classified as Green List (High Evidence).
Pierre Robin Sequence v0.45 ARCN1 Zornitza Stark gene: ARCN1 was added
gene: ARCN1 was added to Pierre Robin Sequence. Sources: Expert Review
Mode of inheritance for gene: ARCN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ARCN1 were set to 35300924
Phenotypes for gene: ARCN1 were set to Short stature-micrognathia syndrome, MIM# 617164
Review for gene: ARCN1 was set to GREEN
Added comment: Significant PRS requiring surgical management is a feature.
Sources: Expert Review
Clefting disorders v0.190 ARCN1 Zornitza Stark reviewed gene: ARCN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 35300924; Phenotypes: Short stature-micrognathia syndrome, MIM# 617164; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Deafness_Isolated v1.40 USP48 Zornitza Stark Phenotypes for gene: USP48 were changed from Nonsyndromic genetic deafness, MONDO:0019497 to Deafness, autosomal dominant 85, MIM# 620227
Deafness_Isolated v1.39 USP48 Zornitza Stark edited their review of gene: USP48: Changed phenotypes: Deafness, autosomal dominant 85, MIM# 620227
Deafness_IsolatedAndComplex v1.156 USP48 Zornitza Stark Phenotypes for gene: USP48 were changed from Nonsyndromic genetic deafness, MONDO:0019497 to Deafness, autosomal dominant 85, MIM# 620227
Deafness_IsolatedAndComplex v1.155 USP48 Zornitza Stark edited their review of gene: USP48: Changed phenotypes: Deafness, autosomal dominant 85, MIM# 620227
Mendeliome v1.623 USP48 Zornitza Stark Phenotypes for gene: USP48 were changed from non-syndromic hearing loss; nonsyndromic genetic deafness, MONDO:0019497 to Deafness, autosomal dominant 85, MIM# 620227
Mendeliome v1.622 USP48 Zornitza Stark edited their review of gene: USP48: Changed rating: GREEN; Changed phenotypes: Deafness, autosomal dominant 85, MIM# 620227; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary Spastic Paraplegia - paediatric v1.55 UCHL1 Zornitza Stark Phenotypes for gene: UCHL1 were changed from Spastic paraplegia 79, autosomal recessive, 615491; MONDO:0014209; Neurodegenerative disease, MONDO:0005559, UCHL1-related to Spastic paraplegia 79A, autosomal dominant, MIM# 620221; Spastic paraplegia 79, autosomal recessive, 615491; MONDO:0014209; Neurodegenerative disease, MONDO:0005559, UCHL1-related
Hereditary Spastic Paraplegia - paediatric v1.54 UCHL1 Zornitza Stark edited their review of gene: UCHL1: Changed phenotypes: Spastic paraplegia 79A, autosomal dominant, MIM# 620221, Spastic paraplegia 79, autosomal recessive, MIM#615491, Neurodegenerative disease, MONDO:0005559, UCHL1-related
Incidentalome v0.223 UCHL1 Zornitza Stark Phenotypes for gene: UCHL1 were changed from Spastic paraplegia 79, autosomal recessive, MIM# 615491; MONDO:0014209; Neurodegenerative disease, MONDO:0005559, UCHL1-related to Spastic paraplegia 79A, autosomal dominant, MIM# 620221; Spastic paraplegia 79, autosomal recessive, MIM# 615491; MONDO:0014209; Neurodegenerative disease, MONDO:0005559, UCHL1-related
Incidentalome v0.222 UCHL1 Zornitza Stark edited their review of gene: UCHL1: Changed phenotypes: Spastic paraplegia 79A, autosomal dominant, MIM# 620221, Spastic paraplegia 79, autosomal recessive, MIM# 615491, MONDO:0014209, Neurodegenerative disease, MONDO:0005559, UCHL1-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5158 NAE1 Zornitza Stark Phenotypes for gene: NAE1 were changed from Neurodevelopmental disorder, MONDO:0700092, NAE1-related to Neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia, MIM# 620210
Intellectual disability syndromic and non-syndromic v0.5157 NAE1 Zornitza Stark edited their review of gene: NAE1: Changed phenotypes: Neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia, MIM# 620210
Regression v0.520 NAE1 Zornitza Stark Phenotypes for gene: NAE1 were changed from Neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia, MIM# 620210 to Neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia, MIM# 620210
Regression v0.520 NAE1 Zornitza Stark Phenotypes for gene: NAE1 were changed from Neurodevelopmental disorder, MONDO:0700092, NAE1-related to Neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia, MIM# 620210
Regression v0.519 NAE1 Zornitza Stark edited their review of gene: NAE1: Changed phenotypes: Neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia, MIM# 620210
Mendeliome v1.622 NAE1 Zornitza Stark Phenotypes for gene: NAE1 were changed from Neurodevelopmental disorder, MONDO:0700092, NAE1-related to Neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia, MIM# 620210
Mendeliome v1.621 NAE1 Zornitza Stark edited their review of gene: NAE1: Changed phenotypes: Neurodevelopmental disorder with dysmorphic facies and ischiopubic hypoplasia, MIM# 620210
Retinitis pigmentosa_Autosomal Dominant v0.55 SAG Zornitza Stark edited their review of gene: SAG: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinitis pigmentosa_Autosomal Dominant v0.55 SAG Zornitza Stark Mode of inheritance for gene: SAG was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Retinitis pigmentosa_Autosomal Dominant v0.54 SAG Zornitza Stark changed review comment from: Autosomal recessive, homozygous founder variant.; to: Multiple families with same variant: founder effect?
Congenital Diarrhoea v1.12 AGR2 Zornitza Stark Phenotypes for gene: AGR2 were changed from CF-like disorder to Recurrent respiratory infections and failure to thrive with or without diarrhea (RIFTD), MIM#620233
Congenital Diarrhoea v1.11 AGR2 Zornitza Stark edited their review of gene: AGR2: Changed phenotypes: Recurrent respiratory infections and failure to thrive with or without diarrhea (RIFTD), MIM#620233
Ciliary Dyskinesia v1.25 AGR2 Zornitza Stark Phenotypes for gene: AGR2 were changed from CF-like disorder to Recurrent respiratory infections and failure to thrive with or without diarrhea (RIFTD), MIM#620233
Ciliary Dyskinesia v1.24 AGR2 Zornitza Stark edited their review of gene: AGR2: Changed phenotypes: Recurrent respiratory infections and failure to thrive with or without diarrhea (RIFTD), MIM#620233
Mendeliome v1.621 AGR2 Zornitza Stark Phenotypes for gene: AGR2 were changed from CF-like disorder to Recurrent respiratory infections and failure to thrive with or without diarrhea (RIFTD), MIM#620233
Mendeliome v1.620 AGR2 Zornitza Stark edited their review of gene: AGR2: Changed phenotypes: Recurrent respiratory infections and failure to thrive with or without diarrhea (RIFTD), MIM#620233
Short QT syndrome v1.5 SLC4A3 Zornitza Stark Phenotypes for gene: SLC4A3 were changed from Short QT syndrome to Short QT syndrome 7, MIM#620231
Short QT syndrome v1.4 SLC4A3 Zornitza Stark edited their review of gene: SLC4A3: Changed phenotypes: Short QT syndrome 7, MIM#620231
Mendeliome v1.620 SLC4A3 Zornitza Stark Phenotypes for gene: SLC4A3 were changed from Short QT syndrome to Short QT syndrome 7, MIM#620231
Dystonia - complex v0.220 NUP54 Zornitza Stark Marked gene: NUP54 as ready
Dystonia - complex v0.220 NUP54 Zornitza Stark Gene: nup54 has been classified as Amber List (Moderate Evidence).
Dystonia - complex v0.220 NUP54 Zornitza Stark Classified gene: NUP54 as Amber List (moderate evidence)
Dystonia - complex v0.220 NUP54 Zornitza Stark Gene: nup54 has been classified as Amber List (Moderate Evidence).
Dystonia - complex v0.219 NUP54 Zornitza Stark gene: NUP54 was added
gene: NUP54 was added to Dystonia - complex. Sources: Literature
Mode of inheritance for gene: NUP54 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUP54 were set to 36333996
Phenotypes for gene: NUP54 were set to Striatonigral degeneration, MONDO:0003122, NUP54-related; Early onset dystonia; progressive neurological deterioration; ataxia; dysarthria; dysphagia; hypotonia
Review for gene: NUP54 was set to AMBER
Added comment: From PMID: 36333996.; Harrer, P. et al. (2022) Ann Neurol. doi: 10.1002/ana.26544.

Three patients from unrelated families with dystonia and/or Leigh(-like) syndromes, with biallelic variants in NUP54, in the C-terminal protein region that interacts with NUP62. Onset was between 12 months and 5 years. All had progressive neurological deterioration with dystonia, ataxia, dysarthria, dysphagia, hypotonia.

Patient / Family A (consanguineous) was homozygous for c.1073T>G p.(Ile358Ser).

Patient / Family B was compound heterozygous for c.1073T>G p.(Ile358Ser) and c.1126A>G p.(Lys376Glu).

Patient / Family C was compound heterozygosity for c.1410_1412del p.(Gln471del) and two missense variants c.1414G>A, p.(Glu472Lys); c.1420C>T, p.(Leu474Phe)

The phenotypes were similar to those of NUP62 including early-onset dystonia with dysphagic choreoathetosis, and T2-hyperintense lesions in striatum.

Brain MRIs showed T2/FLAIR hyperintensities in the dorsal putamina.

Western blots showing reduced expression of NUP54 and its interaction partners NUP62/NUP58 in patient fibroblasts.
Sources: Literature
Mendeliome v1.619 SARS Zornitza Stark Phenotypes for gene: SARS were changed from neurodevelopmental disorder MONDO#070009, SARS1-related to neurodevelopmental disorder MONDO#070009, SARS1-related; Genetic peripheral neuropathy MONDO#0020127, SARS1-related
Mendeliome v1.618 SARS Zornitza Stark Publications for gene: SARS were set to 28236339; 34570399; 35790048; 36041817
Mendeliome v1.617 SARS Zornitza Stark Mode of inheritance for gene: SARS was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1859 TMEM43 Zornitza Stark Tag for review was removed from gene: TMEM43.
BabyScreen+ newborn screening v0.1859 LAMP2 Zornitza Stark Tag for review was removed from gene: LAMP2.
BabyScreen+ newborn screening v0.1859 LOX Zornitza Stark Tag for review was removed from gene: LOX.
BabyScreen+ newborn screening v0.1859 TBX1 Zornitza Stark Classified gene: TBX1 as Red List (low evidence)
BabyScreen+ newborn screening v0.1859 TBX1 Zornitza Stark Gene: tbx1 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1858 TBX1 Zornitza Stark reviewed gene: TBX1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: DiGeorge syndrome MIM# 188400, Velocardiofacial syndrome MIM# 192430; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
BabyScreen+ newborn screening v0.1858 TBX1 Zornitza Stark Tag for review was removed from gene: TBX1.
BabyScreen+ newborn screening v0.1858 PRKG1 Zornitza Stark Classified gene: PRKG1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1858 PRKG1 Zornitza Stark Gene: prkg1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1857 PRKG1 Zornitza Stark Tag for review was removed from gene: PRKG1.
BabyScreen+ newborn screening v0.1857 PRKG1 Zornitza Stark edited their review of gene: PRKG1: Changed rating: GREEN
BabyScreen+ newborn screening v0.1857 MYH11 Zornitza Stark Classified gene: MYH11 as Green List (high evidence)
BabyScreen+ newborn screening v0.1857 MYH11 Zornitza Stark Gene: myh11 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1856 MYH11 Zornitza Stark Tag for review was removed from gene: MYH11.
BabyScreen+ newborn screening v0.1856 MYH11 Zornitza Stark edited their review of gene: MYH11: Changed rating: GREEN
BabyScreen+ newborn screening v0.1856 LOX Zornitza Stark Classified gene: LOX as Green List (high evidence)
BabyScreen+ newborn screening v0.1856 LOX Zornitza Stark Gene: lox has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1855 LOX Zornitza Stark edited their review of gene: LOX: Changed rating: GREEN
BabyScreen+ newborn screening v0.1855 KCNQ1 Zornitza Stark Tag for review was removed from gene: KCNQ1.
BabyScreen+ newborn screening v0.1855 KCNQ1 Zornitza Stark Classified gene: KCNQ1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1855 KCNQ1 Zornitza Stark Gene: kcnq1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1854 KCNQ1 Zornitza Stark edited their review of gene: KCNQ1: Changed rating: GREEN
BabyScreen+ newborn screening v0.1854 DSG2 Zornitza Stark Tag for review was removed from gene: DSG2.
BabyScreen+ newborn screening v0.1854 COL3A1 Zornitza Stark Tag for review was removed from gene: COL3A1.
BabyScreen+ newborn screening v0.1854 JUP Zornitza Stark Mode of inheritance for gene: JUP was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1853 JUP Zornitza Stark Classified gene: JUP as Green List (high evidence)
BabyScreen+ newborn screening v0.1853 JUP Zornitza Stark Gene: jup has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1852 JUP Zornitza Stark Tag for review was removed from gene: JUP.
BabyScreen+ newborn screening v0.1852 JUP Zornitza Stark edited their review of gene: JUP: Added comment: Screen for bi-allelic disease as can be earlier onset, more severe.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1852 DSP Zornitza Stark Mode of inheritance for gene: DSP was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1851 DSP Zornitza Stark Classified gene: DSP as Green List (high evidence)
BabyScreen+ newborn screening v0.1851 DSP Zornitza Stark Gene: dsp has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1850 DSP Zornitza Stark Tag for review was removed from gene: DSP.
BabyScreen+ newborn screening v0.1850 DSP Zornitza Stark edited their review of gene: DSP: Added comment: Screen for bi-allelic disease as can be more severe, earlier onset.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1850 CALM3 Zornitza Stark Phenotypes for gene: CALM3 were changed from Ventricular tachycardia, catecholaminergic polymorphic 6 , MIM# 618782 to Ventricular tachycardia, catecholaminergic polymorphic 6 , MIM# 618782; Long QT syndrome 16, MIM#618782
BabyScreen+ newborn screening v0.1849 CALM3 Zornitza Stark edited their review of gene: CALM3: Added comment: Variants in this gene also cause Long QT syndrome, and other Long QT syndrome genes have been included in the panel.; Changed phenotypes: Ventricular tachycardia, catecholaminergic polymorphic 6 , MIM# 618782, Long QT syndrome 16, MIM#618782
BabyScreen+ newborn screening v0.1849 CALM3 Zornitza Stark Tag for review was removed from gene: CALM3.
BabyScreen+ newborn screening v0.1849 CALM2 Zornitza Stark Tag for review was removed from gene: CALM2.
BabyScreen+ newborn screening v0.1849 LAMP2 Zornitza Stark Tag cardiac tag was added to gene: LAMP2.
BabyScreen+ newborn screening v0.1849 TRPM4 Zornitza Stark Tag cardiac tag was added to gene: TRPM4.
BabyScreen+ newborn screening v0.1849 TMEM43 Zornitza Stark changed review comment from: Rated as 'strong actionability' in paediatric patients by ClinGen together with other ARVC genes.

ARVC is a progressive heart disease characterized by degeneration of cardiac myocytes and their subsequent replacement by fat and fibrous tissue primarily in the right ventricle, though the left ventricle may also be affected. It is associated with an increased risk of ventricular arrhythmia (VA) and sudden cardiac death (SCD) in young individuals and athletes. The VA is usually in proportion to the degree of ventricular remodeling and dysfunction, and electrical instability. The mechanism of SCD is cardiac arrest due to sustained ventricular tachycardia (VT) or ventricular fibrillation (VF).

Age of onset is highly variable with a mean age of diagnosis of 31 years and a range of 4 to 64 years.

Antiarrhythmic drugs and beta-blockers are not recommended in healthy gene carriers. In patients with ARVC and ventricular arrhythmia (VA), a beta-blocker or other antiarrhythmic is recommended.

Recommendations for ICD placement in patients with ARVC differ across guidelines, both in terms of the indications for placement and whether recommendations are based on evidence or expert opinion. Recommendations based on non-randomized studies support ICD placement in patients with ARVC and an additional marker of increased risk of SCD (resuscitated SCA, sustained VT hemodynamically tolerated, and significant ventricular dysfunction with RVEF or LVEF ≤35%) and in patients with ARVC and syncope presumed to be due to VA if meaningful survival greater than 1 year is expected. The presence of a combination of other risk factors (e.g., male sex, frequent PVCs, syncope) may also be used to indicate implantation.

Serial screening for the emergence of cardiomyopathy is recommended for clinically unaffected individuals who carry a variant associated with ARVC, including:

• Medical history, with special attention to heart failure symptoms, arrhythmias, presyncope or syncope, and thromboembolism
• Physical examination with special attention to cardiac and neuromuscular systems and examination of the integumentary system if ARVC is suspected
• Electrocardiography
• Cardiovascular imaging.

Penetrance:
In a study of 264 probands with genetic variants associated with ARVC who presented alive, 73% had sustained VA, 13% had symptomatic HF, and 5% had cardiac death (2% SCD, 2% HF, and 1% HF with VA) during median 8-year follow-up. Among 385 family members of the probands who also carried an ARVC variant, 32% met clinical criteria for ARVC, 11% experienced sustained VA, and 2% died during follow-up (1% from SCD, 0.5% from HF, and 0.5% non-cardiac issues). In a second study of 220 probands with genetic variants associated with ARVC who presented alive, 54% presented with sustained VT. In 321 family members of the probands who also carried an ARVC variant, 14% were symptomatic at presentation but 8% experienced VA during a mean 4-year follow-up. For all 541 cases, 60% met clinical criteria for ARVC, 30% had sustained VA, 14% developed ventricular dysfunction, 5% experienced HF, 4% had a resuscitated SCD/VF, and 2% died over a mean follow-up of 6 years.; to: Rated as 'strong actionability' in paediatric patients by ClinGen together with other ARVC genes.

ARVC is a progressive heart disease characterized by degeneration of cardiac myocytes and their subsequent replacement by fat and fibrous tissue primarily in the right ventricle, though the left ventricle may also be affected. It is associated with an increased risk of ventricular arrhythmia (VA) and sudden cardiac death (SCD) in young individuals and athletes. The VA is usually in proportion to the degree of ventricular remodeling and dysfunction, and electrical instability. The mechanism of SCD is cardiac arrest due to sustained ventricular tachycardia (VT) or ventricular fibrillation (VF).

Age of onset is highly variable with a mean age of diagnosis of 31 years and a range of 4 to 64 years.

Antiarrhythmic drugs and beta-blockers are not recommended in healthy gene carriers. In patients with ARVC and ventricular arrhythmia (VA), a beta-blocker or other antiarrhythmic is recommended.

Recommendations for ICD placement in patients with ARVC differ across guidelines, both in terms of the indications for placement and whether recommendations are based on evidence or expert opinion. Recommendations based on non-randomized studies support ICD placement in patients with ARVC and an additional marker of increased risk of SCD (resuscitated SCA, sustained VT hemodynamically tolerated, and significant ventricular dysfunction with RVEF or LVEF ≤35%) and in patients with ARVC and syncope presumed to be due to VA if meaningful survival greater than 1 year is expected. The presence of a combination of other risk factors (e.g., male sex, frequent PVCs, syncope) may also be used to indicate implantation.

Serial screening for the emergence of cardiomyopathy is recommended for clinically unaffected individuals who carry a variant associated with ARVC, including:

• Medical history, with special attention to heart failure symptoms, arrhythmias, presyncope or syncope, and thromboembolism
• Physical examination with special attention to cardiac and neuromuscular systems and examination of the integumentary system if ARVC is suspected
• Electrocardiography
• Cardiovascular imaging.

Penetrance:
In a study of 264 probands with genetic variants associated with ARVC who presented alive, 73% had sustained VA, 13% had symptomatic HF, and 5% had cardiac death (2% SCD, 2% HF, and 1% HF with VA) during median 8-year follow-up. Among 385 family members of the probands who also carried an ARVC variant, 32% met clinical criteria for ARVC, 11% experienced sustained VA, and 2% died during follow-up (1% from SCD, 0.5% from HF, and 0.5% non-cardiac issues). In a second study of 220 probands with genetic variants associated with ARVC who presented alive, 54% presented with sustained VT. In 321 family members of the probands who also carried an ARVC variant, 14% were symptomatic at presentation but 8% experienced VA during a mean 4-year follow-up. For all 541 cases, 60% met clinical criteria for ARVC, 30% had sustained VA, 14% developed ventricular dysfunction, 5% experienced HF, 4% had a resuscitated SCD/VF, and 2% died over a mean follow-up of 6 years.

Note founder variant in Newfoundland.
BabyScreen+ newborn screening v0.1849 TMEM43 Zornitza Stark edited their review of gene: TMEM43: Changed rating: RED
BabyScreen+ newborn screening v0.1849 SCN5A Zornitza Stark Classified gene: SCN5A as Green List (high evidence)
BabyScreen+ newborn screening v0.1849 SCN5A Zornitza Stark Gene: scn5a has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1848 SCN5A Zornitza Stark Tag for review was removed from gene: SCN5A.
BabyScreen+ newborn screening v0.1848 SCN5A Zornitza Stark edited their review of gene: SCN5A: Changed rating: GREEN
BabyScreen+ newborn screening v0.1848 KCNH2 Zornitza Stark Classified gene: KCNH2 as Green List (high evidence)
BabyScreen+ newborn screening v0.1848 KCNH2 Zornitza Stark Gene: kcnh2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1847 KCNH2 Zornitza Stark Tag for review was removed from gene: KCNH2.
BabyScreen+ newborn screening v0.1847 KCNH2 Zornitza Stark edited their review of gene: KCNH2: Changed rating: GREEN
BabyScreen+ newborn screening v0.1847 DSC2 Zornitza Stark Tag for review was removed from gene: DSC2.
BabyScreen+ newborn screening v0.1847 CASQ2 Zornitza Stark Mode of inheritance for gene: CASQ2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1846 CASQ2 Zornitza Stark Classified gene: CASQ2 as Green List (high evidence)
BabyScreen+ newborn screening v0.1846 CASQ2 Zornitza Stark Gene: casq2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1845 CASQ2 Zornitza Stark Tag for review was removed from gene: CASQ2.
BabyScreen+ newborn screening v0.1845 CASQ2 Zornitza Stark changed review comment from: Well established gene-disease association.

ClinGen: 'strong actionability' both for adult and paediatric patients. Treatment: beta blockers first line; ICD. There are also numerous known arrhythmia triggers which can be avoided.

The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease.

For review.; to: Well established gene-disease association.

ClinGen: 'strong actionability' both for adult and paediatric patients. Treatment: beta blockers first line; ICD. There are also numerous known arrhythmia triggers which can be avoided.

The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease.
BabyScreen+ newborn screening v0.1845 CASQ2 Zornitza Stark edited their review of gene: CASQ2: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
BabyScreen+ newborn screening v0.1845 CASQ2 Zornitza Stark edited their review of gene: CASQ2: Changed rating: GREEN
BabyScreen+ newborn screening v0.1845 ACTA2 Zornitza Stark Classified gene: ACTA2 as Green List (high evidence)
BabyScreen+ newborn screening v0.1845 ACTA2 Zornitza Stark Gene: acta2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1844 ACTA2 Zornitza Stark Tag for review was removed from gene: ACTA2.
BabyScreen+ newborn screening v0.1844 ACTA2 Zornitza Stark edited their review of gene: ACTA2: Changed rating: GREEN
BabyScreen+ newborn screening v0.1844 TRDN Zornitza Stark Tag for review was removed from gene: TRDN.
BabyScreen+ newborn screening v0.1844 TECRL Zornitza Stark Tag for review was removed from gene: TECRL.
BabyScreen+ newborn screening v0.1844 RYR2 Zornitza Stark Tag for review was removed from gene: RYR2.
BabyScreen+ newborn screening v0.1844 CALM1 Zornitza Stark Tag for review was removed from gene: CALM1.
Pseudohypoparathyroidism and Albright Hereditary Osteodystrophy v0.13 Bryony Thompson Panel types changed to Victorian Clinical Genetics Services; Royal Melbourne Hospital; Rare Disease
Oligodontia v0.29 Bryony Thompson Panel types changed to Victorian Clinical Genetics Services; Royal Melbourne Hospital; Rare Disease
Prepair 1000+ v1.0 AIRE Zornitza Stark changed review comment from: Highly variable phenotype in terms of severity and age of onset. Manifestations of the condition are generally treatable.; to: Highly variable phenotype in terms of severity and age of onset. Manifestations of the condition are generally treatable.
Leukodystrophy - paediatric v0.282 HMBS Zornitza Stark Marked gene: HMBS as ready
Leukodystrophy - paediatric v0.282 HMBS Zornitza Stark Gene: hmbs has been classified as Green List (High Evidence).
Leukodystrophy - paediatric v0.282 HMBS Zornitza Stark Publications for gene: HMBS were set to 27558376
Leukodystrophy - paediatric v0.281 HMBS Zornitza Stark Phenotypes for gene: HMBS were changed from Acute intermittent porphyria-related leukoencephalopathy to Porphyria, acute intermittent, MIM#176000; Acute intermittent porphyria-related leukoencephalopathy
Leukodystrophy - paediatric v0.280 HMBS Zornitza Stark Classified gene: HMBS as Green List (high evidence)
Leukodystrophy - paediatric v0.280 HMBS Zornitza Stark Gene: hmbs has been classified as Green List (High Evidence).
Leukodystrophy - paediatric v0.279 HMBS Zornitza Stark reviewed gene: HMBS: Rating: GREEN; Mode of pathogenicity: None; Publications: 27558376, 34089223; Phenotypes: Porphyria, acute intermittent, MIM#176000; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Aminoacidopathy v1.1 PPM1K Suliman Khan reviewed gene: PPM1K: Rating: AMBER; Mode of pathogenicity: None; Publications: PMID: 36706222; Phenotypes: Maple syrup urine disease (MSUD); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.616 DRC1 Zornitza Stark Phenotypes for gene: DRC1 were changed from Ciliary dyskinesia, primary, 21, MIM# 615294; Male infertility to Ciliary dyskinesia, primary, 21, MIM# 615294; Spermatogenic failure 80, MIM# 620222
Mendeliome v1.615 DRC1 Zornitza Stark edited their review of gene: DRC1: Changed phenotypes: Ciliary dyskinesia, primary, 21, MIM# 615294, Spermatogenic failure 80, MIM# 620222
Regression v0.519 TCEAL1 Zornitza Stark Phenotypes for gene: TCEAL1 were changed from Neurodevelopmental disorder, MONDO:0700092, TCEAL1-related; hypotonia; abnormal gait; developmental delay; intellectual disability; autism; dysmorphic facial features to Neurodevelopmental disorder with gait disturbance, dysmorphic facies and behavioral abnormalities, X-linked, MIM# 301094
Regression v0.518 TCEAL1 Zornitza Stark reviewed gene: TCEAL1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with gait disturbance, dysmorphic facies and behavioral abnormalities, X-linked, MIM# 301094; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Genetic Epilepsy v0.1830 TCEAL1 Zornitza Stark Phenotypes for gene: TCEAL1 were changed from Neurodevelopmental disorder, MONDO:0700092, TCEAL1-related hypotonia, abnormal gait, developmental delay, intellectual disability, autism, dysmorphic facial features. to Neurodevelopmental disorder with gait disturbance, dysmorphic facies and behavioral abnormalities, X-linked, MIM# 301094
Genetic Epilepsy v0.1829 TCEAL1 Zornitza Stark reviewed gene: TCEAL1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with gait disturbance, dysmorphic facies and behavioral abnormalities, X-linked, MIM# 301094; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability syndromic and non-syndromic v0.5157 TCEAL1 Zornitza Stark Phenotypes for gene: TCEAL1 were changed from Neurodevelopmental disorder, MONDO:0700092, TCEAL1-related; hypotonia; abnormal gait; developmental delay; intellectual disability; autism; dysmorphic facial features to Neurodevelopmental disorder with gait disturbance, dysmorphic facies and behavioral abnormalities, X-linked, MIM# 301094
Intellectual disability syndromic and non-syndromic v0.5156 TCEAL1 Zornitza Stark reviewed gene: TCEAL1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with gait disturbance, dysmorphic facies and behavioral abnormalities, X-linked, MIM# 301094; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Mendeliome v1.615 TCEAL1 Zornitza Stark Phenotypes for gene: TCEAL1 were changed from Neurodevelopmental disorder, MONDO:0700092, TCEAL1-related; hypotonia, abnormal gait, developmental delay, intellectual disability, autism, dysmorphic facial features. to Neurodevelopmental disorder with gait disturbance, dysmorphic facies and behavioral abnormalities, X-linked, MIM# 301094
Mendeliome v1.614 TCEAL1 Zornitza Stark reviewed gene: TCEAL1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with gait disturbance, dysmorphic facies and behavioral abnormalities, X-linked, MIM# 301094; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
BabyScreen+ newborn screening v0.1844 CAD Zornitza Stark Marked gene: CAD as ready
BabyScreen+ newborn screening v0.1844 CAD Zornitza Stark Gene: cad has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1844 CAD Zornitza Stark Classified gene: CAD as Green List (high evidence)
BabyScreen+ newborn screening v0.1844 CAD Zornitza Stark Gene: cad has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1843 CAD Zornitza Stark gene: CAD was added
gene: CAD was added to gNBS. Sources: Expert list
treatable, metabolic tags were added to gene: CAD.
Mode of inheritance for gene: CAD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAD were set to 28007989
Phenotypes for gene: CAD were set to Developmental and epileptic encephalopathy 50, MIM# 616457
Review for gene: CAD was set to GREEN
Added comment: Developmental and epileptic encephalopathy-50 (DEE50) is an autosomal recessive progressive neurodegenerative neurometabolic disorder characterized by delayed psychomotor development, early-onset refractory seizures, severe developmental regression, and normocytic anemia. Onset is within the first months or years of life.

Affected children can have a favourable response to treatment with uridine, PMID 28007989
Sources: Expert list
BabyScreen+ newborn screening v0.1842 CA12 Zornitza Stark Marked gene: CA12 as ready
BabyScreen+ newborn screening v0.1842 CA12 Zornitza Stark Gene: ca12 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1842 CA12 Zornitza Stark Classified gene: CA12 as Green List (high evidence)
BabyScreen+ newborn screening v0.1842 CA12 Zornitza Stark Gene: ca12 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1841 CA12 Zornitza Stark gene: CA12 was added
gene: CA12 was added to gNBS. Sources: Expert Review
treatable, metabolic tags were added to gene: CA12.
Mode of inheritance for gene: CA12 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CA12 were set to Hyperchlorhidrosis, isolated MIM#143860
Review for gene: CA12 was set to GREEN
Added comment: Glu143Lys found in 4 Israeli Bedouin families. 2 other unrelated families reported with 1 missense (LoF demonstrated), 1 splice (aberrant splicing proven) and 1 fs (protein truncating, not NMD).

Excessive salt wasting in sweat can result in severe infantile hyponatraemic dehydration and hyperkalaemia.

Treatment: sodium chloride supplementation
Sources: Expert Review
BabyScreen+ newborn screening v0.1840 AICDA Zornitza Stark Marked gene: AICDA as ready
BabyScreen+ newborn screening v0.1840 AICDA Zornitza Stark Gene: aicda has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1840 AICDA Zornitza Stark Classified gene: AICDA as Green List (high evidence)
BabyScreen+ newborn screening v0.1840 AICDA Zornitza Stark Gene: aicda has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1839 AICDA Zornitza Stark gene: AICDA was added
gene: AICDA was added to gNBS. Sources: Expert Review
treatable, immunological tags were added to gene: AICDA.
Mode of inheritance for gene: AICDA was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: AICDA were set to Immunodeficiency with hyper-IgM, type 2, MIM# 605258
Review for gene: AICDA was set to GREEN
Added comment: Hyper-IgM syndrome type 2 (HIGM2) is a rare immunodeficiency characterized by normal or elevated serum IgM levels with absence of IgG, IgA, and IgE, resulting in a profound susceptibility to bacterial infections. Well established gene-disease association.

Severe, congenital disorder.

Treatment: immunoglobulin replacement therapy.

Confirmatory testing: antibody levels.
Sources: Expert Review
BabyScreen+ newborn screening v0.1838 AGPAT2 Zornitza Stark Marked gene: AGPAT2 as ready
BabyScreen+ newborn screening v0.1838 AGPAT2 Zornitza Stark Gene: agpat2 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1838 AGPAT2 Zornitza Stark Classified gene: AGPAT2 as Amber List (moderate evidence)
BabyScreen+ newborn screening v0.1838 AGPAT2 Zornitza Stark Gene: agpat2 has been classified as Amber List (Moderate Evidence).
BabyScreen+ newborn screening v0.1837 AGPAT2 Zornitza Stark gene: AGPAT2 was added
gene: AGPAT2 was added to gNBS. Sources: Expert list
for review, treatable, endocrine tags were added to gene: AGPAT2.
Mode of inheritance for gene: AGPAT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AGPAT2 were set to 29704234
Phenotypes for gene: AGPAT2 were set to Lipodystrophy, congenital generalized, type 1, MIM# 608594
Review for gene: AGPAT2 was set to AMBER
Added comment: Established gene-disease association.

Congenital generalized lipodystrophy (CGL), or Berardinelli-Seip syndrome, is a rare autosomal recessive disease characterized by a near absence of adipose tissue from birth or early infancy and severe insulin resistance. Other clinical and biologic features include acanthosis nigricans, muscular hypertrophy, hepatomegaly, altered glucose tolerance or diabetes mellitus, and hypertriglyceridemia.

Leptin replacement therapy (metreleptin) has been found to improve metabolic parameters in many patients with lipodystrophy. Metreleptin is approved in the United States as replacement therapy to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy and has been submitted for approval elsewhere.

For review regarding availability and use of treatment locally.
Sources: Expert list
Craniosynostosis v1.45 ADAMTSL4 Zornitza Stark Phenotypes for gene: ADAMTSL4 were changed from Ectopia lentis et pupillae MIM#225200 to Ectopia lentis et pupillae MIM#225200; Craniosynostosis with ectopia lentis MONDO#0011347, ADAMTSL4-related
Craniosynostosis v1.44 ADAMTSL4 Zornitza Stark Publications for gene: ADAMTSL4 were set to 22871183; 20702823
Craniosynostosis v1.43 ADAMTSL4 Zornitza Stark Classified gene: ADAMTSL4 as Green List (high evidence)
Craniosynostosis v1.43 ADAMTSL4 Zornitza Stark Gene: adamtsl4 has been classified as Green List (High Evidence).
Prepair 1000+ v1.0 BRIP1 Himanshu Goel gene: BRIP1 was added
gene: BRIP1 was added to Prepair 1000+. Sources: Literature
Mode of inheritance for gene: BRIP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BRIP1 were set to 16116423
Phenotypes for gene: BRIP1 were set to Fanconi Anaemia
Penetrance for gene: BRIP1 were set to Complete
Mode of pathogenicity for gene: BRIP1 was set to Other
Review for gene: BRIP1 was set to GREEN
gene: BRIP1 was marked as current diagnostic
Added comment: Sources: Literature
Craniosynostosis v1.42 ADAMTSL4 Michelle Torres reviewed gene: ADAMTSL4: Rating: GREEN; Mode of pathogenicity: None; Publications: 35378950, 28642162; Phenotypes: Craniosynostosis with ectopia lentis MONDO#0011347, ADAMTSL4-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.614 LY96 Zornitza Stark Marked gene: LY96 as ready
Mendeliome v1.614 LY96 Zornitza Stark Gene: ly96 has been classified as Red List (Low Evidence).
Mendeliome v1.614 LY96 Zornitza Stark gene: LY96 was added
gene: LY96 was added to Mendeliome. Sources: Expert Review
Mode of inheritance for gene: LY96 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LY96 were set to 36462957
Phenotypes for gene: LY96 were set to Inborn error of immunity, MONDO:0003778, LY96-related
Review for gene: LY96 was set to RED
Added comment: Single individual with infantile colitis associated with failure-to-thrive, bloody diarrhoea, and perianal abscesses since the age of 4 months. Later developed bronchiectasis and persistent pneumonia, which required lobectomy at the age of 6 years. Found to have homozygous inflame deletion. Brother with same deletion presented with recurrent otitis media and pneumonia but exhibited no signs of intestinal inflammation.
Sources: Expert Review
Inflammatory bowel disease v0.88 LY96 Zornitza Stark Marked gene: LY96 as ready
Inflammatory bowel disease v0.88 LY96 Zornitza Stark Gene: ly96 has been classified as Red List (Low Evidence).
Inflammatory bowel disease v0.88 LY96 Zornitza Stark Phenotypes for gene: LY96 were changed from Colitis to Inborn error of immunity, MONDO:0003778, LY96-related; Colitis
Inflammatory bowel disease v0.87 LY96 Zornitza Stark Classified gene: LY96 as Red List (low evidence)
Inflammatory bowel disease v0.87 LY96 Zornitza Stark Gene: ly96 has been classified as Red List (Low Evidence).
Inflammatory bowel disease v0.86 LY96 Zornitza Stark reviewed gene: LY96: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Inborn error of immunity, MONDO:0003778, LY96-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Cardiomyopathy_Paediatric v0.154 SLC22A5 Zornitza Stark Marked gene: SLC22A5 as ready
Cardiomyopathy_Paediatric v0.154 SLC22A5 Zornitza Stark Gene: slc22a5 has been classified as Green List (High Evidence).
Cardiomyopathy_Paediatric v0.154 SLC22A5 Zornitza Stark Phenotypes for gene: SLC22A5 were changed from HCM, mixed; Carnitine transporter deficiency (Disorders of carnitine transport and the carnitine cycle); Arrhythmia, muscle weakness or hypotonia, liver disease, hypoketotic hypoglycaemia; DCM; Carnitine transporter deficiency (primary carnitine deficiency); Propionicacidemia to Carnitine deficiency, systemic primary MIM#212140
Cardiomyopathy_Paediatric v0.153 SLC22A5 Zornitza Stark Publications for gene: SLC22A5 were set to 24816252; 27604308
Cardiomyopathy_Paediatric v0.152 SLC22A5 Zornitza Stark Mode of inheritance for gene: SLC22A5 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Inflammatory bowel disease v0.86 LY96 Peter McNaughton gene: LY96 was added
gene: LY96 was added to Inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: LY96 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LY96 were set to PMID: 36462957
Phenotypes for gene: LY96 were set to Colitis
Review for gene: LY96 was set to RED
Added comment: Single patient with infantile colitis associated with failure-to-thrive, bloody diarrhea, and perianal abscesses since the age of 4 months. Later developed bronchiectasis and persistent pneumonia, which required lobectomy at the age of 6 years. Brother with same deletion presented with recurrent otitis media and pneumonia but exhibited no signs of intestinal inflammation.
Sources: Literature
Cardiomyopathy_Paediatric v0.151 SLC22A5 Paul De Fazio reviewed gene: SLC22A5: Rating: GREEN; Mode of pathogenicity: None; Publications: 22989098, 18337137, 27807682; Phenotypes: Carnitine deficiency, systemic primary MIM#212140; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Intellectual disability syndromic and non-syndromic v0.5156 FGF13 Zornitza Stark Phenotypes for gene: FGF13 were changed from Developmental and epileptic encephalopathy 90, MIM# 301058; Intellectual disability; epilepsy to Developmental and epileptic encephalopathy 90, MIM# 301058; Intellectual developmental disorder, X-linked 110, MIM# 301095
Intellectual disability syndromic and non-syndromic v0.5155 FGF13 Zornitza Stark Publications for gene: FGF13 were set to 33245860
Intellectual disability syndromic and non-syndromic v0.5154 FGF13 Zornitza Stark Tag 5'UTR tag was added to gene: FGF13.
Intellectual disability syndromic and non-syndromic v0.5154 FGF13 Zornitza Stark edited their review of gene: FGF13: Added comment: PMID 34184986: 3 individuals reported with moderate to severe ID and maternally inherited 5' variant c.-32C-G; Changed publications: 33245860, 34184986; Changed phenotypes: Developmental and epileptic encephalopathy 90, MIM# 301058, Intellectual developmental disorder, X-linked 110, MIM# 301095
Mendeliome v1.613 FGF13 Zornitza Stark Phenotypes for gene: FGF13 were changed from Developmental and epileptic encephalopathy 90, MIM# 301058; Intellectual disability; epilepsy to Developmental and epileptic encephalopathy 90, MIM# 301058; Intellectual developmental disorder, X-linked 110, MIM# 301095
Mendeliome v1.612 FGF13 Zornitza Stark Publications for gene: FGF13 were set to 33245860
Mendeliome v1.611 FGF13 Zornitza Stark Tag 5'UTR tag was added to gene: FGF13.
Mendeliome v1.611 FGF13 Zornitza Stark edited their review of gene: FGF13: Added comment: PMID 34184986: 3 individuals reported with moderate to severe ID and maternally inherited 5' variant c.-32C-G; Changed publications: 33245860, 34184986
Mendeliome v1.611 FGF13 Zornitza Stark edited their review of gene: FGF13: Changed phenotypes: Developmental and epileptic encephalopathy 90, MIM# 301058, Intellectual developmental disorder, X-linked 110, MIM# 301095
BabyScreen+ newborn screening v0.1836 APC Zornitza Stark Classified gene: APC as Red List (low evidence)
BabyScreen+ newborn screening v0.1836 APC Zornitza Stark Gene: apc has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1835 APC Zornitza Stark Tag cancer tag was added to gene: APC.
BabyScreen+ newborn screening v0.1835 WT1 Zornitza Stark Classified gene: WT1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1835 WT1 Zornitza Stark Gene: wt1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1834 WT1 Zornitza Stark Tag for review was removed from gene: WT1.
BabyScreen+ newborn screening v0.1834 WT1 Zornitza Stark changed review comment from: Rated as 'moderate actionability' in paediatric patients by ClinGen.

Individuals with germline WT1 pathogenic variants are more likely to have bilateral or multicentric tumors and to develop tumors at an early age. The median age of diagnosis is between 3 and 4 years and both kidneys are affected in ~5% of children. Significantly more females than males have the bilateral disease. Adult forms are very rare. In the majority of cases, the prognosis is favorable with a survival rate of over 90%.

The goal of surveillance in individuals with a genetic predisposition to WT is to

detect tumors while they are low-stage and require less treatment compared to advanced-stage tumors. Surveillance is not a one-time event and should continue through the period of risk. WTs can double in size every week, leading to the recommendation that evaluation with abdominal ultrasound be performed every 3-4 months, with and no less frequently than 3 times a year, until age five years. Even at this frequency, occasional tumors may present clinically between scans and families should be made aware of this. However, there is no evidence to suggest that such tumors have a worse outcome.

No evidence was found on the effectiveness of surveillance in children with WT due to WT1 pathogenic variants. In addition, there is no clear evidence that surveillance results in a significant decrease in mortality or tumor stage generally. However, tumors detected by surveillance would be anticipated to be on average smaller than tumors that present clinically. There have been three small retrospective evaluations of WT surveillance published, only one of which reported a significant difference in stage distribution between screened and unscreened individuals. This report was a case series of children with Beckwith-Wiedemann syndrome and idiopathic hemihypertropy, where 0/12 screened children with WT had late-stage disease and 25/59 (42%) of unscreened children had late-stage WT (p<0.003). In addition, in Germany, where abdominal ultrasound in children is common and 10% of WT are diagnosed prior to symptoms, there are some data to suggest that asymptomatic tumors are of lower stage than those present due to clinical symptoms.

Penetrance is unclear. For review.; to: Rated as 'moderate actionability' in paediatric patients by ClinGen.

Individuals with germline WT1 pathogenic variants are more likely to have bilateral or multicentric tumors and to develop tumors at an early age. The median age of diagnosis is between 3 and 4 years and both kidneys are affected in ~5% of children. Significantly more females than males have the bilateral disease. Adult forms are very rare. In the majority of cases, the prognosis is favorable with a survival rate of over 90%.

The goal of surveillance in individuals with a genetic predisposition to WT is to

detect tumors while they are low-stage and require less treatment compared to advanced-stage tumors. Surveillance is not a one-time event and should continue through the period of risk. WTs can double in size every week, leading to the recommendation that evaluation with abdominal ultrasound be performed every 3-4 months, with and no less frequently than 3 times a year, until age five years. Even at this frequency, occasional tumors may present clinically between scans and families should be made aware of this. However, there is no evidence to suggest that such tumors have a worse outcome.

No evidence was found on the effectiveness of surveillance in children with WT due to WT1 pathogenic variants. In addition, there is no clear evidence that surveillance results in a significant decrease in mortality or tumor stage generally. However, tumors detected by surveillance would be anticipated to be on average smaller than tumors that present clinically. There have been three small retrospective evaluations of WT surveillance published, only one of which reported a significant difference in stage distribution between screened and unscreened individuals. This report was a case series of children with Beckwith-Wiedemann syndrome and idiopathic hemihypertropy, where 0/12 screened children with WT had late-stage disease and 25/59 (42%) of unscreened children had late-stage WT (p<0.003). In addition, in Germany, where abdominal ultrasound in children is common and 10% of WT are diagnosed prior to symptoms, there are some data to suggest that asymptomatic tumors are of lower stage than those present due to clinical symptoms.
BabyScreen+ newborn screening v0.1834 GLA Zornitza Stark Tag for review was removed from gene: GLA.
BabyScreen+ newborn screening v0.1834 GLA Zornitza Stark changed review comment from: Assessed as 'moderate actionability' in paediatric patients by ClinGen.

In classic FD, the first symptoms, including chronic neuropathic pain and episodic severe pain crises, emerge during childhood (typically age 3-10 years). Heterozygous females typically have a later median age of onset than males (9-13 years versus 13-23 years). Rarely, females may be relatively asymptomatic and have a normal life span or may have symptoms as severe as males with the classic phenotype.

Cardiac and/or cerebrovascular disease is present in most males by middle age while ESRD usually develops during the third to fifth decade. Renal and cardiac failure represent major sources of morbidity, and account for the reduced lifespan among affected males (50-58 years) and females (70-75 years) compared to the normal population.

A systematic review of RCTs of ERT reported on nine studies of 351 FD patients; however, many of these studies reported only on the effect of ERT on levels of enzyme substrate. Data from 2 trials (n=39 males) found no statistically significant differences in plasma enzyme substrate and one trial (n=24 males) found no statistical differences in renal function between individuals treated with agalsidase alfa and placebo (up to 6-month follow-up). Similar results were seen for agalsidase beta. One trial of 26 male patients found a statistically significant difference in pain, favoring agalsidase alfa compared to placebo at 5-6 months after treatment. No trial reported on the effect of agalsidase alfa on mortality or cardiac/cerebrovascular disease. One trial of agalsidase beta (n=82 males and females) found no difference in mortality, renal function, or symptoms or complications of cardiac or cerebrovascular disease over 18 months. The long-term influence of ERT on risk of morbidity and mortality related to FD remains to be established.

Migalastat, an oral chaperone drug, is recommended as an option for treatment for some patients with FD who are over 16 years with an amenable genetic variant who would usually be offered ERT. For non-amenable genotypes, migalastat may result in a net loss of alpha-Gal A activity, potentially worsening the disease condition.

A systematic review evaluated 2 phase III RCTs that both included males and females. One RCT randomized patients to switch from ERT to migalastat (n = 36) or continue with ERT (n = 24) during an 18-month period with a 12-month extension in which all patients received migalastat. During the treatment period, the percentage of patients who had a renal, cardiac, or cerebrovascular event or died was 29% of patients on migalastat compared to 44% of patients on ERT. However, this difference was not statistically significant. A second RCT compared migalastat (n=34) with placebo (n=33) over a 6-month period, with an 18-month extension study. The primary outcome was change from baseline in interstitial capillary inclusions of the enzyme substrate globotriaosylceramide (GL-3), which was not significantly different between groups. Results from both trials indicate that migalastat does not have a significant beneficial effect on pain, health-related quality of life outcomes, or glomerular filtration rate (results were uncertain due to large confidence intervals, small sample sizes, and/or short follow-up time). Migalastat did not influence left ventricular ejection fraction but did improve left ventricular mass over 18 months.

There are a number of recommendations for surveillance and agents to avoid (amiodarone). There is no consensus as to when ERT should be started.; to: Assessed as 'moderate actionability' in paediatric patients by ClinGen.

In classic FD, the first symptoms, including chronic neuropathic pain and episodic severe pain crises, emerge during childhood (typically age 3-10 years). Heterozygous females typically have a later median age of onset than males (9-13 years versus 13-23 years). Rarely, females may be relatively asymptomatic and have a normal life span or may have symptoms as severe as males with the classic phenotype.

Cardiac and/or cerebrovascular disease is present in most males by middle age while ESRD usually develops during the third to fifth decade. Renal and cardiac failure represent major sources of morbidity, and account for the reduced lifespan among affected males (50-58 years) and females (70-75 years) compared to the normal population.

A systematic review of RCTs of ERT reported on nine studies of 351 FD patients; however, many of these studies reported only on the effect of ERT on levels of enzyme substrate. Data from 2 trials (n=39 males) found no statistically significant differences in plasma enzyme substrate and one trial (n=24 males) found no statistical differences in renal function between individuals treated with agalsidase alfa and placebo (up to 6-month follow-up). Similar results were seen for agalsidase beta. One trial of 26 male patients found a statistically significant difference in pain, favoring agalsidase alfa compared to placebo at 5-6 months after treatment. No trial reported on the effect of agalsidase alfa on mortality or cardiac/cerebrovascular disease. One trial of agalsidase beta (n=82 males and females) found no difference in mortality, renal function, or symptoms or complications of cardiac or cerebrovascular disease over 18 months. The long-term influence of ERT on risk of morbidity and mortality related to FD remains to be established.

Migalastat, an oral chaperone drug, is recommended as an option for treatment for some patients with FD who are over 16 years with an amenable genetic variant who would usually be offered ERT. For non-amenable genotypes, migalastat may result in a net loss of alpha-Gal A activity, potentially worsening the disease condition.

A systematic review evaluated 2 phase III RCTs that both included males and females. One RCT randomized patients to switch from ERT to migalastat (n = 36) or continue with ERT (n = 24) during an 18-month period with a 12-month extension in which all patients received migalastat. During the treatment period, the percentage of patients who had a renal, cardiac, or cerebrovascular event or died was 29% of patients on migalastat compared to 44% of patients on ERT. However, this difference was not statistically significant. A second RCT compared migalastat (n=34) with placebo (n=33) over a 6-month period, with an 18-month extension study. The primary outcome was change from baseline in interstitial capillary inclusions of the enzyme substrate globotriaosylceramide (GL-3), which was not significantly different between groups. Results from both trials indicate that migalastat does not have a significant beneficial effect on pain, health-related quality of life outcomes, or glomerular filtration rate (results were uncertain due to large confidence intervals, small sample sizes, and/or short follow-up time). Migalastat did not influence left ventricular ejection fraction but did improve left ventricular mass over 18 months.

There are a number of recommendations for surveillance and agents to avoid (amiodarone). There is no consensus as to when ERT should be started. Note ERT is licensed in Australia from age 7 years.

However, carbamazepine relieves neuropathic pain, which has onset in early childhood. Overall, include.
BabyScreen+ newborn screening v0.1834 GLA Zornitza Stark edited their review of gene: GLA: Changed rating: GREEN
BabyScreen+ newborn screening v0.1834 SMAD2 Zornitza Stark Marked gene: SMAD2 as ready
BabyScreen+ newborn screening v0.1834 SMAD2 Zornitza Stark Gene: smad2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1834 SMAD2 Zornitza Stark Classified gene: SMAD2 as Green List (high evidence)
BabyScreen+ newborn screening v0.1834 SMAD2 Zornitza Stark Gene: smad2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1833 SMAD2 Zornitza Stark Tag cardiac tag was added to gene: SMAD2.
Tag treatable tag was added to gene: SMAD2.
BabyScreen+ newborn screening v0.1833 SMAD2 Zornitza Stark gene: SMAD2 was added
gene: SMAD2 was added to gNBS. Sources: Expert Review
Mode of inheritance for gene: SMAD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: SMAD2 were set to Loeys-Dietz syndrome 6, MIM# 619656
Review for gene: SMAD2 was set to GREEN
Added comment: 9 individuals from 5 unrelated families reported with LDS phenotype. Gene-disease association rated 'moderate' by ClinGen but this gene is included in our diagnostic testing.

LDS included in gNBS panel as in general medical actionability for the LDS group of disorders is considered established.

Can manifest in early childhood.

Treatment: different interventions, including beta-blockers, surgical and monitoring

Non-genetic confirmatory test: characteristic clinical findings
Sources: Expert Review
BabyScreen+ newborn screening v0.1832 SMAD3 Zornitza Stark Tag for review was removed from gene: SMAD3.
Tag treatable tag was added to gene: SMAD3.
BabyScreen+ newborn screening v0.1832 TGFB3 Zornitza Stark Tag for review was removed from gene: TGFB3.
BabyScreen+ newborn screening v0.1832 TGFB2 Zornitza Stark Tag for review was removed from gene: TGFB2.
BabyScreen+ newborn screening v0.1832 PMS2 Zornitza Stark Classified gene: PMS2 as Green List (high evidence)
BabyScreen+ newborn screening v0.1832 PMS2 Zornitza Stark Gene: pms2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1831 PMS2 Zornitza Stark Tag for review was removed from gene: PMS2.
BabyScreen+ newborn screening v0.1831 PMS2 Zornitza Stark edited their review of gene: PMS2: Changed rating: GREEN
BabyScreen+ newborn screening v0.1831 MSH6 Zornitza Stark Classified gene: MSH6 as Green List (high evidence)
BabyScreen+ newborn screening v0.1831 MSH6 Zornitza Stark Gene: msh6 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1830 MSH6 Zornitza Stark Tag for review was removed from gene: MSH6.
BabyScreen+ newborn screening v0.1830 MSH6 Zornitza Stark edited their review of gene: MSH6: Changed rating: GREEN
BabyScreen+ newborn screening v0.1830 MSH2 Zornitza Stark Classified gene: MSH2 as Green List (high evidence)
BabyScreen+ newborn screening v0.1830 MSH2 Zornitza Stark Gene: msh2 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1829 MSH2 Zornitza Stark Tag for review was removed from gene: MSH2.
BabyScreen+ newborn screening v0.1829 MSH2 Zornitza Stark edited their review of gene: MSH2: Changed rating: GREEN
BabyScreen+ newborn screening v0.1829 MLH1 Zornitza Stark Classified gene: MLH1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1829 MLH1 Zornitza Stark Gene: mlh1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1828 MLH1 Zornitza Stark edited their review of gene: MLH1: Changed rating: GREEN
BabyScreen+ newborn screening v0.1828 SLC13A5 Zornitza Stark Classified gene: SLC13A5 as Red List (low evidence)
BabyScreen+ newborn screening v0.1828 SLC13A5 Zornitza Stark Gene: slc13a5 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1827 PTCH1 Zornitza Stark Classified gene: PTCH1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1827 PTCH1 Zornitza Stark Gene: ptch1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1826 PTCH1 Zornitza Stark Tag for review was removed from gene: PTCH1.
BabyScreen+ newborn screening v0.1826 PMM2 Zornitza Stark Classified gene: PMM2 as Red List (low evidence)
BabyScreen+ newborn screening v0.1826 PMM2 Zornitza Stark Gene: pmm2 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1825 PMM2 Zornitza Stark changed review comment from: Well established gene-disease association.

Two clinical presentations - solely neurologic form and a neurologic-multivisceral form
Mortality approximately 20% in first 2 years

Treatment: epalrestat

PMID 31636082: Epalrestat increased PMM2 enzymatic activity in four PMM2-CDG patient fibroblast lines with genotypes R141H/F119L, R141H/E139K, R141H/N216I and R141H/F183S. PMM2 enzyme activity gains ranged from 30% to 400% over baseline, depending on genotype. Pharmacological inhibition of aldose reductase by epalrestat may shunt glucose from the polyol pathway to glucose-1,6-bisphosphate, which is an endogenous stabilizer and coactivator of PMM2 homodimerization. Epalrestat is a safe, oral and brain penetrant drug that was approved 27 years ago in Japan to treat diabetic neuropathy in geriatric populations.

For review: uncertain if in use for CDG; to: Well established gene-disease association.

Two clinical presentations - solely neurologic form and a neurologic-multivisceral form
Mortality approximately 20% in first 2 years

Treatment: epalrestat

PMID 31636082: Epalrestat increased PMM2 enzymatic activity in four PMM2-CDG patient fibroblast lines with genotypes R141H/F119L, R141H/E139K, R141H/N216I and R141H/F183S. PMM2 enzyme activity gains ranged from 30% to 400% over baseline, depending on genotype. Pharmacological inhibition of aldose reductase by epalrestat may shunt glucose from the polyol pathway to glucose-1,6-bisphosphate, which is an endogenous stabilizer and coactivator of PMM2 homodimerization. Epalrestat is a safe, oral and brain penetrant drug that was approved 27 years ago in Japan to treat diabetic neuropathy in geriatric populations.

Treatment not well established in patients.
BabyScreen+ newborn screening v0.1825 PMM2 Zornitza Stark edited their review of gene: PMM2: Changed rating: RED
BabyScreen+ newborn screening v0.1825 PMM2 Zornitza Stark Tag for review was removed from gene: PMM2.
Tag metabolic was removed from gene: PMM2.
BabyScreen+ newborn screening v0.1825 PIK3CA Zornitza Stark Classified gene: PIK3CA as Red List (low evidence)
BabyScreen+ newborn screening v0.1825 PIK3CA Zornitza Stark Gene: pik3ca has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1824 PIK3CA Zornitza Stark Tag for review was removed from gene: PIK3CA.
BabyScreen+ newborn screening v0.1824 PIK3CA Zornitza Stark edited their review of gene: PIK3CA: Changed rating: RED
BabyScreen+ newborn screening v0.1824 MEN1 Zornitza Stark Tag for review was removed from gene: MEN1.
BabyScreen+ newborn screening v0.1824 HPRT1 Zornitza Stark Classified gene: HPRT1 as Red List (low evidence)
BabyScreen+ newborn screening v0.1824 HPRT1 Zornitza Stark Gene: hprt1 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1823 HPRT1 Zornitza Stark changed review comment from: Uncertain if these are essentially symptomatic treatments.; to: Symptomatic treatments.
BabyScreen+ newborn screening v0.1823 HPRT1 Zornitza Stark edited their review of gene: HPRT1: Changed rating: RED
BabyScreen+ newborn screening v0.1823 GLDC Zornitza Stark Tag for review was removed from gene: GLDC.
Tag treatable tag was added to gene: GLDC.
Tag metabolic tag was added to gene: GLDC.
BabyScreen+ newborn screening v0.1823 GLDC Zornitza Stark edited their review of gene: GLDC: Changed rating: GREEN
BabyScreen+ newborn screening v0.1823 FBN1 Zornitza Stark Classified gene: FBN1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1823 FBN1 Zornitza Stark Gene: fbn1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1822 FBN1 Zornitza Stark Tag for review was removed from gene: FBN1.
Tag cardiac tag was added to gene: FBN1.
Tag treatable tag was added to gene: FBN1.
BabyScreen+ newborn screening v0.1822 FBN1 Zornitza Stark edited their review of gene: FBN1: Changed rating: GREEN
BabyScreen+ newborn screening v0.1822 DICER1 Zornitza Stark Classified gene: DICER1 as Green List (high evidence)
BabyScreen+ newborn screening v0.1822 DICER1 Zornitza Stark Gene: dicer1 has been classified as Green List (High Evidence).
BabyScreen+ newborn screening v0.1821 DICER1 Zornitza Stark Tag for review was removed from gene: DICER1.
BabyScreen+ newborn screening v0.1821 DICER1 Zornitza Stark edited their review of gene: DICER1: Changed rating: GREEN
BabyScreen+ newborn screening v0.1821 TP53 Zornitza Stark Tag for review was removed from gene: TP53.
BabyScreen+ newborn screening v0.1821 SLC5A6 Zornitza Stark Tag for review was removed from gene: SLC5A6.
Tag treatable tag was added to gene: SLC5A6.
Tag metabolic tag was added to gene: SLC5A6.
BabyScreen+ newborn screening v0.1821 RET Zornitza Stark Tag for review was removed from gene: RET.
BabyScreen+ newborn screening v0.1821 RET Zornitza Stark changed review comment from: Established gene-disease associations.

Assessed as 'strong actionability' in paediatric patients by ClinGen.

Onset of MEN2A is typically prior to age 35, usually between ages 5 and 25. MTC is generally the first manifestation in MEN2A with probands presenting with a neck mass or neck pain. Metastatic spread is common. MTC is the most common cause of death in patients with MEN2A.

PHEOs usually present after MTC or concomitantly but are the first manifestation in 13-27% of individuals; they occur in about 50% of individuals. PHEOs are diagnosed at an earlier age, have subtler symptoms, and are more likely to be bilateral than sporadic tumors, with malignant transformation occurring in about 4% of cases. Even without malignant progression, PHEOs can be lethal from intractable hypertension or anesthesia-induced hypertensive crises. Depending on the risk category of the RET pathogenic variant, PHEOs have been observed as early as 5 years of age.

For MEN2A children with a “high-risk” pathogenic variant, patients should undergo annual ultrasound and screening for increased calcitonin levels starting at 3 years of age and proceed to thyroidectomy when elevated levels are detected or at 5 years of age. For patients with a “moderate-risk” pathogenic variant, considering the clinical variability of disease expression in family members in this category, annual physical examination, cervical US, and measurement of serum calcitonin levels, should begin at 5 years of age.

Biochemical surveillance for PHPT should begin at 11 years and 16 years of age for patients with high- and moderate-risk variants, respectively; this screening is recommended annually for “high-risk” patients and at least every 2-3 years in “moderate-risk” patients.

Biochemical screening for PHEO should begin at age 11 for patients with high-risk variants and age 16 for patients with moderate-risk variants.

For review: actionable in first 5 years of life?; to: Established gene-disease associations.

Assessed as 'strong actionability' in paediatric patients by ClinGen.

Onset of MEN2A is typically prior to age 35, usually between ages 5 and 25. MTC is generally the first manifestation in MEN2A with probands presenting with a neck mass or neck pain. Metastatic spread is common. MTC is the most common cause of death in patients with MEN2A.

PHEOs usually present after MTC or concomitantly but are the first manifestation in 13-27% of individuals; they occur in about 50% of individuals. PHEOs are diagnosed at an earlier age, have subtler symptoms, and are more likely to be bilateral than sporadic tumors, with malignant transformation occurring in about 4% of cases. Even without malignant progression, PHEOs can be lethal from intractable hypertension or anesthesia-induced hypertensive crises. Depending on the risk category of the RET pathogenic variant, PHEOs have been observed as early as 5 years of age.

For MEN2A children with a “high-risk” pathogenic variant, patients should undergo annual ultrasound and screening for increased calcitonin levels starting at 3 years of age and proceed to thyroidectomy when elevated levels are detected or at 5 years of age. For patients with a “moderate-risk” pathogenic variant, considering the clinical variability of disease expression in family members in this category, annual physical examination, cervical US, and measurement of serum calcitonin levels, should begin at 5 years of age.

Biochemical surveillance for PHPT should begin at 11 years and 16 years of age for patients with high- and moderate-risk variants, respectively; this screening is recommended annually for “high-risk” patients and at least every 2-3 years in “moderate-risk” patients.

Biochemical screening for PHEO should begin at age 11 for patients with high-risk variants and age 16 for patients with moderate-risk variants.

For review: some actionability in first 5 years, variants can be stratified in terms of risk.
BabyScreen+ newborn screening v0.1821 RB1 Zornitza Stark Tag for review was removed from gene: RB1.
BabyScreen+ newborn screening v0.1821 PRKAR1A Zornitza Stark Tag for review was removed from gene: PRKAR1A.
BabyScreen+ newborn screening v0.1821 NF1 Zornitza Stark Classified gene: NF1 as Red List (low evidence)
BabyScreen+ newborn screening v0.1821 NF1 Zornitza Stark Gene: nf1 has been classified as Red List (Low Evidence).
BabyScreen+ newborn screening v0.1820 NF1 Zornitza Stark changed review comment from: For review: does this meet the definition of 'treatable'?; to: Mainly surveillance.
BabyScreen+ newborn screening v0.1820 NF1 Zornitza Stark edited their review of gene: NF1: Changed rating: RED
BabyScreen+ newborn screening v0.1820 MCEE Zornitza Stark Tag for review was removed from gene: MCEE.
Renal Glomerular Disease_SuperPanel v1.68 Zornitza Stark HPO terms changed from to Abnormal glomerular filtration rate, HP:0012212; Hematuria, HP:0000790;Proteinuria, HP:0000093
List of related panels changed from to Abnormal glomerular filtration rate; HP:0012212; Hematuria; HP:0000790;Proteinuria; HP:0000093
Renal Ciliopathies and Nephronophthisis v1.19 Zornitza Stark HPO terms changed from Abnormality of renal medullary morphology, HP:0025361 to Abnormality of renal medullary morphology, HP:0025361; Renal cyst, HP:0000107
List of related panels changed from Abnormality of renal medullary morphology; HP:0025361 to Abnormality of renal medullary morphology; HP:0025361; Renal cyst; HP:0000107
Renal Cystic Disease_SuperPanel v1.47 Zornitza Stark HPO terms changed from to Renal cyst, HP:0000107
List of related panels changed from to Renal cyst; HP:0000107
Renal Macrocystic Disease v0.66 Zornitza Stark HPO terms changed from to Renal cyst, HP:0000107
List of related panels changed from to Renal cyst; HP:0000107
Renal Tubulointerstitial Disease v1.3 Zornitza Stark HPO terms changed from to Abnormal tubulointerstitial morphology, HP:0001969
List of related panels changed from to Abnormal tubulointerstitial morphology; HP:0001969
Renal Tubulopathies and related disorders v1.4 Zornitza Stark HPO terms changed from to Renal tubular dysfunction, HP:0000124; Nephrolithiasis, HP:0000787; Abnormal circulating aldosterone, HP:0040085
List of related panels changed from to Renal tubular dysfunction; HP:0000124; Nephrolithiasis; HP:0000787; Abnormal circulating aldosterone; HP:0040085
Retinal Disorders Superpanel v6.156 Zornitza Stark HPO terms changed from to Abnormal retinal morphology, HP:0000479
List of related panels changed from to Abnormal retinal morphology; HP:0000479
Retinitis pigmentosa_Autosomal Dominant v0.54 Zornitza Stark HPO terms changed from to Abnormal retinal morphology, HP:0000479
List of related panels changed from to Abnormal retinal morphology; HP:0000479
Retinitis pigmentosa_Autosomal Recessive/X-linked v0.131 Zornitza Stark HPO terms changed from to Abnormal retinal morphology, HP:0000479
List of related panels changed from to Abnormal retinal morphology; HP:0000479
Retinitis Pigmentosa Superpanel v0.185 Zornitza Stark HPO terms changed from to Abnormal retinal morphology, HP:0000479
List of related panels changed from to Abnormal retinal morphology; HP:0000479
Rhabdomyolysis and Metabolic Myopathy v0.92 Zornitza Stark HPO terms changed from to Rhabdomyolysis, HP:0003201
List of related panels changed from to Rhabdomyolysis; HP:0003201
Rhabdomyolysis and Metabolic Myopathy v0.92 Zornitza Stark HPO terms changed from to Rhabdomyolysis, HP:0003201
List of related panels changed from to Rhabdomyolysis; HP:0003201
Severe Combined Immunodeficiency (absent T absent B cells) v1.4 Zornitza Stark HPO terms changed from to Severe combined immunodeficiency, HP:0004430
List of related panels changed from to Severe combined immunodeficiency; HP:0004430
Severe Combined Immunodeficiency (absent T present B cells) v1.1 Zornitza Stark HPO terms changed from to Severe combined immunodeficiency, HP:0004430
List of related panels changed from to Severe combined immunodeficiency; HP:0004430
Panel types changed to Melbourne Genomics; Victorian Clinical Genetics Services; Rare Disease
Severe early-onset obesity v1.6 Zornitza Stark HPO terms changed from to Obesity, HP:0001513
List of related panels changed from to Obesity; HP:0001513
Short QT syndrome v1.4 Zornitza Stark HPO terms changed from to Shortened QT interval, HP:0012232
List of related panels changed from to Shortened QT interval; HP:0012232
Short Rib Polydactyly_Jeune Asphyxiating Thoracic Dystrophy_Skeletal Ciliopathy v1.8 Zornitza Stark HPO terms changed from Short rib, HP:0000773; Polydactyly, HP:0010442 to Short rib, HP:0000773; Polydactyly, HP:0010442; Bell-shaped thorax, HP:0001591
List of related panels changed from Short rib; HP:0000773; Polydactyly; HP:0010442 to Short rib; HP:0000773; Polydactyly; HP:0010442; Bell-shaped thorax; HP:0001591
Short Rib Polydactyly_Jeune Asphyxiating Thoracic Dystrophy_Skeletal Ciliopathy v1.7 Zornitza Stark HPO terms changed from to Short rib, HP:0000773; Polydactyly, HP:0010442
List of related panels changed from to Short rib; HP:0000773; Polydactyly; HP:0010442
Sick sinus syndrome v1.1 Zornitza Stark HPO terms changed from to Sick sinus syndrome, HP:0011704
List of related panels changed from to Sick sinus syndrome; HP:0011704
Skeletal dysplasia v0.229 Zornitza Stark HPO terms changed from to Skeletal dysplasia, HP:0002652
List of related panels changed from to Skeletal dysplasia; HP:0002652
Skeletal Muscle Channelopathies v1.1 Zornitza Stark HPO terms changed from to Periodic paralysis, HP:0003768; Myotonia, HP:0002486
List of related panels changed from to Periodic paralysis; HP:0003768; Myotonia; HP:0002486
Spondylocostal Dysostosis v0.9 Zornitza Stark HPO terms changed from to Spondylocostal dysostosis, MONDO:0000359
List of related panels changed from to Spondylocostal dysostosis; MONDO:0000359
Stickler Syndrome v1.5 Zornitza Stark HPO terms changed from to Myopia, HP:0000545; Retinal detachment, HP:0000541; Cleft palate, HP:0000175
List of related panels changed from to Myopia; HP:0000545; Retinal detachment; HP:0000541; Cleft palate; HP:0000175
Stroke v1.8 Zornitza Stark HPO terms changed from to Stroke, HP:0001297
List of related panels changed from to Stroke; HP:0001297
Susceptibility to Fungal Infections v1.7 Zornitza Stark HPO terms changed from to Recurrent fungal infections, HP:0002841
List of related panels changed from to Recurrent fungal infections; HP:0002841
Susceptibility to Viral Infections v0.109 Zornitza Stark HPO terms changed from to Recurrent viral infections, HP:0004429; Severe viral infection, HP:0031691
List of related panels changed from to Recurrent viral infections; HP:0004429; Severe viral infection; HP:0031691
Syndromic Retinopathy v0.197 Zornitza Stark HPO terms changed from to Retinopathy, HP:0000488
List of related panels changed from to Retinopathy; HP:0000488
Tubulinopathies v1.1 Zornitza Stark HPO terms changed from to Abnormal cortical gyration, HP:0002536
List of related panels changed from to Abnormal cortical gyration; HP:0002536
Usher Syndrome v1.5 Zornitza Stark HPO terms changed from to Usher syndrome, MONDO:0019501
List of related panels changed from to Usher syndrome; MONDO:0019501
Vascular Malformations SuperPanel v1.21 Zornitza Stark HPO terms changed from to Abnormal vascular morphology HP:0025015
List of related panels changed from to Abnormal vascular morphology HP:0025015
Vitreoretinopathy v1.4 Zornitza Stark HPO terms changed from to Abnormal posterior eye segment morphology, HP:0004329
List of related panels changed from to Abnormal posterior eye segment morphology; HP:0004329
Fetal anomalies v1.84 ZNF668 Zornitza Stark Phenotypes for gene: ZNF668 were changed from DNA damage repair defect; microcephaly; growth deficiency; severe global developmental delay; brain malformation; facial dysmorphism to Neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies, MIM# 620194
Growth failure v1.59 ZNF668 Zornitza Stark Phenotypes for gene: ZNF668 were changed from DNA damage repair defect; microcephaly; growth deficiency; severe global developmental delay; brain malformation; facial dysmorphism to Neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies, MIM# 620194
Intellectual disability syndromic and non-syndromic v0.5154 ZNF668 Zornitza Stark Phenotypes for gene: ZNF668 were changed from DNA damage repair defect; microcephaly; growth deficiency; severe global developmental delay; brain malformation; facial dysmorphism to Neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies, MIM# 620194
Microcephaly v1.188 ZNF668 Zornitza Stark Phenotypes for gene: ZNF668 were changed from DNA damage repair defect; microcephaly; growth deficiency; severe global developmental delay; brain malformation; facial dysmorphism to Neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies, MIM# 620194
Mendeliome v1.611 ZNF668 Zornitza Stark Phenotypes for gene: ZNF668 were changed from DNA damage repair defect; microcephaly; growth deficiency; severe global developmental delay; brain malformation; facial dysmorphism to Neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies, MIM# 620194
Mendeliome v1.610 ZNF668 Zornitza Stark reviewed gene: ZNF668: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Neurodevelopmental disorder with poor growth, large ears, and dysmorphic facies, MIM# 620194; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Growth failure v1.58 SMC5 Zornitza Stark Phenotypes for gene: SMC5 were changed from Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042, SLF2-related; Atelis syndrome; microcephaly; short stature; ID to Atelis syndrome 2, MIM# 620185
Growth failure v1.57 SMC5 Zornitza Stark edited their review of gene: SMC5: Changed phenotypes: Atelis syndrome 2, MIM# 620185
Intellectual disability syndromic and non-syndromic v0.5153 SMC5 Zornitza Stark Phenotypes for gene: SMC5 were changed from Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042, SLF2-related; Atelis syndrome; microcephaly; short stature; ID to Atelis syndrome 2, MIM# 620185
Intellectual disability syndromic and non-syndromic v0.5152 SMC5 Zornitza Stark edited their review of gene: SMC5: Changed phenotypes: Atelis syndrome 2, MIM# 620185
Microcephaly v1.187 SMC5 Zornitza Stark Phenotypes for gene: SMC5 were changed from Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042, SLF2-related; Atelis syndrome; microcephaly; short stature; ID to Atelis syndrome 2, MIM# 620185
Microcephaly v1.186 SMC5 Zornitza Stark edited their review of gene: SMC5: Changed phenotypes: Atelis syndrome 2, MIM# 620185
Mendeliome v1.610 SMC5 Zornitza Stark Phenotypes for gene: SMC5 were changed from Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042, SLF2-related; Atelis syndrome; microcephaly; short stature; ID to Atelis syndrome 2, MIM# 620185
Mendeliome v1.609 SMC5 Zornitza Stark edited their review of gene: SMC5: Changed phenotypes: Atelis syndrome 2, MIM# 620185
Chromosome Breakage Disorders v1.17 SMC5 Zornitza Stark Phenotypes for gene: SMC5 were changed from Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042, SLF2-related; Atelis syndrome; microcephaly; short stature; ID to Atelis syndrome 2, MIM# 620185
Chromosome Breakage Disorders v1.16 SMC5 Zornitza Stark edited their review of gene: SMC5: Changed phenotypes: Atelis syndrome 2, MIM# 620185
Growth failure v1.57 SLF2 Zornitza Stark Phenotypes for gene: SLF2 were changed from Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042, SLF2-related; Atelis syndrome; microcephaly; short stature; ID to Atelis syndrome 1, MIM# 620184
Growth failure v1.56 SLF2 Zornitza Stark edited their review of gene: SLF2: Changed phenotypes: Atelis syndrome 1, MIM# 620184
Intellectual disability syndromic and non-syndromic v0.5152 SLF2 Zornitza Stark Phenotypes for gene: SLF2 were changed from Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042, SLF2-related; Atelis syndrome; microcephaly; short stature; ID to Atelis syndrome 1, MIM# 620184
Intellectual disability syndromic and non-syndromic v0.5151 SLF2 Zornitza Stark edited their review of gene: SLF2: Changed phenotypes: Atelis syndrome 1, MIM# 620184
Microcephaly v1.186 SLF2 Zornitza Stark Phenotypes for gene: SLF2 were changed from Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042, SLF2-related; Atelis syndrome; microcephaly; short stature; ID to Atelis syndrome 1, MIM# 620184
Mendeliome v1.609 SLF2 Zornitza Stark Phenotypes for gene: SLF2 were changed from Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042, SLF2-related; Atelis syndrome; microcephaly; short stature; ID to Atelis syndrome 1, MIM# 620184
Mendeliome v1.608 SLF2 Zornitza Stark edited their review of gene: SLF2: Changed phenotypes: Atelis syndrome 1, MIM# 620184
Chromosome Breakage Disorders v1.16 SLF2 Zornitza Stark Phenotypes for gene: SLF2 were changed from Multiple congenital anomalies/dysmorphic syndrome, MONDO:0019042, SLF2-related; Atelis syndrome; microcephaly; short stature; ID to Atelis syndrome 1, MIM# 620184
Chromosome Breakage Disorders v1.15 SLF2 Zornitza Stark edited their review of gene: SLF2: Changed phenotypes: Atelis syndrome 1, MIM# 620184
Renal Tubulopathies and related disorders v1.3 SLC6A6 Zornitza Stark Marked gene: SLC6A6 as ready
Renal Tubulopathies and related disorders v1.3 SLC6A6 Zornitza Stark Gene: slc6a6 has been classified as Red List (Low Evidence).
Renal Tubulopathies and related disorders v1.3 SLC6A6 Zornitza Stark gene: SLC6A6 was added
gene: SLC6A6 was added to Renal Tubulopathies and related disorders. Sources: Literature
Mode of inheritance for gene: SLC6A6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SLC6A6 were set to 35115415; 21170874; 32660969
Phenotypes for gene: SLC6A6 were set to Primary hyperoxaluria, MONDO:0002474, SLC26A6-related
Review for gene: SLC6A6 was set to RED
Added comment: Cornière et al. 2022 (PMID: 35115415) identified a single family with a heterozygous missense VUS (c.1519C>T/p.R507W) in the SLC26A6 gene. However, the variant was found in 5 out of 280 674 alleles reported in gnomAD (Europeans and South Asians). In vitro studies showed that the variant affects both SLC26A6 transport activity and membrane surface expression, in turn reducing Cl− dependant oxalate transport. Cotransfection studies indicated a dominant-negative effect on WT. Slc26a6 null mice similarly displayed hyperoxalemia and hyperoxaluria which were caused by defective intestinal back-secretion of dietary oxalate (PMID: 21170874; 32660969)
Sources: Literature
Regression v0.518 NAE1 Zornitza Stark Marked gene: NAE1 as ready
Regression v0.518 NAE1 Zornitza Stark Gene: nae1 has been classified as Green List (High Evidence).
Regression v0.518 NAE1 Zornitza Stark Classified gene: NAE1 as Green List (high evidence)
Regression v0.518 NAE1 Zornitza Stark Gene: nae1 has been classified as Green List (High Evidence).
Regression v0.517 NAE1 Zornitza Stark gene: NAE1 was added
gene: NAE1 was added to Regression. Sources: Literature
Mode of inheritance for gene: NAE1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAE1 were set to 36608681
Phenotypes for gene: NAE1 were set to Neurodevelopmental disorder, MONDO:0700092, NAE1-related
Review for gene: NAE1 was set to GREEN
Added comment: Four individuals reported with bi-allelic variants and intellectual disability, ischiopubic hypoplasia, stress-mediated lymphopenia and neurodegeneration.
Sources: Literature
Intellectual disability syndromic and non-syndromic v0.5151 NAE1 Zornitza Stark Marked gene: NAE1 as ready
Intellectual disability syndromic and non-syndromic v0.5151 NAE1 Zornitza Stark Gene: nae1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5151 NAE1 Zornitza Stark Classified gene: NAE1 as Green List (high evidence)
Intellectual disability syndromic and non-syndromic v0.5151 NAE1 Zornitza Stark Gene: nae1 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5150 NAE1 Zornitza Stark gene: NAE1 was added
gene: NAE1 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: NAE1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAE1 were set to 36608681
Phenotypes for gene: NAE1 were set to Neurodevelopmental disorder, MONDO:0700092, NAE1-related
Review for gene: NAE1 was set to GREEN
Added comment: Four individuals reported with bi-allelic variants and intellectual disability, ischiopubic hypoplasia, stress-mediated lymphopenia and neurodegeneration.
Sources: Literature
Mendeliome v1.608 NAE1 Zornitza Stark Marked gene: NAE1 as ready
Mendeliome v1.608 NAE1 Zornitza Stark Gene: nae1 has been classified as Green List (High Evidence).
Mendeliome v1.608 NAE1 Zornitza Stark Classified gene: NAE1 as Green List (high evidence)
Mendeliome v1.608 NAE1 Zornitza Stark Gene: nae1 has been classified as Green List (High Evidence).
Mendeliome v1.607 NAE1 Zornitza Stark gene: NAE1 was added
gene: NAE1 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: NAE1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAE1 were set to 36608681
Phenotypes for gene: NAE1 were set to Neurodevelopmental disorder, MONDO:0700092, NAE1-related
Review for gene: NAE1 was set to GREEN
Added comment: Four individuals reported with bi-allelic variants and intellectual disability, ischiopubic hypoplasia, stress-mediated lymphopenia and neurodegeneration.
Sources: Literature
Mendeliome v1.606 SLC26A6 Zornitza Stark Marked gene: SLC26A6 as ready
Mendeliome v1.606 SLC26A6 Zornitza Stark Gene: slc26a6 has been classified as Red List (Low Evidence).
Mendeliome v1.606 SLC26A6 Zornitza Stark Phenotypes for gene: SLC26A6 were changed from Enteric hyperoxaluria and nephrolithiasis to Primary hyperoxaluria, MONDO:0002474, SLC26A6-related
Mendeliome v1.605 SLC26A6 Zornitza Stark Classified gene: SLC26A6 as Red List (low evidence)
Mendeliome v1.605 SLC26A6 Zornitza Stark Gene: slc26a6 has been classified as Red List (Low Evidence).
Mendeliome v1.604 SLC26A6 Zornitza Stark reviewed gene: SLC26A6: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Primary hyperoxaluria, MONDO:0002474, SLC26A6-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability syndromic and non-syndromic v0.5149 TRPC5 Zornitza Stark Marked gene: TRPC5 as ready
Intellectual disability syndromic and non-syndromic v0.5149 TRPC5 Zornitza Stark Gene: trpc5 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5149 TRPC5 Zornitza Stark Classified gene: TRPC5 as Amber List (moderate evidence)
Intellectual disability syndromic and non-syndromic v0.5149 TRPC5 Zornitza Stark Gene: trpc5 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5148 TRPC5 Zornitza Stark gene: TRPC5 was added
gene: TRPC5 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature
Mode of inheritance for gene: TRPC5 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: TRPC5 were set to 36323681; 24817631; 23033978; 33504798; 28191890
Phenotypes for gene: TRPC5 were set to Neurodevelopmental disorder, MONDO:0700092, TRPC5-related
Review for gene: TRPC5 was set to AMBER
Added comment: PMID: 36323681; Leitão E. et al. (2022) Nat Commun.13(1):6570:
Missense variant NM_012471.2:c.523C>T, p.(Arg175Cys in three brothers with intellectual disability (ID) and autistic spectrum disorder (ASD), inherited from an asymptomatic mother and absent in the maternal grandparents.
Whole cell patch clamp studies of HEK293 created by site-directed mutagenesis showed increased current of this calcium channel (constitutively opened).
(This variant is absent in gnomAD v2.1.1).

Also, the nonsense variant, c.965G> A, p.(Trp322*) was found in a high functioning ASD male (maternally inherited), NMD-predicted.

Other papers and TRPC5 variants that were cited to associate this gene with X-linked ID and/or ASD include:
PMID: 24817631; Mignon-Ravix, C. et al. (2014) Am. J.Med. Genet. A 164A: 1991–1997: A hemizygous 47-kb deletion in Xq23 including exon 1 of the TRPC5 gene. He had macrocephaly, delayed psychomotor development, speech delay, behavioural problems, and autistic features. Maternally inherited, and a family history compatible with X-linked inheritance (i.e., maternal great uncle was also affected, although not tested).

In addition, PMID: 36323681; Leitão E. et al. (2022) cites papers with the variants p.(Pro667Thr), p.(Arg71Gln) and p.(Trp225*).
NB. p.(Pro667Thr) is absent in gnomAD (v2.1.1), p.(Arg71Gln) is also absent (the alternative variant p.(Arg71Trp) is present once as heterozygous only). p.(Trp225*) is absent, and it should be noted that PTCs / LoF variants are very rare (pLI = 1).

However, looking further into the three references, the evidence is not as clear or as accurate as was stated.

The missense variant c.1999C>A, p.(Pro667Thr), was stated as de novo, but was actually maternally inherited but was still considered a candidate for severe intellectual disability (shown in the Appendix, Patient 93, with severe speech delay, autism spectrum disorder and Gilles de la Tourette). This patient also has a de novo MTF1 variant. Reference: PMID: 23033978; de Ligt, J. et al. (2012) N. Engl. J. Med. 367: 1921–1929).

Missense variant (de novo): c.212G>A, p.(Arg71Gln), was found as part of the Deciphering Developmental Disorders (DDD) study and is shown in individual 164 in Supplementary Table 2 of PMID: 33504798; Martin, HC. et al. (2021) Nat. Commun.12: 627. Also displayed in DECIPHER (DDD research variant) with several phenotype traits, but ID and ASD are not specifically mentioned.

Nonsense variant: c.674G>A. p.(Trp225*) was stated as de novo but was inherited (reference PMID: 28191890; Kosmicki, JA. et al. (2017) Nat. Genet. 49: 504–510. Supplement Table 7). This was a study of severe intellectual delay, developmental delay / autism. (NB. The de novo p.(Arg71Gln) variant from the DDD study is also listed (subject DDD 342 in Supplement 4 / Table 2).
Sources: Literature
Mendeliome v1.604 TRPC5 Zornitza Stark Marked gene: TRPC5 as ready
Mendeliome v1.604 TRPC5 Zornitza Stark Gene: trpc5 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.604 TRPC5 Zornitza Stark Phenotypes for gene: TRPC5 were changed from Intellectual disability; autistic spectrum disorder to Neurodevelopmental disorder, MONDO:0700092, TRPC5-related
Mendeliome v1.603 TRPC5 Zornitza Stark Classified gene: TRPC5 as Amber List (moderate evidence)
Mendeliome v1.603 TRPC5 Zornitza Stark Gene: trpc5 has been classified as Amber List (Moderate Evidence).
Cardiomyopathy_Paediatric v0.151 CRLS1 Zornitza Stark Phenotypes for gene: CRLS1 were changed from Mitochondrial disease MONDO:0044970 CRLS1-related to Combined oxidative phosphorylation deficiency 57, MIM# 620167
Intellectual disability syndromic and non-syndromic v0.5147 CRLS1 Zornitza Stark Phenotypes for gene: CRLS1 were changed from Mitochondrial disease MONDO:0044970 CRLS1-related to Combined oxidative phosphorylation deficiency 57, MIM# 620167
Deafness_IsolatedAndComplex v1.155 CRLS1 Zornitza Stark Phenotypes for gene: CRLS1 were changed from Mitochondrial disease MONDO:0044970 CRLS1-related to Combined oxidative phosphorylation deficiency 57, MIM# 620167
Mitochondrial disease v0.852 CRLS1 Zornitza Stark Phenotypes for gene: CRLS1 were changed from Mitochondrial disease MONDO:0044970 CRLS1-related to Combined oxidative phosphorylation deficiency 57, MIM# 620167
Mendeliome v1.602 CRLS1 Zornitza Stark Phenotypes for gene: CRLS1 were changed from Mitochondrial disease MONDO:0044970 CRLS1-related to Combined oxidative phosphorylation deficiency 57, MIM# 620167
Mendeliome v1.601 CRLS1 Zornitza Stark edited their review of gene: CRLS1: Changed phenotypes: Combined oxidative phosphorylation deficiency 57, MIM# 620167
Mendeliome v1.601 TRPC5 Hazel Phillimore gene: TRPC5 was added
gene: TRPC5 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: TRPC5 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: TRPC5 were set to PMID: 36323681; 24817631; 23033978; 33504798; 28191890
Phenotypes for gene: TRPC5 were set to Intellectual disability; autistic spectrum disorder
Review for gene: TRPC5 was set to AMBER
Added comment: PMID: 36323681; Leitão E. et al. (2022) Nat Commun.13(1):6570:
Missense variant NM_012471.2:c.523C>T, p.(Arg175Cys in three brothers with intellectual disability (ID) and autistic spectrum disorder (ASD), inherited from an asymptomatic mother and absent in the maternal grandparents.
Whole cell patch clamp studies of HEK293 created by site-directed mutagenesis showed increased current of this calcium channel (constitutively opened).
(This variant is absent in gnomAD v2.1.1).

Also, the nonsense variant, c.965G> A, p.(Trp322*) was found in a high functioning ASD male (maternally inherited), NMD-predicted.

Other papers and TRPC5 variants that were cited to associate this gene with X-linked ID and/or ASD include:
PMID: 24817631; Mignon-Ravix, C. et al. (2014) Am. J.Med. Genet. A 164A: 1991–1997: A hemizygous 47-kb deletion in Xq23 including exon 1 of the TRPC5 gene. He had macrocephaly, delayed psychomotor development, speech delay, behavioural problems, and autistic features. Maternally inherited, and a family history compatible with X-linked inheritance (i.e., maternal great uncle was also affected, although not tested).

In addition, PMID: 36323681; Leitão E. et al. (2022) cites papers with the variants p.(Pro667Thr), p.(Arg71Gln) and p.(Trp225*).
NB. p.(Pro667Thr) is absent in gnomAD (v2.1.1), p.(Arg71Gln) is also absent (the alternative variant p.(Arg71Trp) is present once as heterozygous only). p.(Trp225*) is absent, and it should be noted that PTCs / LoF variants are very rare (pLI = 1).

However, looking further into the three references, the evidence is not as clear or as accurate as was stated.

The missense variant c.1999C>A, p.(Pro667Thr), was stated as de novo, but was actually maternally inherited but was still considered a candidate for severe intellectual disability (shown in the Appendix, Patient 93, with severe speech delay, autism spectrum disorder and Gilles de la Tourette). This patient also has a de novo MTF1 variant. Reference: PMID: 23033978; de Ligt, J. et al. (2012) N. Engl. J. Med. 367: 1921–1929).

Missense variant (de novo): c.212G>A, p.(Arg71Gln), was found as part of the Deciphering Developmental Disorders (DDD) study and is shown in individual 164 in Supplementary Table 2 of PMID: 33504798; Martin, HC. et al. (2021) Nat. Commun.12: 627. Also displayed in DECIPHER (DDD research variant) with several phenotype traits, but ID and ASD are not specifically mentioned.

Nonsense variant: c.674G>A. p.(Trp225*) was stated as de novo but was inherited (reference PMID: 28191890; Kosmicki, JA. et al. (2017) Nat. Genet. 49: 504–510. Supplement Table 7). This was a study of severe intellectual delay, developmental delay / autism. (NB. The de novo p.(Arg71Gln) variant from the DDD study is also listed (subject DDD 342 in Supplement 4 / Table 2).
Sources: Literature
Mendeliome v1.601 ZMYM3 Zornitza Stark Marked gene: ZMYM3 as ready
Mendeliome v1.601 ZMYM3 Zornitza Stark Gene: zmym3 has been classified as Green List (High Evidence).
Renal Ciliopathies and Nephronophthisis v1.18 Zornitza Stark HPO terms changed from to Abnormality of renal medullary morphology, HP:0025361
List of related panels changed from to Abnormality of renal medullary morphology; HP:0025361
Amyloidosis v0.22 Zornitza Stark HPO terms changed from to Renal amyloidosis, HP:0001917
List of related panels changed from to Renal amyloidosis; HP:0001917
Regression v0.516 Zornitza Stark HPO terms changed from to Developmental regression, HP:0002376
List of related panels changed from to Developmental regression; HP:0002376
Regression v0.516 Zornitza Stark HPO terms changed from to Developmental regression, HP:0002376
List of related panels changed from to Developmental regression; HP:0002376
Red cell disorders v1.19 Zornitza Stark HPO terms changed from to Abnormal erythrocyte morphology, HP:0001877
List of related panels changed from to Abnormal erythrocyte morphology; HP:0001877
Rasopathy v0.97 Zornitza Stark HPO terms changed from to Rasopathy, MONDO:0021060
List of related panels changed from to Rasopathy; MONDO:0021060
Radial Ray Abnormalities v1.5 Zornitza Stark HPO terms changed from to Abnormality of radial ray, HP:0410049
List of related panels changed from to Abnormality of radial ray; HP:0410049
Mendeliome v1.601 BSN Krithika Murali changed review comment from: Ye et al 2022, Neurogenetics identified 4 unrelated individuals with epilepsy and compound heterozygous BSN variants via trio WES (combination of null and missense). Homozygous knockout mouse models showed abnormal CNS transmission and seizure activity. None of the identified variants were present in population databases as homozygotes. One individual had ID and microcephaly but all other individuals with biallelic variants had normal development.

In addition, heterozygous variants were identified in unrelated affected individuals - 2 apparently co-segregating missense variants and 2 de novo null variants. These variants were either absent in population databases or rare. The authors note that affected individuals with heterozygous variants had milder disease - either requiring no therapy or monotherapy only. Heterozygous knockout mice had no phenotype and there were not enough affected individuals in the families to truly determine co-segregation. In addition, carrier parents of individuals with biallelic variants did not appear to be affected.

Association between biallelic variants and epilepsy stronger than for monoallelic.
Sources: Literature; to: Ye et al 2022, Neurogenetics - https://jmg.bmj.com/content/early/2022/12/12/jmg-2022-108865
Identified 4 unrelated individuals with epilepsy and compound heterozygous BSN variants via trio WES (combination of null and missense). Homozygous knockout mouse models showed abnormal CNS transmission and seizure activity. None of the identified variants were present in population databases as homozygotes. One individual had ID and microcephaly but all other individuals with biallelic variants had normal development.

In addition, heterozygous variants were identified in unrelated affected individuals - 2 apparently co-segregating missense variants and 2 de novo null variants. These variants were either absent in population databases or rare. The authors note that affected individuals with heterozygous variants had milder disease - either requiring no therapy or monotherapy only. Heterozygous knockout mice had no phenotype and there were not enough affected individuals in the families to truly determine co-segregation. In addition, carrier parents of individuals with biallelic variants did not appear to be affected.

Association between biallelic variants and epilepsy stronger than for monoallelic.
Sources: Literature
Genetic Epilepsy v0.1829 BSN Krithika Murali changed review comment from: Ye et al 2022, Neurogenetics identified 4 unrelated individuals with epilepsy and compound heterozygous BSN variants via trio WES (combination of null and missense). Homozygous knockout mouse models showed abnormal CNS transmission and seizure activity. None of the identified variants were present in population databases as homozygotes. One individual had ID and microcephaly but all other individuals with biallelic variants had normal development.

In addition, heterozygous variants were identified in unrelated affected individuals - 2 apparently co-segregating missense variants and 2 de novo null variants. These variants were either absent in population databases or rare. The authors note that affected individuals with heterozygous variants had milder disease - either requiring no therapy or monotherapy only. Heterozygous knockout mice had no phenotype and there were not enough affected individuals in the families to truly determine co-segregation. In addition, carrier parents of individuals with biallelic variants did not appear to be affected.

Association between biallelic variants and epilepsy stronger than for monoallelic.
Sources: Literature; to: Ye et al 2022, Neurogenetics https://jmg.bmj.com/content/early/2022/12/12/jmg-2022-108865
Identified 4 unrelated individuals with epilepsy and compound heterozygous BSN variants via trio WES (combination of null and missense). Homozygous knockout mouse models showed abnormal CNS transmission and seizure activity. None of the identified variants were present in population databases as homozygotes. One individual had ID and microcephaly but all other individuals with biallelic variants had normal development.

In addition, heterozygous variants were identified in unrelated affected individuals - 2 apparently co-segregating missense variants and 2 de novo null variants. These variants were either absent in population databases or rare. The authors note that affected individuals with heterozygous variants had milder disease - either requiring no therapy or monotherapy only. Heterozygous knockout mice had no phenotype and there were not enough affected individuals in the families to truly determine co-segregation. In addition, carrier parents of individuals with biallelic variants did not appear to be affected.

Association between biallelic variants and epilepsy stronger than for monoallelic.
Sources: Literature
Mendeliome v1.601 RIC1 Paul De Fazio reviewed gene: RIC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 36493769; Phenotypes: Cleft lip/palate MONDO:0016044, RIC1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Mendeliome v1.601 UHRF1 Zornitza Stark Phenotypes for gene: UHRF1 were changed from Multi locus imprinting disturbance in offspring to Multi locus imprinting disturbance in offspring; chromosome instability
Mendeliome v1.600 UHRF1 Zornitza Stark Publications for gene: UHRF1 were set to 29574422; 28976982
Mendeliome v1.599 UHRF1 Zornitza Stark Mode of inheritance for gene: UHRF1 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability syndromic and non-syndromic v0.5146 SLC31A1 Zornitza Stark Publications for gene: SLC31A1 were set to PMID: 35913762
Intellectual disability syndromic and non-syndromic v0.5145 SLC31A1 Zornitza Stark reviewed gene: SLC31A1: Rating: RED; Mode of pathogenicity: None; Publications: 36562171; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.598 SLC31A1 Zornitza Stark Publications for gene: SLC31A1 were set to PMID: 35913762
Mendeliome v1.597 SLC31A1 Zornitza Stark reviewed gene: SLC31A1: Rating: AMBER; Mode of pathogenicity: None; Publications: 36562171; Phenotypes: Neurodevelopmental disorder, SLC31A1-related (MONDO#0700092); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.83 SLC31A1 Zornitza Stark Marked gene: SLC31A1 as ready
Fetal anomalies v1.83 SLC31A1 Zornitza Stark Gene: slc31a1 has been classified as Amber List (Moderate Evidence).
Fetal anomalies v1.83 SLC31A1 Zornitza Stark Classified gene: SLC31A1 as Amber List (moderate evidence)
Fetal anomalies v1.83 SLC31A1 Zornitza Stark Gene: slc31a1 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.597 BSN Zornitza Stark Marked gene: BSN as ready
Mendeliome v1.597 BSN Zornitza Stark Added comment: Comment when marking as ready: We are aware of additional mono-allelic cases.
Mendeliome v1.597 BSN Zornitza Stark Gene: bsn has been classified as Green List (High Evidence).
Mendeliome v1.597 BSN Zornitza Stark Mode of inheritance for gene: BSN was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.596 BSN Zornitza Stark Classified gene: BSN as Green List (high evidence)
Mendeliome v1.596 BSN Zornitza Stark Gene: bsn has been classified as Green List (High Evidence).
Mendeliome v1.595 UHRF1 Chern Lim changed review comment from: PMID: 29574422 Begemann et al. 2018
- Het missense in mother and proband, family recruited due to detection of multilocus imprinting disturbance (MLID) in offspring. Proband is one of discordant monozygotic twin. SRS: NH-CSS 5/6; also kidney failure in infancy, bilateral renal dysplasia. Variant present in both twins, no functional studies done on the missense.; to: PMID: 29574422 Begemann et al. 2018
- Het missense in mother and proband, family recruited due to detection of multilocus imprinting disturbance (MLID) in offspring. Proband is one of discordant monozygotic twin. SRS: NH-CSS 5/6; also kidney failure in infancy, bilateral renal dysplasia. Variant present in both twins, no functional studies done on the missense. Her cotwin was clinically and epigenetically normal
Genetic Epilepsy v0.1829 BSN Zornitza Stark Marked gene: BSN as ready
Genetic Epilepsy v0.1829 BSN Zornitza Stark Added comment: Comment when marking as ready: We are aware of additional mono allelic cases.
Genetic Epilepsy v0.1829 BSN Zornitza Stark Gene: bsn has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1829 BSN Zornitza Stark Mode of inheritance for gene: BSN was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Genetic Epilepsy v0.1828 BSN Zornitza Stark Classified gene: BSN as Green List (high evidence)
Genetic Epilepsy v0.1828 BSN Zornitza Stark Gene: bsn has been classified as Green List (High Evidence).
Hereditary Neuropathy - complex v0.140 COQ7 Zornitza Stark Marked gene: COQ7 as ready
Hereditary Neuropathy - complex v0.140 COQ7 Zornitza Stark Gene: coq7 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.595 ARHGAP35 Zornitza Stark Phenotypes for gene: ARHGAP35 were changed from neurodevelopmental disorder, ARHGAP35-related MONDO#0700092 to neurodevelopmental disorder, ARHGAP35-related MONDO#0700092; Developmental defect of the eye (MONDO:0020145), ARHGAP35-related
Mendeliome v1.594 ARHGAP35 Zornitza Stark Publications for gene: ARHGAP35 were set to 33057194
Mendeliome v1.593 UHRF1 Chern Lim edited their review of gene: UHRF1: Changed publications: 36458887, 29574422; Changed phenotypes: chromosome instability, Multi locus imprinting disturbance in offspring; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v1.82 SLC31A1 Daniel Flanagan gene: SLC31A1 was added
gene: SLC31A1 was added to Fetal anomalies. Sources: Expert list
Mode of inheritance for gene: SLC31A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC31A1 were set to PMID: 35913762; 36562171
Phenotypes for gene: SLC31A1 were set to Neurodevelopmental disorder, SLC31A1-related (MONDO#0700092)
Review for gene: SLC31A1 was set to AMBER
Added comment: PMID:36562171
Homozygous c.236T>C; p.(Leu79Pro) identified in a newborn of consanguineous parents. Variant absent from gnomAD. Prenatal ultrasound showed a male fetus with short femoral bones, an apparently enlarged heart-to-thorax ratio, and a wide cisterna magna. The infant was born with pulmonary hypoplasia. At 2 weeks of age, multifocal brain hemorrhages were diagnosed and the infant developed seizures. The infant died at 1 month of age. The Mother had three healthy children while nine pregnancies had been extrauterine gravidities or ended in first or mid-trimester spontaneous abortions.

PMID: 35913762
SLC31A1 is also referred to as CTR1.
Monozygotic twins with hypotonia, global developmental delay, seizures, and rapid brain atrophy, consistent with profound central nervous system copper deficiency. Homozygous for a novel missense variant (p.(Arg95His)) in copper transporter CTR1, both parents heterozygous. A mouse knock-out model of CTR1 deficiency resulted in prenatal lethality.
Sources: Expert list
Mendeliome v1.593 ARHGEF38 Zornitza Stark Marked gene: ARHGEF38 as ready
Mendeliome v1.593 ARHGEF38 Zornitza Stark Gene: arhgef38 has been classified as Amber List (Moderate Evidence).
Mendeliome v1.593 UHRF1 Chern Lim edited their review of gene: UHRF1: Added comment: PMID: 36458887 Unoki et al. 2022
- One patient with compound het missense and nonsense variants, both parents are carriers (hets).
- The patient has chromosome instability with hypomethylation of the pericentromeric satellite-2 repeats and facial anomalies as typical symptoms of the ICF syndrome, but did not exhibit immunodeficiency, and developed an adrenocortical adenoma; characteristics that were atypical.
- Genome-wide methylation analysis revealed the patient had a centromeric/pericentromeric hypomethylation, which is the main ICF signature, but also had a distinctive hypomethylation pattern compared to patients with the other ICF syndrome subtypes.
- Structural and biochemical analyses revealed that the R296W variant disrupted the protein conformation and strengthened the binding affinity of UHRF1 with its partner LIG1, and reduced ubiquitylation activity of UHRF1 towards its ubiquitylation substrates, histone H3 and PAF15.; Changed publications: 36458887; Changed phenotypes: chromosome instability; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v1.593 ARHGEF38 Zornitza Stark Mode of inheritance for gene: ARHGEF38 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.592 ARHGEF38 Zornitza Stark Classified gene: ARHGEF38 as Amber List (moderate evidence)
Mendeliome v1.592 ARHGEF38 Zornitza Stark Gene: arhgef38 has been classified as Amber List (Moderate Evidence).
Intellectual disability syndromic and non-syndromic v0.5145 CDK16 Zornitza Stark Publications for gene: CDK16 were set to 25644381
Mendeliome v1.591 UHRF1 Chern Lim reviewed gene: UHRF1: Rating: RED; Mode of pathogenicity: None; Publications: 29574422; Phenotypes: Multi locus imprinting disturbance in offspring; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Genetic Epilepsy v0.1827 EIF4A2 Zornitza Stark Marked gene: EIF4A2 as ready
Genetic Epilepsy v0.1827 EIF4A2 Zornitza Stark Gene: eif4a2 has been classified as Green List (High Evidence).
Genetic Epilepsy v0.1827 EIF4A2 Zornitza Stark Classified gene: EIF4A2 as Green List (high evidence)
Genetic Epilepsy v0.1827 EIF4A2 Zornitza Stark Gene: eif4a2 has been classified as Green List (High Evidence).
Mendeliome v1.591 EIF4A2 Zornitza Stark Marked gene: EIF4A2 as ready
Mendeliome v1.591 EIF4A2 Zornitza Stark Gene: eif4a2 has been classified as Green List (High Evidence).
Mendeliome v1.591 EIF4A2 Zornitza Stark Classified gene: EIF4A2 as Green List (high evidence)
Mendeliome v1.591 EIF4A2 Zornitza Stark Gene: eif4a2 has been classified as Green List (High Evidence).
Intellectual disability syndromic and non-syndromic v0.5144 ZMYM3 Zornitza Stark Mode of inheritance for gene: ZMYM3 was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Mendeliome v1.590 ARHGAP35 Dean Phelan reviewed gene: ARHGAP35: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 36450800; Phenotypes: Developmental defect of the eye (MONDO:0020145), ARHGAP35-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mendeliome v1.590 SLC31A1 Alison Yeung Classified gene: SLC31A1 as Amber List (moderate evidence)
Mendeliome v1.590 SLC31A1 Alison Yeung Gene: slc31a1 has been classified as Amber List (Moderate Evidence).