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Fetal anomalies v1.234 CNOT1 Zornitza Stark edited their review of gene: CNOT1: Added comment: LIMITED by ClinGen for holoprosencephaly 12 with or without pancreatic agenesis, MONDO:0032787

ClinGen curation: CNOT1 was originally reported in cases of holoprosencephaly and/or pancreatic agenesis/insufficiency in 2019 (PMID: 31006513, 31006510). One of the papers included 3 individuals with heterozygous p.Arg535Cys (PMID: 31006513), confirmed to be de novo in 2 individuals. One of these individuals was not scored due to a lack of documentation of holoprosencephaly. The other paper included 2 individuals with de novo p.Arg535Cys, both of whom with holoprosencephaly. A knock-in mouse model of this variant showed neurological and pancreatic abnormalities at E14.5, and this evidence was used to augment the genetic evidence. A mouse brain expression study (PMID: 31006510) was scored as functional evidence. In total, there is Limited evidence to support the gene-disease relationship between CNOT1 and holoprosencephaly with or without pancreatic agenesis. Of note, this gene has also been implicated in Vissers-Bodmer syndrome, which is characterized by global developmental delay and behavioral abnormalities apparent from infancy. As the condition is clinically distinct from holoprosencephaly and/or pancreatic agenesis/insufficiency, lacks specific structural brain anomalies, and likely has different molecular mechanisms, this will be/have been assessed separately.; Changed rating: AMBER; Changed phenotypes: Holoprosencephaly 12 with or without pancreatic agenesis MONDO:0032787
Fetal anomalies v1.197 THSD1 Zornitza Stark gene: THSD1 was added
gene: THSD1 was added to Fetal anomalies. Sources: Expert Review
Mode of inheritance for gene: THSD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: THSD1 were set to 33569873; 27895300
Phenotypes for gene: THSD1 were set to Lymphatic malformation 13, MIM# 620244
Review for gene: THSD1 was set to GREEN
Added comment: PMID: 33569873 - 1 fetus with a homozygous PTC and nonimmune hydrops fetalis (NIHF), congenital heart disease and hemangiomas. FHx of 1/3 triplets with severe hydrops fetalis, not sequenced.
- Paper reviews previous NIHF cases and reports another homozygous PTC in two families ( and a recurring homozygous missense (p.Cys206Tyr) in three families.


PMID: 27895300- Mouse model has hydrocephaly with poor perfusion.
Sources: Expert Review
Fetal anomalies v1.166 PLS3 Zornitza Stark Phenotypes for gene: PLS3 were changed from Bone mineral density QTL18, osteoporosis - MIM#300910; congenital diaphragmatic hernia MONDO:0005711, PLS3-related to Bone mineral density QTL18, osteoporosis - MIM#300910; Diaphragmatic hernia 5, X-linked, MIM# 306950
Fetal anomalies v1.165 PLS3 Zornitza Stark reviewed gene: PLS3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Diaphragmatic hernia 5, X-linked, MIM# 306950; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Fetal anomalies v1.155 PLS3 Ain Roesley Phenotypes for gene: PLS3 were changed from Bone mineral density QTL18, osteoporosis - MIM#300910 to Bone mineral density QTL18, osteoporosis - MIM#300910; congenital diaphragmatic hernia MONDO:0005711, PLS3-related
Fetal anomalies v1.152 PLS3 Lauren Rogers reviewed gene: PLS3: Rating: GREEN; Mode of pathogenicity: None; Publications: 37751738; Phenotypes: congenital diaphragmatic hernia MONDO:0005711, PLS3-related; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Fetal anomalies v1.70 ATP7A Zornitza Stark changed review comment from: Well established gene-disease association, IUGR is a feature.; to: Well established gene-disease association, IUGR is a feature.

Treatment: subcutaneous injections of copper histidine or copper chloride

ClinGen has assessed as moderate evidence for actionability.

Neonatal treatment with subcutaneous copper-histidine (initiated before 30 days of life) is recommended for asymptomatic males with a diagnosis of MD, but is not recommended for symptomatic boys or after 30 days of life. Treatment should be continued indefinitely. In an open-label clinical trial, 12 patients with MD treated with copper-histidine within 22 days of life had 92% survival after a mean follow-up of 4.6 years compared to 13% in a historical control group of 15 patients treated after a late diagnosis (mean age at diagnosis: 163 ± 113 days, range: 42 to 390). Two of the 12 patients with earlier treatment had normal neurological development. A second open-label trial of 35 presymptomatic patients receiving copper-histidine at less than a month of age reported significant improvement of four major neurodevelopmental (gross motor, fine motor/adaptive, personal/social, and language) domains and a non-significant lower mortality (28.5% vs 50%) at age of 3 years (or age of death) compared to 22 patients treated later and after onset of symptoms.
Fetal anomalies v1.67 ALDH1A2 Zornitza Stark Phenotypes for gene: ALDH1A2 were changed from Multiple congenital anomalies, ALDH1A2-related, MONDO:0019042 to Diaphragmatic hernia 4, with cardiovascular defects, MIM# 620025
Fetal anomalies v1.66 ALDH1A2 Zornitza Stark reviewed gene: ALDH1A2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Diaphragmatic hernia 4, with cardiovascular defects, MIM# 620025; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.57 MDFIC Zornitza Stark Phenotypes for gene: MDFIC were changed from Hydrops fetalis MONDO:0015193 to Lymphatic malformation 12, MIM# 620014
Fetal anomalies v1.56 MDFIC Zornitza Stark reviewed gene: MDFIC: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Lymphatic malformation 12, MIM# 620014; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v1.41 WNT7B Zornitza Stark gene: WNT7B was added
gene: WNT7B was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: WNT7B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WNT7B were set to 35790350
Phenotypes for gene: WNT7B were set to Pulmonary hypoplasia, Diaphragmatic anomalies, Anophthalmia/microphthalmia and Cardiac defects syndrome; Multiple congenital anomalies/dysmorphic features syndrome MONDO:0043005, WNT7B-related
Review for gene: WNT7B was set to GREEN
Added comment: Three families reported with fetuses with multiple congenital anomalies and bi-allelic LoF variants. Two of the families had at the same variant. Supportive zebrafish model.
Sources: Literature
Fetal anomalies v1.15 MDFIC Belinda Chong gene: MDFIC was added
gene: MDFIC was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: MDFIC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MDFIC were set to 35235341
Phenotypes for gene: MDFIC were set to Hydrops fetalis MONDO:0015193
Review for gene: MDFIC was set to GREEN
Added comment: Central conducting lymphatic anomaly (CCLA), characterized by the dysfunction of core collecting lymphatic vessels including the thoracic duct and cisterna chyli, and presenting as chylothorax, pleural effusions, chylous ascites, and lymphedema, is a severe disorder often resulting in fetal or perinatal demise.

Seven individuals with CCLA from six independent families. Clinical manifestations of affected fetuses and children included nonimmune hydrops fetalis (NIHF), pleural and pericardial effusions, and lymphedema. Generation of a mouse model of human MDFIC truncation variants revealed that homozygous mutant mice died perinatally exhibiting chylothorax.
Sources: Literature
Fetal anomalies v0.4682 ANGPT2 Alison Yeung Phenotypes for gene: ANGPT2 were changed from Hydrops; Lymphatic malformation-10, MIM#619369 to Hydrops fetalis, MONDO:0015193; Lymphatic malformation-10, MIM#619369
Fetal anomalies v0.4681 ALDH1A2 Alison Yeung Phenotypes for gene: ALDH1A2 were changed from Congenital heart defects; diaphragmatic eventration; pulmonary hypoplasia; thymus aplasia to Multiple congenital anomalies, ALDH1A2-related, MONDO:0019042
Fetal anomalies v0.4658 NPHP3 Zornitza Stark Phenotypes for gene: NPHP3 were changed from RENAL-HEPATIC-PANCREATIC DYSPLASIA; NEPHRONOPHTHISIS TYPE 3; MECKEL SYNDROME TYPE 7 to Meckel syndrome 7, MIM# 267010; Nephronophthisis 3, MIM# 604387; Renal-hepatic-pancreatic dysplasia 1, MIM# 208540
Fetal anomalies v0.4656 NPHP3 Zornitza Stark edited their review of gene: NPHP3: Changed phenotypes: Meckel syndrome 7, MIM# 267010, Nephronophthisis 3, MIM# 604387, Renal-hepatic-pancreatic dysplasia 1, MIM# 208540
Fetal anomalies v0.4575 PIK3CA Zornitza Stark Phenotypes for gene: PIK3CA were changed from CLOVES: CONGENITAL LIPOMATOUS OVERGROWTH, VASCULAR MALFORMATIONS, AND EPIDERMAL NEVI; HEMIMEGALENCEPHALY PIK3CA; MEGALENCEPHALY-CAPILLARY MALFORMATION-POLYMICROGYRIA SYNDROME, SOMATIC 3 to Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2, MIM# 615937
Fetal anomalies v0.4563 PKHD1 Zornitza Stark Phenotypes for gene: PKHD1 were changed from POLYCYSTIC KIDNEY DISEASE, AUTOSOMAL RECESSIVE to Polycystic kidney disease 4, with or without hepatic disease, MIM# 263200
Fetal anomalies v0.4532 PSAP Zornitza Stark Phenotypes for gene: PSAP were changed from Combined SAP deficiency, MIM# 611721; Encephalopathy due to prosaposin deficiency, MONDO:0012719; Krabbe disease, atypical, MIM# 611722, MONDO:0012720; Metachromatic leukodystrophy due to SAP-b deficiency, MIM# 249900, MONDO:0009590; Gaucher disease, atypical, MIM# 610539, MONDO:0012517 to Combined SAP deficiency, MIM# 611721
Fetal anomalies v0.4490 RARB Zornitza Stark Phenotypes for gene: RARB were changed from MICROPHTHALMIA AND DIAPHRAGMATIC HERNIA to Microphthalmia, syndromic 12, MIM# 615524
Fetal anomalies v0.4478 PSAP Seb Lunke Phenotypes for gene: PSAP were changed from ATYPICAL KRABBE DISEASE to Combined SAP deficiency, MIM# 611721; Encephalopathy due to prosaposin deficiency, MONDO:0012719; Krabbe disease, atypical, MIM# 611722, MONDO:0012720; Metachromatic leukodystrophy due to SAP-b deficiency, MIM# 249900, MONDO:0009590; Gaucher disease, atypical, MIM# 610539, MONDO:0012517
Fetal anomalies v0.4476 PSAP Seb Lunke reviewed gene: PSAP: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Combined SAP deficiency, MIM# 611721, Encephalopathy due to prosaposin deficiency, MONDO:0012719, Krabbe disease, atypical, MIM# 611722, MONDO:0012720, Metachromatic leukodystrophy due to SAP-b deficiency, MIM# 249900, MONDO:0009590, Gaucher disease, atypical, MIM# 610539, MONDO:0012517 Edit; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.4404 RHEB Krithika Murali gene: RHEB was added
gene: RHEB was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: RHEB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RHEB were set to 29051493; 31337748
Phenotypes for gene: RHEB were set to Intellectual disability; Macrocephaly; Focal cortical dysplasia
Review for gene: RHEB was set to GREEN
Added comment: No new publications since last PanelApp review. Reviewed PMID: 29051493 supplementary information - three individuals with short stature and macrocephaly. Limited antenatal information provided/birth HC parameters, but one of the affected individuals was noted to have a large head circumference from 20 weeks gestation. PMID 31337748: Somatic variant in this gene found in one individual with focal cortical dysplasia.

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3 individuals from two families with heterozygous RHEB variants. Two siblings carried the c.110 C > T (p.Pro37Leu) variant, and a sporadic individual carried the c.202 T>C (p.Ser68Pro) allele. All 3 individuals had short stature (−2 to −3 SD) and early brain overgrowth with pronounced macrocephaly during childhood (+2.5/+3 SD). They had severe to profound ID with hypotonia, as well as autism spectrum disorder. 2 of 3 individuals were reported to have epilepsy. In a zebrafish model, overexpression of RHEB produced megalencephaly, supporting a hyperactivating effect. This is supported in mice where loss of RHEB activity does not cause an overt neurological phenotype
Single individual with somatic variants in this gene and focal cortical dysplasia also reported.
Sources: Literature
Fetal anomalies v0.4355 SMO Zornitza Stark edited their review of gene: SMO: Added comment: Bi-allelic loss-of-function variations in SMO reported in seven individuals from five independent families. Wide phenotypic spectrum of developmental anomalies affecting the brain (hypothalamic hamartoma and microcephaly), heart (atrioventricular septal defect), skeleton (postaxial polydactyly, narrow chest, and shortening of long bones), and enteric nervous system (aganglionosis).
Somatic recurrent missense variant, L412F causes Curry-Jones syndrome.; Changed publications: 32413283, 27236920; Changed phenotypes: Microcephaly, congenital heart disease, polydactyly, aganglionosis, Pallister-Hall-like syndrome, MIM# 241800; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v0.4355 SMO Zornitza Stark Phenotypes for gene: SMO were changed from Curry-Jones Syndrome to Curry-Jones syndrome, somatic mosaic, MIM#601707
Fetal anomalies v0.4273 DICER1 Krithika Murali gene: DICER1 was added
gene: DICER1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: DICER1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: DICER1 were set to 27960159; 29343557; 26227654; 33208384; 35114704; 31232238; 24676357
Phenotypes for gene: DICER1 were set to GLOW syndrome, somatic mosaic - MIM#618272; Goiter, multinodular 1, with or without Sertoli-Leydig cell tumors - MIM#138800; Pleuropulmonary blastoma - MIM#601200
Review for gene: DICER1 was set to GREEN
Added comment: Heterozygous pathogenic germline DICER1 variants are associated with pleuropulmonary blastoma, multinodular goiter, embryonal rhabdomyosarcoma and other tumour types, while mosaic somatic missense DICER1 variants in the RNase IIIb domain are linked to GLOW syndrome (global developmental delay, lung cysts, overgrowth, and Wilms’ tumor) syndrome. While the DICER1 syndrome is classically caused by frameshift, nonsense or other mutations that ablate DICER1 function in a true heterozygous state, GLOW-syndrome mutations occur at specific residues within the RNase IIIb domain that only affect the function of this domain.

Both syndromes have been reported to have features that can be detected prenatally.

PMID 33208384 - report a patient with heterozygous germline DICER1 variant. The patient was born at gestational week 39 after a difficult delivery due to macrocephaly. Clinical findings at birth included two blood vessels in the umbilical cord, undescended testis, inguinal hernia, postaxial polydactyly, ear pits and rocker bottom feet.

PMID: 34331184 - report 4 unrelated families with germline DICER1 variants. In family 1 - one child was born with Pierre Robin sequence, shortening of the left arm and leg and bilateral
hip dysplasia. In Family 2 a child had macrosomia and macrocephaly at birth. Family 4 - born at 33 weeks, dysmorphic facies including hypertelorism and macroglossia.

PMID 24676357 - report 2 unrelated children with GLOW syndrome. Patient 1 was noted to have enlarged kidneys on 24 week ultrasound. At birth was found to have renal and pulmonary cysts. Patient 2 - macrocephaly was noted at birth.

DICER1 implicated in ~60% of PPB - reports of PPB detecteed antenatally, although no reports in the context of confirmed DICER1 syndrome.
Sources: Literature
Fetal anomalies v0.4229 MYRF Alison Yeung Phenotypes for gene: MYRF were changed from Congenital diaphragmatic hernia (CDH); Cardiac-urogenital syndrome, 618280; Disorders of sex development (DSD) to Cardiac-urogenital syndrome, MIM# 618280
Fetal anomalies v0.4132 FERMT3 Krithika Murali gene: FERMT3 was added
gene: FERMT3 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: FERMT3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FERMT3 were set to 31068971; 34485203; 33391282; 31724816; 30412664; 25854317; 28095295; 26359933; 25072369; 22134107; 20216991; 19234463; 19234460; 18779414
Phenotypes for gene: FERMT3 were set to Leukocyte adhesion deficiency, type III - MIM#612840
Review for gene: FERMT3 was set to RED
Added comment: Biallelic variants associated with LAD3 syndrome (primary immunodeficiency and platelet function defects). Symptom onset reported from birth, no antenatal features reported.

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PMID: 34485203 Yahya et al 2021 - no antenatal issues reported

PMID: 33391282 Kambli et al 2020 - no antenatal features reported for 5 individuals with LAD3

PMID 31068971 Shahid et al 2019 - no antenatal features

PMID: 31724816 Manukjan et al 2019 - no antenatal issues reported in 1 affected individual

PMID: 28095295 Palagano et al 2017 - report female proband with infantile-onset osteopetrosis and symptomatic haematological anomalies at birth requiring bone marrow transplant. Authors postulate in utero onset but no antenatal features reported.

PMID: 26359933 Suratannon et al 2016 - report a female Thai proband with a milder/atypical phenotype, no antenatal features reported

PMID: 25854317 Crazzolara et al 2015 - presented D7 of life with infection, bleeeding issues and noted radiologically to have dense bones. No antenatal features.

PMID: 25072369 Stepensky et al 2015 - report 3 individuals with bleeding tendency from birth and onset of recurrent infections as an infant, normal antenatal history.

PMID: 20357244 McDowall et al 2010 - symptom onset from birth, no antenatal features

PMID: 20216991 Jurk et al 2010 - 2 affected siblings, no antenatal features reported.

PMID: 19234463 Svensson et al 2009 - no antenatal features reported

PMID: 19234460 Malinin et al 2009 - no antenatal features reported

PMID: 19064721 Kuijpers et al 2009 - 9 individuals from 7 unrelated families, no antenatal features reported.
Sources: Literature
Fetal anomalies v0.3908 PLOD3 Krithika Murali gene: PLOD3 was added
gene: PLOD3 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: PLOD3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLOD3 were set to 30237576; 18834968
Phenotypes for gene: PLOD3 were set to Lysyl hydroxylase 3 deficiency - MIM#612394
Review for gene: PLOD3 was set to GREEN
Added comment: 4 unrelated families reported with biallelic PLOD3 variants and Stickler-syndrome like phenotype including antenatal phenotype of IUGR in one family.
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PMID 30237576 Maddirevula et al 2019 - report homozygous nonsense variant in a proband with dysmorphic facies, microcephaly, ptosis and contractures. No antenatal information provided.

PMID 31129566 Ewans et al 2019 - report 3 affected siblings with a Stickler-syndrome like disorder.
- Patient 1 had congenital nystagmus and presented with hearing loss and myopia. On examination aged 2, noted to have dysmorphic features - prominent eyes, hypertelorism, malar hypoplasia, an upturned nose, low-set ears and microretrognathia.
- Patient 2 noted to have camptodactyly and clinodactyly postnatally. On examination age 5 noted to have DIP joint contractures and mild skin syndactyly.
- Patient 3 - breech delivery. bilateral hand foot camptodactyly, facial dysmorphism.
- No antenatal features reported.

PMID 30463024 Vahidnehzad et al 2019 - report a male proband from a consanguineous Iranian Baloch family referred for assessment age 4.5. Noted to have developmental delay, musculoskeletal manifestations including scoliosis, flexion contractions, cutaneous syndactyly, right diaphragmatic eventration, ocular anomalies, growth failure and skin blisters. No concerns antenatally. Postnatally noted to have cataract and facial dysmorphism (midface hypoplasia). Homozygous PLOD3 missense variant identified, parents unaffected carriers. PLOD3 mRNA levels in the patient’s fibroblasts measured by whole-transcriptome sequencing and confirmed by RT-PCR, were the same as in control cells, however, the expression of type VII collagen was reduced significantly. No antenatal features reported.

PMID: 18834968 Salo et al 2008 - a female proband with significant IUGR, characteristic craniofacial profile, diaphragm eventration, skeletal anomalies (bilateral talipes equinovarus, flexion contractures, scoliosis from age 7), skin anomalies incl blistering and ocular anomalies. One 28 week male stillborn sibling noted to have significant IUGR and skeletal anomalies on post-mortem. Supportive functional evidence. Compound het PLOD3 variants.
Sources: Literature
Fetal anomalies v0.3891 PTF1A Zornitza Stark Phenotypes for gene: PTF1A were changed from PANCREATIC AGENESIS; DIABETES MELLITUS, PERMANENT NEONATAL, WITH CEREBELLAR AGENESIS to Pancreatic and cerebellar agenesis, MIM# 609069
Fetal anomalies v0.3889 PTF1A Zornitza Stark reviewed gene: PTF1A: Rating: GREEN; Mode of pathogenicity: None; Publications: 21749365, 10507728, 15543146, 19650412; Phenotypes: Pancreatic and cerebellar agenesis, MIM# 609069; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.3806 PIEZO1 Zornitza Stark Phenotypes for gene: PIEZO1 were changed from Congenital lymphatic dysplasia with hydrops and/or lymphoedema; hydrops fetalis gene 616843 to Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema, OMIM #194380; Lymphatic malformation 6, OMIM #616843
Fetal anomalies v0.3726 PIEZO1 Chirag Patel reviewed gene: PIEZO1: Rating: GREEN; Mode of pathogenicity: None; Publications: PubMed: 26333996, 23479567, 23695678; Phenotypes: Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema, OMIM #194380, Lymphatic malformation 6, OMIM #616843; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v0.3501 NEK8 Zornitza Stark Phenotypes for gene: NEK8 were changed from Renal-hepatic-pancreatic dysplasia 2, MONDO:0014174; Renal-hepatic-pancreatic dysplasia 2, OMIM:615415; ?Nephronophthisis 9, OMIM:613824; Nephronophthisis 9, MONDO:0013444 to Renal-hepatic-pancreatic dysplasia 2, MONDO:0014174; Renal-hepatic-pancreatic dysplasia 2, OMIM:615415; Nephronophthisis 9, OMIM:613824; Nephronophthisis 9, MONDO:0013444
Fetal anomalies v0.3400 LTBP1 Krithika Murali gene: LTBP1 was added
gene: LTBP1 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: LTBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LTBP1 were set to 33991472
Phenotypes for gene: LTBP1 were set to Cutis laxa, autosomal recessive, type IIE - MIM#619451
Review for gene: LTBP1 was set to GREEN
Added comment: Homozygous premature truncating LTBP1 variants in eight affected individuals from four unrelated consanguineous families reported associated with autosomal recessive cutis laxa type IIE. Phenotypic features relevant in the prenatal setting include:
- Congenital diaphragmatic hernia (1 individual)
- Cleft palate (2 individuals)
- Congenital heart defects
- Renal anomalies (1 individual)
- Microretrognathia (1 individual)
- Hydrocephalus (1 individual)
- Skeletal anomalies (craniosynostosis, short stature, brachydactyly, and syndactyly).

Supportive patient-derived fibroblast and zebrafish studies.
Sources: Literature
Fetal anomalies v0.3400 DDC Belinda Chong reviewed gene: DDC: Rating: RED; Mode of pathogenicity: None; Publications: 20505134, 33528536, 30799092, 33996177; Phenotypes: Aromatic L-amino acid decarboxylase deficiency MIM#608643; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.3380 MN1 Zornitza Stark changed review comment from: Over 20 individuals described with de novo truncating variants in this gene; these cluster in the C-terminal and the authors postulate that that syndrome is not due to MN1 haploinsufficiency but rather is the result of dominantly acting C-terminally truncated MN1 protein.
Sources: Literature; to: Over 20 individuals described with de novo truncating variants in this gene; these cluster in the C-terminal and the authors postulate that that syndrome is not due to MN1 haploinsufficiency but rather is the result of dominantly acting C-terminally truncated MN1 protein.

Diaphragmatic hernia, craniosynostosis and brain abnormalities reported.

Sources: Literature
Fetal anomalies v0.3372 SP110 Daniel Flanagan reviewed gene: SP110: Rating: RED; Mode of pathogenicity: None; Publications: 20301448, 31721003; Phenotypes: Hepatic venoocclusive disease with immunodeficiency (MIM#235550); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.3330 NEXMIF Zornitza Stark changed review comment from: Females have been described as both asymptomatic carriers or affected. Given only PTCs have been reported, there is no genotype-phenotype correlation. OMIM describes that a phenotype manifests depending on X-inactivation skewing No reported pathogenic missense to date except for the one LP hemizygous in DDD that is maternally inherited (Decipher) Compared with its hemizygous male counterpart, the heterozygous female disease has less severe intellectual disability, but is more often associated with a severe and intractable myoclonic epilepsy.; to: Females have been described as both asymptomatic carriers or affected. Given only PTCs have been reported, there is no genotype-phenotype correlation. OMIM describes that a phenotype manifests depending on X-inactivation skewing No reported pathogenic missense to date except for the one LP hemizygous in DDD that is maternally inherited (Decipher) Compared with its hemizygous male counterpart, the heterozygous female disease has less severe intellectual disability, but is more often associated with a severe and intractable myoclonic epilepsy.

Typically presents post-natally.
Fetal anomalies v0.3232 GNAQ Zornitza Stark Phenotypes for gene: GNAQ were changed from Congenital Hemangioma to Sturge-Weber syndrome, somatic, mosaic, MIM#185300
Fetal anomalies v0.3229 GNAQ Zornitza Stark changed review comment from: ID can be part of the phenotype; however this condition is due to somatic mosaic gain of function variants so there may be issues with detection depending on tissue used and sequencing depth.; to: This condition is due to somatic mosaic gain of function variants so there may be issues with detection depending on tissue used and sequencing depth.
Fetal anomalies v0.2728 SHMT2 Krithika Murali gene: SHMT2 was added
gene: SHMT2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: SHMT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SHMT2 were set to 33015733
Phenotypes for gene: SHMT2 were set to Polymicrogyria; corpus callosum anomalies; Microcephaly; Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities - #619121
Review for gene: SHMT2 was set to GREEN
Added comment: Neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities particularly thin corpus callosum and polymicrogyria (NEDCASB) associated with biallelic SHMT2 variants. Antenatal detection of microcephaly reported.

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Detailed PanelApp review Oct 2020 - no new evidence to add

García‑Cazorla et al. (2020 - PMID: 33015733) report 5 individuals (from 4 families) with a novel brain and heart developmental syndrome caused by biallelic SHMT2 pathogenic variants.

All affected subjects presented similar phenotype incl. microcephaly at birth (5/5 with OFC < -2 SD though in 2/5 cases N OFC was observed later), DD and ID (1/5 mild-moderate, 1/5 moderate, 3/5 severe), motor dysfunction in the form of spastic (5/5) paraparesis, ataxia/dysmetria (3/4), intention tremor (in 3/?) and/or peripheral neuropathy (2 sibs). They exhibited corpus callosum hypoplasia (5/5) and perisylvian microgyria-like pattern (4/5). Cardiac problems were reported in all, with hypertrophic cardiomyopathy in 4/5 (from 3 families) and atrial-SD in the 5th individual (1/5). Common dysmorphic features incl. long palpebral/fissures, eversion of lateral third of lower eylids, arched eyebrows, long eyelashes, thin upper lip, short Vth finger, fetal pads, mild 2-3 toe syndactyly, proximally placed thumbs.

Biallelic variants were identified following exome sequencing in all (other investigations not mentioned). Identified variants were in all cases missense SNVs or in-frame del, which together with evidence from population databases and mouse model might suggest a hypomorphic effect of variants and intolerance/embryonic lethality for homozygous LoF ones.

SHMT2 encodes the mitohondrial form of serine hydroxymethyltransferase. The enzyme transfers one-carbon units from serine to tetrahydrofolate (THF) and generates glycine and 5,10,methylene-THF.

Mitochondrial defect was suggested by presence of ragged red fibers in myocardial biopsy of one patient. Quadriceps and myocardial biopsies of the same individual were overall suggestive of myopathic changes.

While plasma metabolites were within N range and SHMT2 protein levels not significantly altered in patient fibroblasts, the authors provide evidence for impaired enzymatic function eg. presence of the SHMT2 substrate (THF) in patient but not control (mitochondria-enriched) fibroblasts , decrease in glycine/serine ratios, impared folate metabolism. Patient fibroblasts displayed impaired oxidative capacity (reduced ATP levels in a medium without glucose, diminished oxygen consumption rates). Mitochondrial membrane potential and ROS levels were also suggestive of redox malfunction.

Shmt2 ko in mice was previously shown to be embryonically lethal attributed to severe mitochondrial respiration defects, although there was no observed brain metabolic defect.

The authors performed Shmt2 knockdown in motoneurons in Drosophila, demonstrating neuromuscular junction (# of satellite boutons) and motility defects (climbing distance/velocity).
Sources: Literature
Fetal anomalies v0.2711 ANGPT2 Zornitza Stark gene: ANGPT2 was added
gene: ANGPT2 was added to Fetal anomalies. Sources: Literature
Mode of inheritance for gene: ANGPT2 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Publications for gene: ANGPT2 were set to 34876502; 32908006
Phenotypes for gene: ANGPT2 were set to Hydrops; Lymphatic malformation-10, MIM#619369
Review for gene: ANGPT2 was set to GREEN
Added comment: Mono-allelic disease: association with lymphoedema in 5 unrelated individuals PMID 32908006

Bi-allelic disease PMID 34876502: single family reported with four fetuses with hydrops fetalis homozygous for ANGPT2 NM_001147.2:c.557A>G. The consanguineous parents and surviving sibblings (a girl and a boy), were heterozygous for this variant. This variant is predicted to create a cryptic exonic splice site, resulting in a r.557_566del and nonsense-mediated mRNA decay. This prediction was supported by the lack of a transcript from this allele in the parents.
Sources: Literature
Fetal anomalies v0.2525 VEGFC Zornitza Stark Phenotypes for gene: VEGFC were changed from Lymphatic malformation 4 to Lymphatic malformation 4, MIM# 615907
Fetal anomalies v0.2522 VEGFC Zornitza Stark reviewed gene: VEGFC: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Lymphatic malformation 4, MIM# 615907; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v0.2352 MYOD1 Ain Roesley reviewed gene: MYOD1: Rating: GREEN; Mode of pathogenicity: None; Publications: 26733463, 30403323, 31260566; Phenotypes: Myopathy, congenital, with diaphragmatic defects, respiratory insufficiency, and dysmorphic facies MIM#618975; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Fetal anomalies v0.2255 HUWE1 Zornitza Stark changed review comment from: Females variably affected, ranging from asymptomatic carriers to fully manifesting the condition (particularly with de novo variants).; to: IUGR, joint contractures, microcephaly/macrocephaly are features.
Fetal anomalies v0.2242 HDAC8 Zornitza Stark changed review comment from: In a recent series of 246 individuals from diverse populations, congenital diaphragmatic hernia was not a common feature of HDAC8-related CdL.; to: Multiple congenital anomalies are a feature.
Fetal anomalies v0.2239 HCCS Zornitza Stark changed review comment from: Diaphragmatic hernia is a recognised feature.; to: Multiple congenital anomalies.
Fetal anomalies v0.1900 SLC25A20 Zornitza Stark changed review comment from: Clinical features include neurologic abnormalities, cardiomyopathy and arrhythmias, skeletal muscle damage, and liver dysfunction. Most patients become symptomatic in the neonatal period with a rapidly progressive deterioration and a high mortality rate.; to: Clinical features include neurologic abnormalities, cardiomyopathy and arrhythmias, skeletal muscle damage, and liver dysfunction. Most patients become symptomatic in the neonatal period with a rapidly progressive deterioration and a high mortality rate.

Unclear if can present antenatally.
Fetal anomalies v0.1900 SLC25A20 Zornitza Stark edited their review of gene: SLC25A20: Added comment: Clinical features include neurologic abnormalities, cardiomyopathy and arrhythmias, skeletal muscle damage, and liver dysfunction. Most patients become symptomatic in the neonatal period with a rapidly progressive deterioration and a high mortality rate.; Changed rating: GREEN
Fetal anomalies v0.1833 GATA6 Zornitza Stark Phenotypes for gene: GATA6 were changed from ATRIOVENTRICULAR SEPTAL DEFECT 5; PANCREATIC AGENESIS, DIAPHRAGMATIC HERNIA AND CONGENITAL HEART DEFECTS; ATRIAL SEPTAL DEFECT 9 to Pancreatic agenesis and congenital heart defects, MIM# 600001
Fetal anomalies v0.1771 GNA11 Zornitza Stark changed review comment from: Post-natal presentation.; to: Post-natal presentation for calcium disorders.

Somatic variants present in cutaneous haemangiomas, which can be of perinatal onset.
Fetal anomalies v0.1641 ATP8B1 Zornitza Stark Phenotypes for gene: ATP8B1 were changed from ATP8B1-RELATED INTRAHEPATIC CHOLESTASIS to Cholestasis, progressive familial intrahepatic 1, MIM# 211600
Fetal anomalies v0.1640 ATP8B1 Zornitza Stark reviewed gene: ATP8B1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cholestasis, progressive familial intrahepatic 1, MIM# 211600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.1611 ALAD Zornitza Stark Phenotypes for gene: ALAD were changed from ACUTE HEPATIC PORPHYRIA to Porphyria, acute hepatic , MIM#612740
Fetal anomalies v0.1610 ALAD Zornitza Stark reviewed gene: ALAD: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Porphyria, acute hepatic , MIM#612740; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.1608 FLT4 Zornitza Stark Phenotypes for gene: FLT4 were changed from MILROY DISEASE to Congenital heart defects, multiple types, 7, MIM# 618780; Lymphatic malformation 1, MIM# 153100
Fetal anomalies v0.1605 FLT4 Zornitza Stark reviewed gene: FLT4: Rating: GREEN; Mode of pathogenicity: None; Publications: 9817924, 10835628, 12960217; Phenotypes: Lymphatic malformation 1, MIM# 153100; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v0.1442 ABCB11 Zornitza Stark Phenotypes for gene: ABCB11 were changed from ABCB11-RELATED INTRAHEPATIC CHOLESTASIS to Cholestasis, benign recurrent intrahepatic, 2, MIM# 605479 AR Cholestasis, progressive familial intrahepatic 2, MIM# 601847 AR
Fetal anomalies v0.1441 ABCB11 Zornitza Stark reviewed gene: ABCB11: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cholestasis, benign recurrent intrahepatic, 2, MIM# 605479 AR Cholestasis, progressive familial intrahepatic 2, MIM# 601847 AR; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.1441 DCDC2 Zornitza Stark Phenotypes for gene: DCDC2 were changed from RENAL-HEPATIC CILIOPATHY to Nephronophthisis 19, MIM# 616217
Fetal anomalies v0.1361 ALDH1A2 Krithika Murali gene: ALDH1A2 was added
gene: ALDH1A2 was added to Fetal anomalies. Sources: Expert list,Literature
Mode of inheritance for gene: ALDH1A2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALDH1A2 were set to 33565183; 19886994; 10192400
Phenotypes for gene: ALDH1A2 were set to Congenital heart defects; diaphragmatic eventration; pulmonary hypoplasia; thymus aplasia
Review for gene: ALDH1A2 was set to GREEN
Added comment: Biallellic variants in two unrelated, non-consanguineous families associated with multiple anomalies - including congenital heart disease, eventration of the diaphragm/diaphragmatic hernia, pulmonary hypoplasia dysmorphic features, thymus aplasia - a number of which were detected antenatally. Functional assays suggest the variants in the 2 families are hypomorphic. Knockout mouse model is embryonic lethal due to in utero defects in early heart morphogenesis.
Sources: Expert list, Literature
Fetal anomalies v0.1232 EFNB1 Zornitza Stark Phenotypes for gene: EFNB1 were changed from CRANIOFRONTONASAL SYNDROME to Craniofrontonasal dysplasia, MIM# 304110; Diaphragmatic hernia
Fetal anomalies v0.1220 CHRNA3 Zornitza Stark changed review comment from: Five individuals from three unrelated families.; to: Five individuals from three unrelated families.

Onset is in utero or early childhood.

Affected individuals have impaired neuronal bladder and ureteral innervation causing coordination defects that result in secondary structural defects of the renal system, including hydronephrosis, vesicoureteral reflux (VUR), and small kidneys, that may result in chronic kidney disease as well as recurrent urinary tract infections (UTIs). Surgical treatment of VUR is not effective. Most individuals also have additional autonomic features, most commonly impaired pupillary reflex and sometimes orthostatic hypotension.
Fetal anomalies v0.1193 CELSR1 Zornitza Stark Phenotypes for gene: CELSR1 were changed from Lymphatic malformation 9, OMIM:619319 to Lymphatic malformation 9, MIM# 619319
Fetal anomalies v0.1189 CELSR1 Zornitza Stark reviewed gene: CELSR1: Rating: RED; Mode of pathogenicity: None; Publications: 31215153, 31403174, 26855770; Phenotypes: Lymphatic malformation 9, MIM# 619319; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v0.1026 EPHB4 Seb Lunke Phenotypes for gene: EPHB4 were changed from hydrops fetalis gene to Capillary malformation-arteriovenous malformation 2 (MIM#618196), AD; Lymphatic malformation 7 (MIM#617300), AD; hydrops fetalis
Fetal anomalies v0.957 EPHB4 Belinda Chong reviewed gene: EPHB4: Rating: GREEN; Mode of pathogenicity: None; Publications: 27400125, 28687708, 29444212, 29905864, 30578106, 30819650; Phenotypes: Capillary malformation-arteriovenous malformation 2 (MIM#618196), AD, Lymphatic malformation 7 (MIM#617300), AD; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Fetal anomalies v0.903 ZFPM2 Zornitza Stark Phenotypes for gene: ZFPM2 were changed from 46XY sex reversal 9 - MIM# 616067; Diaphragmatic hernia 3 - MIM#610187; Tetralogy of Fallot - MIM# 187500 to Diaphragmatic hernia 3 - MIM#610187; Tetralogy of Fallot - MIM# 187500
Fetal anomalies v0.902 ZFPM2 Zornitza Stark reviewed gene: ZFPM2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Diaphragmatic hernia 3 - MIM#610187, Tetralogy of Fallot - MIM# 187500; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v0.886 ZFPM2 Krithika Murali gene: ZFPM2 was added
gene: ZFPM2 was added to Fetal anomalies. Sources: Expert list,Literature
Mode of inheritance for gene: ZFPM2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZFPM2 were set to 16103912; 17568391; 24702427; 10892744; 21919901; 14517948
Phenotypes for gene: ZFPM2 were set to 46XY sex reversal 9 - MIM# 616067; Diaphragmatic hernia 3 - MIM#610187; Tetralogy of Fallot - MIM# 187500
Review for gene: ZFPM2 was set to GREEN
Added comment: Associated with congenital diaphragmatic hernia, congenital heart disease and sex reversal.
Sources: Expert list, Literature
Fetal anomalies v0.886 SLIT3 Krithika Murali gene: SLIT3 was added
gene: SLIT3 was added to Fetal anomalies. Sources: Expert list,Literature
Mode of inheritance for gene: SLIT3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLIT3 were set to 33933663
Phenotypes for gene: SLIT3 were set to Congenital diaphragmatic hernia
Review for gene: SLIT3 was set to AMBER
Added comment: Two affected individuals, single family, supportive mouse model.
Sources: Expert list, Literature
Fetal anomalies v0.832 ALG9 Zornitza Stark changed review comment from: 11 patients from 7 families reported. DD/ID is part of the phenotype.; to: Bi-allelic variants and CDG: At least 7 unrelated families reported, 11 individuals. Clinical features include failure to thrive, dysmorphic features, seizures, hepatic and/or renal cysts; three patients died in utero from a lethal skeletal dysplasia. The severe end of the spectrum is referred to as Gillessen-Kaesbach-Nishimura syndrome and is characterised by skeletal dysplasia, dysmorphic facial features, and variable visceral abnormalities, including polycystic kidneys, diaphragmatic hernia, lung hypoplasia, and congenital heart defects. It may be lethal in utero or early in life.
Fetal anomalies v0.829 ALG2 Zornitza Stark edited their review of gene: ALG2: Added comment: Association with myasthenia: Two families reported, same, likely founder variant. Onset of symptoms was in infancy rather than congenital.

Association with CDG: one individual with multisystemic disorder with ID, seizures, coloboma of the iris, hypomyelination, hepatomegaly, and coagulation abnormalities reported in PMID 12684507. Fibroblasts showed severely reduced enzymatic activity.; Changed publications: 23404334, 24461433, 12684507
Fetal anomalies v0.763 AASS Zornitza Stark changed review comment from: Hyperlysinemia type I is an autosomal recessive metabolic condition with variable clinical features. Some patients who present in infancy with nonspecific seizures, hypotonia, or mildly delayed psychomotor development have been found to have increased serum lysine and pipecolic acid on laboratory analysis. However, about 50% of probands are reported to be asymptomatic. Given the broad range of clinical features and the presence of consanguinity in several families, there was not strong evidence for causality of symptoms. It has been suggested that hyperlysinemia is a benign metabolic variant rather than a disease entity.; to: Hyperlysinemia type I is an autosomal recessive metabolic condition with variable clinical features. Some patients who present in infancy with nonspecific seizures, hypotonia, or mildly delayed psychomotor development have been found to have increased serum lysine and pipecolic acid on laboratory analysis. However, about 50% of probands are reported to be asymptomatic. Given the broad range of clinical features and the presence of consanguinity in several families, there was not strong evidence for causality of symptoms. It has been suggested that hyperlysinemia is a benign metabolic variant rather than a disease entity.

Given the uncertainty about whether this is a disease entity and lack of associated congenital anomalies or other features that would be detectable in the prenatal setting, downgraded to RED on this panel.
Fetal anomalies v0.605 CPT2 Zornitza Stark Phenotypes for gene: CPT2 were changed from Myopathy due to CPT II deficiency 255110; CPT II deficiency, lethal neonatal 608836; CPT deficiency, hepatic, type II 600649 to CPT II deficiency, lethal neonatal, MIM# 608836
Fetal anomalies v0.587 MMP13 Daniel Flanagan changed review comment from: At least 7 families described with either mono or biallelic variants reports.
Autosomal dominant metaphyseal anadysplasia has been described as more severe, with dominant-negative missense mutations in the prodomain of MMP13 that determine autoactivation of MMP13 and intracellular degradation of both MMP13 and MMP9, resulting in a double enzymatic deficiency. Recessive metaphyseal anadysplasia has been described as a milder form, caused by biallelic loss of function of either MMP9 or MMP13.; to: At least 7 families described with either mono (Metaphyseal anadysplasia) or biallelic (Metaphyseal dysplasia, Spahr type) variants reports.
Autosomal dominant metaphyseal anadysplasia has been described as more severe, with dominant-negative missense mutations in the prodomain of MMP13 that determine autoactivation of MMP13 and intracellular degradation of both MMP13 and MMP9, resulting in a double enzymatic deficiency. Recessive metaphyseal anadysplasia has been described as a milder form, caused by biallelic loss of function of either MMP9 or MMP13.
Fetal anomalies v0.525 CNOT1 Zornitza Stark Phenotypes for gene: CNOT1 were changed from Holoprosencephaly 12, with or without pancreatic agenesis, 618500 to Holoprosencephaly 12, with or without pancreatic agenesis, 618500; Vissers-Bodmer syndrome, MIM#619033
Fetal anomalies v0.295 BCAP31 Zornitza Stark changed review comment from: More than 20 unrelated families reported. Clinical features include severe intellectual disability (ID), dystonia, deafness, and central hypomyelination. Female carriers are mostly asymptomatic but may present with deafness. Most patients with a LoF pathogenic BCAP31 variant have permanent or transient liver enzyme elevation.; to: More than 20 unrelated families reported. Clinical features include severe intellectual disability (ID), dystonia, deafness, and central hypomyelination. Female carriers are mostly asymptomatic but may present with deafness. Most patients with a LoF pathogenic BCAP31 variant have permanent or transient liver enzyme elevation.

Microcephaly is a feature.
Fetal anomalies v0.206 ATIC Zornitza Stark Marked gene: ATIC as ready
Fetal anomalies v0.206 ATIC Zornitza Stark Gene: atic has been classified as Green List (High Evidence).
Fetal anomalies v0.206 ATIC Zornitza Stark Phenotypes for gene: ATIC were changed from AICA-RIBOSURIA to AICA-ribosiduria due to ATIC deficiency, MIM# 608688
Fetal anomalies v0.205 ATIC Zornitza Stark Publications for gene: ATIC were set to 15114530; 32557644
Fetal anomalies v0.205 ATIC Zornitza Stark Publications for gene: ATIC were set to
Fetal anomalies v0.180 ARSA Zornitza Stark Phenotypes for gene: ARSA were changed from ARYLSULFATASE A DEFICIENCY to Metachromatic leukodystrophy, MIM# 250100
Fetal anomalies v0.177 ARSA Zornitza Stark reviewed gene: ARSA: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Metachromatic leukodystrophy, MIM# 250100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Fetal anomalies v0.78 AKT1 Zornitza Stark Phenotypes for gene: AKT1 were changed from PROTEUS SYNDROME to Cowden syndrome 6, MIM#615109; Proteus syndrome, somatic, MIM# 176920
Fetal anomalies v0.74 AKT1 Zornitza Stark reviewed gene: AKT1: 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: 23246288, 21793738; Phenotypes: Cowden syndrome 6, MIM#615109, Proteus syndrome, somatic, MIM# 176920; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Fetal anomalies v0.0 SP110 Zornitza Stark gene: SP110 was added
gene: SP110 was added to Fetal anomalies. Sources: Expert Review Red,Genomics England PanelApp
Mode of inheritance for gene: SP110 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SP110 were set to Hepatic venoocclusive disease with immunodeficiency 235550
Fetal anomalies v0.0 GDF2 Zornitza Stark gene: GDF2 was added
gene: GDF2 was added to Fetal anomalies. Sources: Expert Review Red,Genomics England PanelApp
Mode of inheritance for gene: GDF2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GDF2 were set to 32618121
Phenotypes for gene: GDF2 were set to hydrops; hydrothorax; Lymphatic dysplasia
Fetal anomalies v0.0 DDC Zornitza Stark gene: DDC was added
gene: DDC was added to Fetal anomalies. Sources: Expert Review Red,Genomics England PanelApp
Mode of inheritance for gene: DDC was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: DDC were set to Aromatic L-amino acid decarboxylase deficiency, OMIM:608643; Aromatic L-amino acid decarboxylase deficiency, MONDO:0012084
Fetal anomalies v0.0 CALCRL Zornitza Stark gene: CALCRL was added
gene: CALCRL was added to Fetal anomalies. Sources: Expert Review Red,Genomics England PanelApp
Mode of inheritance for gene: CALCRL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CALCRL were set to 16537897; 30115739
Phenotypes for gene: CALCRL were set to Lymphatic malformation 8, MONDO:0032907; Lymphatic malformation 8, OMIM:618773; Hydrops fetalis
Fetal anomalies v0.0 ATP8B1 Zornitza Stark gene: ATP8B1 was added
gene: ATP8B1 was added to Fetal anomalies. Sources: Expert Review Red,Genomics England PanelApp
Mode of inheritance for gene: ATP8B1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ATP8B1 were set to ATP8B1-RELATED INTRAHEPATIC CHOLESTASIS
Fetal anomalies v0.0 ALAD Zornitza Stark gene: ALAD was added
gene: ALAD was added to Fetal anomalies. Sources: Expert Review Red,Genomics England PanelApp
Mode of inheritance for gene: ALAD was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ALAD were set to ACUTE HEPATIC PORPHYRIA
Fetal anomalies v0.0 ABCB11 Zornitza Stark gene: ABCB11 was added
gene: ABCB11 was added to Fetal anomalies. Sources: Expert Review Red,Genomics England PanelApp
Mode of inheritance for gene: ABCB11 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ABCB11 were set to ABCB11-RELATED INTRAHEPATIC CHOLESTASIS
Fetal anomalies v0.0 VEGFC Zornitza Stark gene: VEGFC was added
gene: VEGFC was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp
Mode of inheritance for gene: VEGFC was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: VEGFC were set to Lymphatic malformation 4
Fetal anomalies v0.0 STRADA Zornitza Stark gene: STRADA was added
gene: STRADA was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp
Mode of inheritance for gene: STRADA was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: STRADA were set to Polyhydramnios, megalencephaly, and symptomatic epilepsy, OMIM:611087; Polyhydramnios, megalencephaly, and symptomatic epilepsy, MONDO:0012611
Fetal anomalies v0.0 POLG2 Zornitza Stark gene: POLG2 was added
gene: POLG2 was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp
Mode of inheritance for gene: POLG2 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: POLG2 were set to Mitochondrial DNA depletion syndrome 16 (hepatic type), OMIM:618528; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, MONDO:0012415; Mitochondrial DNA depletion syndrome 16 (hepatic type), MONDO:0032799; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, OMIM:610131
Fetal anomalies v0.0 NEK8 Zornitza Stark gene: NEK8 was added
gene: NEK8 was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp
Mode of inheritance for gene: NEK8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NEK8 were set to 26697755; 18199800; 26967905; 26862157; 23418306
Phenotypes for gene: NEK8 were set to Renal-hepatic-pancreatic dysplasia 2, MONDO:0014174; Renal-hepatic-pancreatic dysplasia 2, OMIM:615415; ?Nephronophthisis 9, OMIM:613824; Nephronophthisis 9, MONDO:0013444
Fetal anomalies v0.0 MYOD1 Zornitza Stark gene: MYOD1 was added
gene: MYOD1 was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp
Mode of inheritance for gene: MYOD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYOD1 were set to 30403323; 26733463; 31260566
Phenotypes for gene: MYOD1 were set to Myopathy, congenital, with diaphragmatic defects, respiratory insufficiency, and dysmorphic facies, OMIM:618975
Fetal anomalies v0.0 DCDC2 Zornitza Stark gene: DCDC2 was added
gene: DCDC2 was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp
Mode of inheritance for gene: DCDC2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: DCDC2 were set to RENAL-HEPATIC CILIOPATHY
Fetal anomalies v0.0 CELSR1 Zornitza Stark gene: CELSR1 was added
gene: CELSR1 was added to Fetal anomalies. Sources: Expert Review Amber,Genomics England PanelApp
Mode of inheritance for gene: CELSR1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: CELSR1 were set to Lymphatic malformation 9, OMIM:619319
Fetal anomalies v0.0 RARB Zornitza Stark gene: RARB was added
gene: RARB was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp
Mode of inheritance for gene: RARB was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: RARB were set to MICROPHTHALMIA AND DIAPHRAGMATIC HERNIA
Fetal anomalies v0.0 PTF1A Zornitza Stark gene: PTF1A was added
gene: PTF1A was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp
Mode of inheritance for gene: PTF1A was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: PTF1A were set to PANCREATIC AGENESIS; DIABETES MELLITUS, PERMANENT NEONATAL, WITH CEREBELLAR AGENESIS
Fetal anomalies v0.0 PIK3CA Zornitza Stark gene: PIK3CA was added
gene: PIK3CA was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp
Mode of inheritance for gene: PIK3CA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PIK3CA were set to 30712880; 28425981
Phenotypes for gene: PIK3CA were set to CLOVES: CONGENITAL LIPOMATOUS OVERGROWTH, VASCULAR MALFORMATIONS, AND EPIDERMAL NEVI; HEMIMEGALENCEPHALY PIK3CA; MEGALENCEPHALY-CAPILLARY MALFORMATION-POLYMICROGYRIA SYNDROME, SOMATIC 3
Fetal anomalies v0.0 PIEZO1 Zornitza Stark gene: PIEZO1 was added
gene: PIEZO1 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp
Mode of inheritance for gene: PIEZO1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: PIEZO1 were set to 23695678; 30712880; 26333996; 28425981
Phenotypes for gene: PIEZO1 were set to Congenital lymphatic dysplasia with hydrops and/or lymphoedema; hydrops fetalis gene 616843
Fetal anomalies v0.0 NPHP3 Zornitza Stark gene: NPHP3 was added
gene: NPHP3 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp
Mode of inheritance for gene: NPHP3 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: NPHP3 were set to RENAL-HEPATIC-PANCREATIC DYSPLASIA; NEPHRONOPHTHISIS TYPE 3; MECKEL SYNDROME TYPE 7
Fetal anomalies v0.0 MYRF Zornitza Stark gene: MYRF was added
gene: MYRF was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp
Mode of inheritance for gene: MYRF was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MYRF were set to 30985895; 30070761; 31069960; 29446546; 30532227
Phenotypes for gene: MYRF were set to Congenital diaphragmatic hernia (CDH); Cardiac-urogenital syndrome, 618280; Disorders of sex development (DSD)
Fetal anomalies v0.0 GATA6 Zornitza Stark gene: GATA6 was added
gene: GATA6 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp
Mode of inheritance for gene: GATA6 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: GATA6 were set to ATRIOVENTRICULAR SEPTAL DEFECT 5; PANCREATIC AGENESIS, DIAPHRAGMATIC HERNIA AND CONGENITAL HEART DEFECTS; ATRIAL SEPTAL DEFECT 9
Fetal anomalies v0.0 CPT2 Zornitza Stark gene: CPT2 was added
gene: CPT2 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp
Mode of inheritance for gene: CPT2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CPT2 were set to Myopathy due to CPT II deficiency 255110; CPT II deficiency, lethal neonatal 608836; CPT deficiency, hepatic, type II 600649
Fetal anomalies v0.0 CNOT1 Zornitza Stark gene: CNOT1 was added
gene: CNOT1 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp
Mode of inheritance for gene: CNOT1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CNOT1 were set to 31006513; 31006510
Phenotypes for gene: CNOT1 were set to Holoprosencephaly 12, with or without pancreatic agenesis, 618500
Mode of pathogenicity for gene: CNOT1 was set to Other - please provide details in the comments
Fetal anomalies v0.0 ATIC Zornitza Stark gene: ATIC was added
gene: ATIC was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp
Mode of inheritance for gene: ATIC was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ATIC were set to AICA-RIBOSURIA