| Date | Panel | Item | Activity | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Mendeliome v1.1306 | KDM2B | Ain Roesley edited their review of gene: KDM2B: Changed phenotypes: neurodevelopmental disorder MONDO#0700092, KDM2B-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1306 | KDM2B | Ain Roesley Phenotypes for gene: KDM2B were changed from neurodevelopmental disorder MONDO#070009, KDM2B-related to neurodevelopmental disorder MONDO#0700092, KDM2B-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1039 | KDM2A | Zornitza Stark Marked gene: KDM2A as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1039 | KDM2A | Zornitza Stark Gene: kdm2a has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1039 | KDM2A | Zornitza Stark Phenotypes for gene: KDM2A were changed from Neurodevelopmental disorder to Neurodevelopmental disorder, MONDO:0700092, KDM2A-related | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1008 | KDM2A | Chirag Patel Classified gene: KDM2A as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1008 | KDM2A | Chirag Patel Gene: kdm2a has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.1007 | KDM2A |
Chirag Patel gene: KDM2A was added gene: KDM2A was added to Mendeliome. Sources: Other Mode of inheritance for gene: KDM2A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: KDM2A were set to Neurodevelopmental disorder Review for gene: KDM2A was set to GREEN gene: KDM2A was marked as current diagnostic Added comment: ESHG 2023: 14 patients with de novo HTZ variants in KDM2A (5 x truncating, 9 x missense) Presentation with DD, ID (mild), seizures, growth retardation, and dysmorphism. Functional studies: -patient blood showed aberrant genome wide methylation profile - potential episignature -HEK293T cells showed altered subcellular localisation of KDM2A -Drosophila models showed variants caused neurotoxicity Sources: Other |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.504 | KDM2B |
Ain Roesley changed review comment from: 27 individuals from 22 families were recruited 12 SNV classified LP/P, all de novo except 2 familial cases 5 variants were classified as VUS if more than 1 het is present in gnomAD or does result in a KDM2B-specific episignature (therefore suggesting normal function) Sources: Literature; to: 27 individuals from 22 families were recruited 13 SNV classified LP/P, all de novo except 2 familial cases 5 variants were classified as VUS if more than 1 het is present in gnomAD or does result in a KDM2B-specific episignature (therefore suggesting normal function) Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.504 | KDM2B | Ain Roesley Marked gene: KDM2B as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.504 | KDM2B | Ain Roesley Gene: kdm2b has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.504 | KDM2B | Ain Roesley Classified gene: KDM2B as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.504 | KDM2B | Ain Roesley Gene: kdm2b has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v1.503 | KDM2B |
Ain Roesley gene: KDM2B was added gene: KDM2B was added to Mendeliome. Sources: Literature Mode of inheritance for gene: KDM2B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: KDM2B were set to 36322151 Phenotypes for gene: KDM2B were set to neurodevelopmental disorder MONDO#070009, KDM2B-related Review for gene: KDM2B was set to GREEN gene: KDM2B was marked as current diagnostic Added comment: 27 individuals from 22 families were recruited 12 SNV classified LP/P, all de novo except 2 familial cases 5 variants were classified as VUS if more than 1 het is present in gnomAD or does result in a KDM2B-specific episignature (therefore suggesting normal function) Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8991 | OPDM2 | Bryony Thompson Marked STR: OPDM2 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8991 | OPDM2 | Bryony Thompson Str: opdm2 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8991 | OPDM2 | Bryony Thompson Classified STR: OPDM2 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8991 | OPDM2 | Bryony Thompson Str: opdm2 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8990 | OPDM2 |
Bryony Thompson STR: OPDM2 was added STR: OPDM2 was added to Mendeliome. Sources: Literature Mode of inheritance for STR: OPDM2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for STR: OPDM2 were set to 32413282; 33374016 Phenotypes for STR: OPDM2 were set to Oculopharyngodistal myopathy 2 MIM#618940 Review for STR: OPDM2 was set to GREEN STR: OPDM2 was marked as clinically relevant Added comment: NM_005716.4:c.-211GGC[X] >15 Chinese families/probands with a heterozygous trinucleotide repeat expansion (CGG(n)) in 5'UTR exon 1 of the GIPC1 gene. The expansion was found by a combination of linkage analysis, whole-exome sequencing, long-range sequencing, and PCR analysis, and segregated with the disorder in the family. Repeat lengths in the patients ranged from 70 to 138. Normal repeat lengths ranged from 12 to 32. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8989 | GIPC1 | Bryony Thompson Added comment: Comment on list classification: Added to panel as an STR under OPDM2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8736 | PIDD1 |
Zornitza Stark gene: PIDD1 was added gene: PIDD1 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: PIDD1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PIDD1 were set to 28397838; 29302074; 33414379; 34163010 Phenotypes for gene: PIDD1 were set to Global developmental delay; Intellectual disability; Seizures; Autism; Behavioral abnormality; Psychosis; Pachygyria; Lissencephaly; Abnormality of the corpus callosum Review for gene: PIDD1 was set to GREEN Added comment: There is enough evidence to include this gene in the current panel with green rating. Biallelic PIDD1 pathogenic variants have been reported in 26 individuals (11 families) with DD (all), variable degrees of ID (mild to severe), behavioral (eg. aggression/self-mutilation in several, ADHD) and/or psychiatric abnormalities (ASD, psychosis in 5 belonging to 3 families), well-controlled epilepsy is some (9 subjects from 6 families) and MRI abnormalities notably abnormal gyration pattern (pachygyria with predominant anterior gradient) as well as corpus callosum anomalies (commonly thinning) in several. Dysmorphic features have been reported in almost all, although there has been no specific feature suggested. The first reports on the phenotype associated with biallelic PIDD1 mutations were made by Harripaul et al (2018 - PMID: 28397838) and Hu et al (2019 - PMID: 29302074) [both studies investigating large cohorts of individuals with ID from consanguineous families]. Sheikh et al (2021 - PMID: 33414379) provided details on the phenotype of 15 individuals from 5 families including those from the previous 2 reports and studied provided evidence on the role of PIDD1 and the effect of variants. Zaki et al (2021 - PMID: 34163010) reported 11 additional individuals from 6 consanguineous families, summarize the features of all subjects published in the literature and review the neuroradiological features of the disorder. PIDD1 encodes p53-induced death domain protein 1. The protein is part of the PIDDosome, a multiprotein complex also composed of the bipartite linker protein CRADD (also known as RAIDD) and the proform of caspase-2 and induces apoptosis in response to DNA damage. There are 5 potential PIDD1 mRNA transcript variants with NM_145886.4 corresponding to the longest. Similar to the protein encoded by CRADD, PIDD1 contains a death domain (DD - aa 774-893). Constitutive post-translational processing gives PIDD1-N, PIDD1-C the latter further processed into PIDD1-CC (by auto-cleavage). Serine residues at pos. 446 and 588 are involved in this autoprocessing generating PIDD1-C (aa 446-910) and PIDD1-CC (aa 774-893). The latter is needed for caspase-2 activation. Most (if not all) individuals belonged to consanguineous families of different origins and harbored pLoF or missense variants. Variants reported so far include : c.2587C>T; p.Gln863* / c.1909C>T ; p.Arg637* / c.2443C>T / p.Arg815Trp / c.2275-1G>A which upon trap assay was shown to lead to skipping of ex15 with direct splicing form exon14 to the terminal exon 16 (resulting to p.Arg759Glyfs*1 with exlcusion of the entire DD) / c.2584C>T; p.Arg862Trp / c.1340G>A; p.Trp447* / c.2116_2120del; p.Val706His*, c.1564_1565del; p.Gly602fs*26 Evidence so far provided includes: - Biallelic CRADD variants cause a NDD disorder and a highly similar gyration pattern. - Confirmation of splicing effect (eg. for c.2275-1G>A premature stop in position 760) or poor expression (NM_145886.3:c.2587C>T; p.Gln863*). Arg815Trp did not affect autoprocessing or protein stability. - Abnormal localization pattern, loss of interaction with CRADD and failure to activate caspase-2 (MDM2 cleavage assay) [p.Gln863* and Arg815Trp] - Available expression data from GTEx (PIDD1 having broad expression in multiple tissues, but higher in brain cerebellum) as well as BrainSpan and PsychEncode studies suggesting high coexpression of PIDD1, CRADD and CASP2 in many regions in the developing human brain. - Variants in other genes encoding proteins interacting with PIDD1 (MADD, FADD, DNAJ, etc) are associated with NDD. Pidd-1 ko mice (ex3-15 removal) lack however CNS-related phenotypes. These show decreased anxiety but no motor anomalies. This has also been the case with Cradd-/- mice displaying no significant CNS phenotypes without lamination defects. There is currently no associated phenotype in OMIM. PIDD1 is listed in the DD panel of G2P (PIDD1-related NDD / biallelic / loss of function / probable) . SysID includes PIDD1 among the current primary ID genes. Sources: Expert Review |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7258 | MDM2 | Zornitza Stark Marked gene: MDM2 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7258 | MDM2 | Zornitza Stark Gene: mdm2 has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7258 | MDM2 | Zornitza Stark Phenotypes for gene: MDM2 were changed from to Lessel-Kubisch syndrome, MIM# 618681 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7257 | MDM2 | Zornitza Stark Publications for gene: MDM2 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7256 | MDM2 | Zornitza Stark Mode of inheritance for gene: MDM2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7255 | MDM2 | Zornitza Stark Classified gene: MDM2 as Red List (low evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7255 | MDM2 | Zornitza Stark Gene: mdm2 has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.7254 | MDM2 | Chern Lim reviewed gene: MDM2: Rating: AMBER; Mode of pathogenicity: None; Publications: 28846075; Phenotypes: ?Lessel-Kubisch syndrome (MIM#618681); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6844 | DM2 | Bryony Thompson Marked STR: DM2 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6844 | DM2 | Bryony Thompson Str: dm2 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6844 | DM2 | Bryony Thompson Classified STR: DM2 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6844 | DM2 | Bryony Thompson Str: dm2 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6843 | DM2 |
Bryony Thompson STR: DM2 was added STR: DM2 was added to Mendeliome. Sources: Expert list Mode of inheritance for STR: DM2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for STR: DM2 were set to 20301639; 29325606 Phenotypes for STR: DM2 were set to Myotonic dystrophy 2 MIM#602668 Review for STR: DM2 was set to GREEN STR: DM2 was marked as clinically relevant Added comment: HGVS nomenclature: NM_003418.4:c.-14-833_-14-830[X] Toxic gain of function RNA expected mechanism of disease Normal: ≤30 uninterrupted CCTG repeats, 11-26 CCTG repeats with any GCTC or TCTG interruptions Unknown significance (normal vs. mutable): 27-29 CCTG repeats Mutable normal (premutation) alleles. ~30-~54 CCTG repeats Unknown significance (premutation vs pathogenic): ~55-74 CCTG repeats Pathogenic: ~75-11,000 CCTG repeats Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.3376 | GIPC1 |
Zornitza Stark gene: GIPC1 was added gene: GIPC1 was added to Mendeliome. Sources: Literature 5'UTR, STR tags were added to gene: GIPC1. Mode of inheritance for gene: GIPC1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: GIPC1 were set to 32413282 Phenotypes for gene: GIPC1 were set to Oculopharyngodistal myopathy-2 (OPDM2), MIM#618940 Review for gene: GIPC1 was set to AMBER Added comment: 19 families reported with heterozygous trinucleotide repeat expansion in the 5-prime untranslated region and onset of distal muscle weakness, mainly of the lower limbs, and/or ophthalmoplegia in the second or third decades of life. Note this is unlikely to be tractable currently by most NGS assays. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.2485 | MDM2 | Belinda Chong reviewed gene: MDM2: Rating: RED; Mode of pathogenicity: None; Publications: 28846075; Phenotypes: ?Lessel-Kubisch syndrome 618681; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.0 | MDM2 |
Zornitza Stark gene: MDM2 was added gene: MDM2 was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: MDM2 was set to Unknown |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||