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| Intellectual disability syndromic and non-syndromic v2.0 | CRIPTO | Gene symbol changed from TDGF1 to CRIPTO during gene set migration (ENSG00000241186 -> ENSG00000241186) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability syndromic and non-syndromic v1.656 | CTNND2 |
Zornitza Stark edited their review of gene: CTNND2: Added comment: PMID 41502569 (preprint) reports phenotypic and molecular information for 57 individuals, 42 previously unpublished, with heterozygous CTNND2 variants. The 41 CTNND2 variants included 12 previously reported loss-of-function- and one missense variant, and 28 novel variants comprising 10 missense and 18 predicted loss-of-function changes. Eight of the novel variants occurred de novo, and 12 were inherited from a parent with a neurodevelopmental phenotype. The most common clinical features were developmental delay (90%), intellectual disability (74%), and behavioral abnormalities (79%). Functional studies revealed impaired early neurogenesis in one patient-derived line, characterized by aberrant neural rosette formation. Transcriptome analysis showed dysregulated WNT signaling, and partial rescue of these defects was achieved by modulating the WNT pathway, highlighting δ-catenin's role in early neural development. Note several of the reported missense variants in this gene have high gnomAD counts so these should be interpreted with caution. Nevertheless, large number of individuals reported now with LoF variants and NDD phenotype.; Changed rating: GREEN; Changed publications: 25839933, 29127138, 25807484, 41502569; Changed phenotypes: Neurodevelopmental disorder, MONDO:0700092, CTNND2-related |
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| Intellectual disability syndromic and non-syndromic v0.6062 | CRNKL1 |
Mark Cleghorn gene: CRNKL1 was added gene: CRNKL1 was added to Intellectual disability syndromic and non-syndromic. Sources: Other Mode of inheritance for gene: CRNKL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: CRNKL1 were set to complex neurodevelopmental disorder MONDO:0100038 Penetrance for gene: CRNKL1 were set to Complete Review for gene: CRNKL1 was set to GREEN Added comment: Unpublished, presented at ESHG June 2024 - Louise Bicknell, University of Otago NZ 8 unrelated families via gene matcher with rare, de novo, missense variants in CRNKL1 severe microcephaly (all, -8 to -11 SD) ID/epilepsy pontocerebellar hypoplasia (6/8) simplified gyration (8/8) 7 variants are missense at p.Arg267 residue 1 variant missense at p.Arg301 RNA-seq on patient fibroblasts - no alteration in gene expression Zebrafish homolog of Arg267 and Arg301 - mimics observed phenotype (reduced brain development), increased in embryo apoptosis RNQ seq on affected zebrafish embryos - transcriptome strongly disrupted Splicing analysis in progress CRKNL1 supports U6 structure in spliceosome Sources: Other |
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| Intellectual disability syndromic and non-syndromic v0.4343 | SNIP1 | Zornitza Stark edited their review of gene: SNIP1: Added comment: A single (founder) variant NM_024700.4:c.1097A>G, p.(Glu366Gly) has been reported in over 30 cases of Psychomotor retardation, epilepsy, and craniofacial dysmorphism OMIM:614501 in the Amish community (PMIDs: 22279524; 34570759). Cases are homozygous for this variant and unaffected members of the families are heterozygous or wt. Overexpression of the equivalent mouse variant in mouse inner medullary collecting duct cells, resulted in a more aggregated appearance in the nucleus compared to wildtype. The variant protein maybe unstable as Western blots showed reduced levels of the variant protein (PMID: 22279524). Whole transcriptomic analysis of patient blood was performed in PMID: 34570759. This revealed 11 upregulated and 32 downregulated genes, of which 24 had previously been associated with neurological disease.; Changed rating: AMBER | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability syndromic and non-syndromic v0.1298 | SMARCC2 |
Chirag Patel gene: SMARCC2 was added gene: SMARCC2 was added to Intellectual disability, syndromic and non-syndromic_GHQ_VCGS. Sources: Literature Mode of inheritance for gene: SMARCC2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SMARCC2 were set to PMID: 30580808 Phenotypes for gene: SMARCC2 were set to Coffin-Siris syndrome 8; OMIM #618362 Review for gene: SMARCC2 was set to GREEN Added comment: 15 individuals with variable degrees of neurodevelopmental delay, growth retardation, prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features. They found heterozygous de novo SMARCC2 variants, but no functional evidence of specific variants. Transcriptomic analysis of fibroblasts from affected individuals highlighted a group of differentially expressed genes with possible roles in regulation of neuronal development and function, namely H19, SCRG1, RELN, and CACNB4. Sources: Literature |
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| Intellectual disability syndromic and non-syndromic v0.1296 | SMARCD1 |
Chirag Patel gene: SMARCD1 was added gene: SMARCD1 was added to Intellectual disability, syndromic and non-syndromic_GHQ_VCGS. Sources: Literature Mode of inheritance for gene: SMARCD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SMARCD1 were set to PMID: 30879640 Phenotypes for gene: SMARCD1 were set to no OMIM number yet Review for gene: SMARCD1 was set to GREEN Added comment: 5 individuals with heterozygous SMARCD1 variants (4 de novo, 1 unk), and developmental delay, intellectual disability, hypotonia, feeding difficulties, dysmorphisms, and small hands and feet. No functional evidence of some variants was not conclusive with immunoblot or co-immunoprecipitation studies. Targeted knockdown of Drosophila ortholog Bap60 in the mushroom body of adult flies causes defects in long-term memory. Mushroom-body-specific transcriptome analysis revealed that Bap60 is required for context-dependent expression of genes involved in neuron function and development in juvenile flies when synaptic connections are actively being formed in response to experience. T Sources: Literature |
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