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| Intellectual disability syndromic and non-syndromic v2.105 | MACROH2A1 |
chirag patel gene: MACROH2A1 was added gene: MACROH2A1 was added to Intellectual disability syndromic and non-syndromic. Sources: Other Mode of inheritance for gene: MACROH2A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: MACROH2A1 were set to Neurodevelopmental disorder, MONDO:0700092, MACROH2A1-related Review for gene: MACROH2A1 was set to AMBER Added comment: ESHG 2026 5 unrelated individuals with 3 different rare heterozygous de novo missense variants in H2A-like domain in MACROH2A1 gene. Two missense variants affected the same amino acid in 4 individuals (p.Arg27Gln and p.Arg27Trp). Individuals presented with global developmental delay (5/5), intellectual disability (5/5), hypotonia (4/4), microcephaly (3/5), seizures (2/5), brain abnormalities (3/4), and dysmorphism (5/5). MACROH2A1 is a distinctive H2A variant involved in transcriptional regulation, chromatin organization, and neuronal differentiation. Structural modeling indicated that variants destabilize the nucleosome and impair MACROH2A1-DNA interactions. Transcriptomic profiling of patient-derived fibroblasts highlighted dysregulation of the actin cytoskeleton organization and cell-matrix interaction dynamics, ER-related trafficking, and neuronal differentiation programs. Patient fibroblasts exhibited disorganized F-actin with defective focal adhesions and ER disorganization with lumen dilation. Patient fibroblasts also showed impaired fibroblast-to-neuronal reprogramming with reduced TuJ1-positive cells, and abnormal neurite morphology. Methylation profiling revealed a distinct episignature discriminating affected individuals from controls, consistent with global epigenetic dysregulation. Sources: Other |
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| Intellectual disability syndromic and non-syndromic v2.103 | RLF |
chirag patel gene: RLF was added gene: RLF was added to Intellectual disability syndromic and non-syndromic. Sources: Other Mode of inheritance for gene: RLF was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: RLF were set to Neurodevelopmental disorder, MONDO:0700092, RLF-related Review for gene: RLF was set to AMBER Added comment: ESHG 2026 22 unrelated individuals with rare heterozygous de novo variants (14 frameshift, 8 nonsense) located in the last exon of RLF gene. Individuals presented with developmental delay, intellectual disability, autism-type behaviour, and Kabuki syndrome-like facial features. RLF is a poly-ZNF protein which acts as a transcription factor. In vitro assays showed the variants profoundly altered the epigenome, the transcriptome and the DNA secondary structure. ONT whole genome sequencing in patient IPSCs showed hypermethylation and hypo-5-hydroxymethylation at multiple CpG sites. ATAC-seq demonstrated altered chromatin accessibility at promoters and enhancers in patient IPSCs. RNA-seq unveiled several differentially expressed genes enriched for disease-relevant gene ontology terms. RLP variants upregulated neuronal differentiation genes. RLF-ChIP-seq data showed a marked reduction in G4 access signal in patient iPSCs. Methylation arrays revealed a distinct methylation profile overlapping with Kabuki syndrome. Sources: Other |
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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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