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| Intellectual disability syndromic and non-syndromic v2.106 | MACROH2A1 | chirag patel Marked gene: MACROH2A1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability syndromic and non-syndromic v2.106 | MACROH2A1 | chirag patel Gene: macroh2a1 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability syndromic and non-syndromic v2.106 | MACROH2A1 | chirag patel Classified gene: MACROH2A1 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability syndromic and non-syndromic v2.106 | MACROH2A1 | chirag patel Gene: macroh2a1 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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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