Systematic analysis of snRNA genes reveals frequent variants in dominant and recessive developmental and epileptic encephalopathies.
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| Abstract | Variants in spliceosomal small nuclear RNA (snRNA) genes (ReNU syndrome), , and have recently been linked to dominant neurodevelopmental disorders (NDDs), revealing a major, previously overlooked role for noncoding snRNAs in human disease. Here, we systematically analysed 200 potentially functional snRNA genes in a French cohort comprising 26,911 individuals with rare disorders and through international collaborations. We identify and biallelic variants in associated with both dominant and recessive NDDs in 126 individuals from 108 unrelated families. Recessive NDD is at least twice as frequent as the dominant NDD caused by n.4G>A and n.35A>G, and often arises from a variant in with an inherited allele, reflecting the high mutability of snRNA genes. Dominant and recessive -NDDs share overlapping clinical features with frequent epilepsy. Blood transcriptomics and DNA methylation analyses revealed subtle, variant-specific effects on splicing and episignatures. Our findings support a gradient-of-impact model and a continuum between dominant and recessive inheritance, establishing variants as a frequent cause of NDDs, nearly as prevalent as ReNU syndrome. |
| Year of Publication | 2025
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| Journal | medRxiv : the preprint server for health sciences
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| Date Published | 09/2025
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| DOI | 10.1101/2025.09.02.25334923
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| PubMed ID | 40950445
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