Systematic analysis of snRNA genes reveals frequent RNU2-2 variants in dominant and recessive developmental and epileptic encephalopathies

Journal article

Small nuclear RNAs (snRNAs) are essential components of the spliceosome. De novo variants in snRNA genes RNU4-2 (ReNU syndrome), RNU5B-1 and RNU2-2 have been linked to dominant neurodevelopmental disorders (NDDs), revealing a large unexpected contribution of noncoding RNA genes to genetic diseases. Here, through international collaborations, we analyze systematically 200 potentially functional snRNA genes in a French cohort of 34,329 people with rare disorders. We report RNU2-2 variants in 141 individuals, including 35 with recurrent dominant pathogenic variants and 91 affected members from 73 families with biallelic variants. Recessive RNU2-2 NDD is at least twice as frequent as the dominant form and often involves a de novo variant in trans with an inherited allele, consistent with the high mutability of snRNA genes. Dominant and recessive RNU2-2 NDDs share overlapping clinical features, with frequent epilepsy. Blood transcriptomics and DNA methylation analyses revealed subtle, variant-specific effects on splicing and episignatures. Our results support a gradient-of-impact model bridging dominant and recessive inheritance, and establish RNU2-2 variants as a principal contributor to NDDs, nearly as prevalent as ReNU syndrome.

Authors: Leitão, E; Santini, A; Cogne, B; Essid, M; Athanasiadou, M

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Nature Genetics
• Volume: 58
• Issue: 4
• Pages: 782-797
• Publication date: 2026-03-30
• Acceptance date: 2026-02-12
• DOI: 10.1038/s41588-026-02547-5
• EISSN: 1546-1718
• ISSN: 1061-4036
• Language: English
• Keywords: Small nuclear RNA; Gene; RNA splicing; snRNP; Transcriptome; RNA; Human genetics