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

Variants in spliceosomal small nuclear RNA (snRNA) genes <i>RNU4-2</i> (ReNU syndrome), <i>RNU5B-1</i>, and <i>RNU2-2</i> 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 <i>de novo</i> and biallelic variants in <i>RNU2-2</i> associated with both dominant and recessive NDDs in 126 individuals from 108 unrelated families. Recessive <i>RNU2-2</i> 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 <i>de novo</i> variant in <i>trans</i> with an inherited allele, reflecting the high mutability of snRNA genes. Dominant and recessive <i>RNU2-2</i>-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 <i>RNU2-2</i> variants as a frequent cause of NDDs, nearly as prevalent as ReNU syndrome.