Biallelic variants in RNU2-2 cause a remarkably frequent developmental and epileptic encephalopathy

Journal article

Neurodevelopmental disorders (NDDs) affect 2–4% of the population, are predominantly genetic and remain unsolved in ~50% of individuals. We show that rare biallelic variants in RNU2-2 are enriched and over-transmitted in individuals with unresolved NDDs. We define a recessive RNU2-2 syndrome, delineate its unique genetic architecture and show that it manifests clinically as a severe developmental and epileptic encephalopathy. We find that candidate biallelic variants are significantly correlated with reduced U2-2 abundance, implicating compromised transcript stability as a probable pathomechanism. We identify a decreased ratio of U2-2 to its paralog U2-1 as a potential diagnostic biomarker for this condition. We show that the recessive RNU2-2 syndrome is genetically, clinically and mechanistically distinct from the dominant RNU2-2 disorder. Within our cohort, the recessive RNU2-2 syndrome emerges as by far the most frequent recessive NDD, greatly disproportionate to the small genomic footprint of this non-protein-coding gene.

Authors: Jackson, A; Blakes, AJM; Alhaddad, B; Henry, OJ; Delgado-Vega, AM

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Nature Genetics
• Volume: 58
• Issue: 4
• Pages: 798-809
• Publication date: 2026-03-30
• Acceptance date: 2026-02-23
• DOI: 10.1038/s41588-026-02551-9
• EISSN: 1546-1718
• ISSN: 1061-4036
• Language: English
• Keywords: Genetic architecture; Epilepsy; Neurodevelopmental disorder; Encephalopathy; Allele; Phenotype; Gene