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

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.

Citation

Jackson, A., Blakes, A. J. M., Alhaddad, B., Henry, O. J., Delgado-Vega, A. M., Wall, E., Abdelhadi, O., Agrawal, S., Bakur, K., Blair, E., Brady, A. F., Brittain, H., Chandler, K. E., Clarke, N., Danelli, M., Drinkall, N., Duba, I., Elmslie, F., Ellingford, J., Ewans, L. J., … Banka, S. (2026). Biallelic variants in RNU2-2 cause a remarkably frequent developmental and epileptic encephalopathy. Nature genetics, 10.1038/s41588-026-02551-9. Advance online publication. https://doi.org/10.1038/s41588-026-02551-9

DOI

10.1038/s41588-026-02551-9

URI

https://hdl.handle.net/20.500.14709/1444

License

CC BY 4.0

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Usage rights

CC BY 4.0

License

https://creativecommons.org/licenses/by/4.0/