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 novel recessive RNU2-2 syndrome, delineate its unique genetic architecture and show that clinically it manifests as a severe developmental epileptic encephalopathy. We find that candidate biallelic variants are significantly correlated with reduced U2-2 abundance, implicating compromised transcript stability as likely pathomechanism. We identify 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.

L.M. has received personal consultancy fees from Mendelian Ltd., a rare disease digital health company, outside of the submitted work. No other authors have any conflicts to declare.

A.J. and S.B. acknowledge the support of SolveRD. The SolveRD project has received funding from the European Unions Horizon 2020 research and innovation program under grant agreement 779257. This study has been delivered through the National Institute for Health and Care Research (NIHR) Manchester Biomedical Research Centre (NIHR203308). A.B. is supported by a Wellcome PhD Training Fellowship for Clinicians and the 4Ward North PhD Programme for Health Professionals (223521/Z/21/Z). This research was made possible through access to data in the National Genomic Research Library, which is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The National Genomic Research Library holds data provided by patients and collected by the NHS as part of their care and data collected as part of their participation in research. The National Genomic Research Library is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. This research has been conducted using the UK Biobank Resource under Application Number 90952. The Australian Undiagnosed Diseases Network (UDN-Aus) acknowledges financial support from the Australian Governments Medical Research Future Fund (2007567), Australian Genomics and The Centre for Population Genomics (Garvan Institute of Medical Research and Murdoch Childrens Research Institute); funded in part by a Medical Research Future Fund (MRFF) Genomics Health Futures Mission grant (2008820).

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