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

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ABSTRACT 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.

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