Publication Date
8-1-2024
Journal
Nature
DOI
10.1038/s41586-024-07773-7
PMID
38991538
PMCID
PMC11338827
PubMedCentral® Posted Date
7-11-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Adolescent, Child, Child, Preschool, Female, Humans, Infant, Male, Young Adult, Alleles, Brain, Heterozygote, Mutation, Neurodevelopmental Disorders, RNA Splice Sites, RNA, Small Nuclear, Spliceosomes, Syndrome, Rare Diseases, Gene Expression Regulation, Developmental
Abstract
Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here we identify the non-coding RNA RNU4-2 as a syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 base pair region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals in whom it could be determined, the de novo variants were all on the maternal allele. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to RNU4-1 and other U4 homologues. Using RNA sequencing, we show how 5′ splice-site use is systematically disrupted in individuals with RNU4-2 variants, consistent with the known role of this region during spliceosome activation. Finally, we estimate that variants in this 18 base pair region explain 0.4% of individuals with NDD. This work underscores the importance of non-coding genes in rare disorders and will provide a diagnosis to thousands of individuals with NDD worldwide.
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