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De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome.
- Source :
-
Nature [Nature] 2024 Aug; Vol. 632 (8026), pp. 832-840. Date of Electronic Publication: 2024 Jul 11. - Publication Year :
- 2024
-
Abstract
- Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes <superscript>1</superscript> . 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 spliceosome <superscript>2</superscript> . 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&#95;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.<br /> (© 2024. The Author(s).)
- Subjects :
- Adolescent
Child
Child, Preschool
Female
Humans
Infant
Male
Young Adult
Alleles
Brain growth & development
Brain metabolism
Heterozygote
RNA Splice Sites genetics
Spliceosomes genetics
Syndrome
Rare Diseases genetics
Gene Expression Regulation, Developmental
Mutation
Neurodevelopmental Disorders genetics
RNA, Small Nuclear genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 632
- Issue :
- 8026
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 38991538
- Full Text :
- https://doi.org/10.1038/s41586-024-07773-7