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De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome.

Yuyang ChenRuebena DawesHyung Chul KimAlicia LjungdahlSarah L StentonSusan WalkerJenny LordGabrielle LemireAlexandra C Martin-GearyVijay S GaneshJialan MaJamie M EllingfordErwan DelageElston N D'SouzaShan DongDavid R AdamsKirsten AllanMadhura BakshiErin E BaldwinSeth I BergerJonathan A BernsteinIshita BhatnagarEd BlairNatasha J BrownLindsay C BurrageKimberly ChapmanDavid John ComanAlison G ComptonChloe A CunninghamPrecilla D'SouzaPetr DanecekEmmanuèle C DélotKerith-Rae DiasEllen R EliasFrances ElmslieCare-Anne EvansLisa EwansKimberly EzellJamie L FraserLyndon GallacherCasie A GenettiAnne GorielyChristina L GrantTobias B HaackJenny E HiggsAnjali Gupta HinchMatthew E HurlesAlma KuechlerKatherine L LachlanSeema R LalaniFrançois LecoquierreElsa LeitãoAnna Le FevreRichard J LeventerJan E LiebeltSarah J LindsayPaul J LockhartAlan S MaEllen F MacnamaraSahar MansourTaylor M MaurerHector R MendezKay MetcalfeStephen B MontgomeryMariya MoosajeeMarie-Cécile NassogneSerena NeumannMichael O'DonoghueMelanie O'LearyElizabeth E PalmerNikhil PattaniJohn PhillipsGeorgia PitsavaRyan PysarHeidi L RehmChloe M ReuterNicole RevencuAngelika RiessRocio RiusLance RodanTony RoscioliJill Anne RosenfeldRani SachdevCharles J Shaw-SmithCas SimonsSanjay M SisodiyaPenny SnellLaura St ClairZornitza StarkHelen S StewartTiong Yang TanNatalie B TanSuzanna E L TempleDavid R ThorburnCynthia J TifftEloise UebergangGrace E VanNoyPradeep VasudevanEric VilainDavid H ViskochilLaura WeddMatthew T WheelerSusan M WhiteMonica WojcikLynne A WolfeZoe WolfensonCaroline Fiona WrightChangrui XiaoDavid ZoccheJohn L RubensteinEirene Markenscoff-PapadimitriouSebastian M FicaDiana BaralleChristel DepienneDaniel G MacArthurJoanna M M HowsonStephan J SandersAnne H O'Donnell-LuriaNicola Whiffin
Published in: Nature (2024)
Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes 1 . 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 2 . 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.
Keyphrases
  • copy number
  • genome wide
  • magnetic resonance
  • gene expression
  • magnetic resonance imaging
  • transcription factor
  • intellectual disability
  • physical activity
  • weight loss
  • functional connectivity
  • binding protein