biostudies-literatureUnknownChen YNICHD NIH HHSNIMH NIH HHSNHGRI NIH HHSNINDS NIH HHSNIAMS NIH HHSWellcome TrustAround 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes¹. Increasingly, large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here, we identify the non-coding RNA <i>RNU4-2</i> as a novel syndromic NDD gene. <i>RNU4-2</i> 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 bp region of <i>RNU4-2</i> 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 119 individuals withmedRxiv : the preprint server for health sciences2024.04.07.24305438https://www.ebi.ac.uk/biostudies/studies/S-EPMC11030480biostudies-literature&lt;i&gt;De novo&lt;/i&gt; variants in the non-coding spliceosomal snRNA gene &lt;i&gt;RNU4-2&lt;/i&gt; are a frequent cause of syndromic neurodevelopmental disorders.PMC11030480U01 HG007942U01 NS106845U01 HG010217U24 NS131172U01 MH122681U01 HG011745U01 HG011755U01 NS134358U24 HG011746K23 AR083505R01 MH122681220134/Z/20/ZP50 HD103555U01 HG011762U01 MH111662R01 HG009141R01 MH129751U01 HG007709U54 NS115052R21 HG012397UM1 HG008900Fraser JLBakshi MStark ZGenetti CADepienne CClair LFevre ALTifft CJWhite SMEzell KRubenstein JLSachdev RWalker SLeitao EThorburn DRMontgomery SBPitsava GZocche DLockhart PJO'Leary MLiebelt JETan NBViskochil DHBerger SIAdams DRWojcik MMendez HRPysar RTan TYStenton SLWhiffin NDias KREvans CATemple SEVilain EMa ASMaurer TMPalmer EEReuter CMXiao CKuechler AD'Souza ENRehm HLBurrage LCMacnamara EFDong SEllingford JMElias ERLjungdahl ARodan LFica SMChen YRoscioli TBaralle DLeventer RJMacArthur DGVanNoy GELemire GEwans LWedd LWolfenson ZDawes RHowson JMSanders SJBrown NJBernstein JACompton AGRosenfeld JAHaack TRius RGrant CLNassogne MCGanesh VSGallacher LUebergang ELalani SRMartin-Geary ACRiess APhillips JWheeler MTSnell PDelot ECSisodiya SMO'Donnell-Luria ABaldwin EENeumann SWolfe LAKim HCAllan KD'Souza PMa JRevencu NChapman KMarkenscoff-Papadimitriou ELord JCunningham CASimons Cfalse&lt;i&gt;De novo&lt;/i&gt; variants in the non-coding spliceosomal snRNA gene &lt;i&gt;RNU4-2&lt;/i&gt; are a frequent cause of syndromic neurodevelopmental disorders.Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes¹. Increasingly, large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here, we identify the non-coding RNA <i>RNU4-2</i> as a novel syndromic NDD gene. <i>RNU4-2</i> 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 bp region of <i>RNU4-2</i> 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 119 individuals with2024-01-01T00:00:00Z2024 Apr2026-04-08T18:57:14.699Z2026-04-08T11:06:19.373ZS-EPMC110304803864509410.1101/2024.04.07.24305438