biostudies-literatureUnknownLeitao ENICHD NIH HHSNHGRI NIH HHSWellcome TrustVariants in spliceosomal small nuclear RNA (snRNA) genes <i>RNU4-2</i> (ReNU syndrome), <i>RNU5B-1</i>, and <i>RNU2-2</i> have recently been linked to dominant neurodevelopmental disorders (NDDs), revealing a major, previously overlooked role for noncoding snRNAs in human disease. Here, we systematically analysed 200 potentially functional snRNA genes in a French cohort comprising 26,911 individuals with rare disorders and through international collaborations. We identify <i>de novo</i> and biallelic variants in <i>RNU2-2</i> associated with both dominant and recessive NDDs in 126 individuals from 108 unrelated families. Recessive <i>RNU2-2</i> NDD is at least twice as frequent as the dominant NDD caused by n.4G>A and n.35A>G, and often arises from a <i>de novo</i> variant in <i>trans</i> medRxiv : the preprint server for health sciences2025.09.02.25334923https://www.ebi.ac.uk/biostudies/studies/S-EPMC12424890biostudies-literatureSystematic analysis of snRNA genes reveals frequent &lt;i&gt;RNU2-2&lt;/i&gt; variants in dominant and recessive developmental and epileptic encephalopathies.PMC12424890U24 HD090743U01 HG011755UM1 HG008900Bernard VRossi MJousselin KChehadeh SEde Saint Martin AO'Leary MCBensabath URichard ACGaignard PProuteau CThiyagarajah HBris CLevy JDang LTKaya SRivier CLeitao ERupin MLyonnet SGueguen PMacdonald SLermine AFaivre LChatron NZaki MSZiegler ANabbout Rde Sainte Agathe JMKurth IYammine TBogoin JGrisel CBaer SLabalme ASchluth-Bolard CSeplyarskiy VStenton SLJacquette AHeide SCharenton CDucreux SFaoucher MWitkowski TGeraud JCogne BVille DThevenon JKeren BGill DSarrazin EDenomme-Pichon ASFaudet ALaloy JSBesnard TValleix SKirstetter RBruel ALColin EPanagiotakaki ERobin-Renaldo FDufour LBegemann MSaneto RSadleir LGGoldenberg APouzet APatat OWaernessyckle ADoco-Fenzy MWeirauch NBHammer TBSaugier-Veber PAllan THausler MGNava CMessaoud OBonanno ELebrun MLesca GGarde ABhouri RBak MChambon PPoirsier CAustin-Tse CBahi-Buisson NMorel GCourtin TFuerte EPANavarro VZaafrane-Khachnaoui KO'Donnell-Luria APetit FNambot SNizon MWeber YRollier POdent SChesneau BGueden SBuratti JLieffering NMarijon PConrad SLaugel VWieczorek DDepienne CBoussion SBaulac SBramswig NCScheffer IETharreau MJean-Marcais NHeron BAn IHeron DMansour-Hendili LOunap KIsidor BSperelakis-Beedham BPaluch RToulouse JAraujo CMilh MKaiser FJGleeson JGDubourg CTorun DBarth MDuquet RChemaly NHarting NVilleneuve NSchneider AHildebrand MSCharbonnier CCharles PVillard LOjeda NMPlanes MBrosseau-Beauvir ALeguern EOlin VYadavilli MLaFlamme CWWhiffin NBlanc PGanne BHeulin MAuvin SBarcia GValence SRenaud MMefford HCKuechler AStock FSchaefer EAthanasiadou MSantini APiton AArpin SQuemener-Redon SRio MBiehler MBennett MFPerrin-Sabourin LSmol TRamond FVitobello ABezieau SLebre ASMaraval JKraft FMunnich APhilippe CDubucs CHoudayer CForlani SPais LSEssid MBricquir FLRoubertie ASchumann IMignot CGuerrot AMNowak FNeale Ade Vanssay de Blavous Legendre CJanuel LNicolas GGrabli DSengupta SKrause JMattausch CSunyaev SDurand BKonyukh MColmard MKing CMortreux JNguyen LFradin MLuthy KGuichet AElbracht MDiTroia SfalseSystematic analysis of snRNA genes reveals frequent &lt;i&gt;RNU2-2&lt;/i&gt; variants in dominant and recessive developmental and epileptic encephalopathies.Variants in spliceosomal small nuclear RNA (snRNA) genes <i>RNU4-2</i> (ReNU syndrome), <i>RNU5B-1</i>, and <i>RNU2-2</i> have recently been linked to dominant neurodevelopmental disorders (NDDs), revealing a major, previously overlooked role for noncoding snRNAs in human disease. Here, we systematically analysed 200 potentially functional snRNA genes in a French cohort comprising 26,911 individuals with rare disorders and through international collaborations. We identify <i>de novo</i> and biallelic variants in <i>RNU2-2</i> associated with both dominant and recessive NDDs in 126 individuals from 108 unrelated families. Recessive <i>RNU2-2</i> NDD is at least twice as frequent as the dominant NDD caused by n.4G>A and n.35A>G, and often arises from a <i>de novo</i> variant in <i>trans</i> 2025-01-01T00:00:00Z2025 Sep2026-05-02T03:19:57.79Z2026-05-02T03:11:56.369ZS-EPMC124248904095044510.1101/2025.09.02.25334923