biostudies-literatureZhou XHoward Hughes Medical InstituteNIMH NIH HHSNIDCD NIH HHSNIGMS NIH HHS1305-1319https://www.ebi.ac.uk/biostudies/studies/S-EPMC9470534biostudies-literatureUnknown54(9)To capture the full spectrum of genetic risk for autism, we performed a two-stage analysis of rare de novo and inherited coding variants in 42,607 autism cases, including 35,130 new cases recruited online by SPARK. We identified 60 genes with exome-wide significance (P < 2.5 × 10^-6), including five new risk genes (NAV3, ITSN1, MARK2, SCAF1 and HNRNPUL2). The association of NAV3 with autism risk is primarily driven by rare inherited loss-of-function (LoF) variants, with an estimated relative risk of 4, consistent with moderate effect. Autistic individuals with LoF variants in the four moderate-risk genes (NAV3, ITSN1, SCAF1 and HNRNPUL2; n = 95) have less cognitive impairment than 129 autistic individuals with LoF variants in highly penetrant genes (CHD8, SCN2A, ADNP, FOXP1 and SNature geneticsIntegrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes.PMC9470534T32 GM008629R01 MH105527R01 DC014489T32 GM139776K99 MH117165R01 MH101221R01 GM120609Shu CDillon EStephens ANTurner TNCordova JEdmonson CAbbeduto LLillie NErickson CAGunter CObiajulu JUManning PDaniels AMWeaver WCRussell NBerger NXu SDennis MYQi HHale MNWhite SRoche CPolite JLopez MTso IFMathai SMorrier MJPiven JPama KBaer MCartner LAPlate SBashar AFox EABeckwith MBerman APawlowski KGHyun SValicenti-McDermott MDiggins CBardett NOrrick EShir MJacob SGrosvenor LPGalbraith VMurali SCFischer GJHernandez JKlaiman CGoler AConyers SMurray KRemington RChen TNeely JFriedman SLTsai KTiede GEarl RKFassler CGupta ARLamarche EMcCracken JTHaley MPierre COcampo EShaffer RCRhea AMorales-Lara AWodka ELAcampado JIbanez TPerez ELeonczyk CZaydens HSahin MPhillips DVeenstra-Vanderweele JCoury DLHarris NDoyle ESnyder LGSweeney MHarris JFPandey JTesng AMohiuddin SJean SSchwind BYu TWDecius NShah NHunter SShah SBradley CCPedapati EVLimon DCallahan KScherr JShen YMcTaggart MKramer SRachubinski ALMarzano GManoharan JLo NRandall SSinger KOchoa-Lubinoff CKowanda MLash AEButter EMSinger ERuzzo EKryszak EMann LVerdi MMccoy NBrueggeman LNorris MDent KDoan RNSantangelo SVanMetre BLimpoco DHowes DBlank ETargalia NRigby CDichter GSToroney JHan BTran TAmatya AMiller FKGreene TBerry-Kravis ECordiero LAce AJAnnett RDNicholson AMcKenzie APLanda RJCarbone PSSingh VKoene HRusso-Ponsaran NMMiceli ASoorya LVAnglo CSteele MMatthews ETCorzo LFChoi YBThomas TRJelinek AHess AWard AJarratt ABower EMankar AComitre JHerbert LMZaro CAberbach GCho DOusley OYZick ANowell KTakahashi NRosenberg CRGiancarla DGruber AJSmith CCubells JFAhlers KFish ASabiha MSmith KPaolicelli AMKaplan HED'Ambrosi SGiven ELord CRosewater JGordon RASandhu STjernagel JBentley DSiegel MStephenson KGonzalez NWalston CHGriswold AJMalloch LO'Roak BJGrimes EVan Wade CMyers VJLibove RChin WGoin-Kochel RPDuhon GSullivan CAWShaikh TGutierrez AHorner SRojas DCampo-Soria CFrayne MHall JBRayos MWalsh LKAberle SGonzalez AProck LMSkinner SGulsrud ACJones EBernier RAFleisch CFombonne EJFazal FDunlevy MHardan AHilscher BAGerdts JAChintalapalli SZhao HMilliken APacheco LDRice CELee SJNagpal NTafolla MBarns SDChang TSVernoia BMMorotti HSchneider HLGray CBeard KCohen CFanta ARana RWright JRJudge JClark RDKanne SMHutter HGazestani VQiu SEnright BGwynette MFCalderon NDiehl KO'Connor ELi HPierce KLLi DGunderson JMontezuma JAlbright CMason AJurayj JAmaral DGCourchesne ESPARK ConsortiumSoucy AJordy MSarver DENishida ALobisi BJensen BAstrovskaya IFrancis SFitzgerald KDSziklay AMelnyk SWhite-Lehman CCaI WLuo ARaven AMarini RBell BAlvarez NMontes DVVolfovsky NCottrell HMurillo KThompson SSutcliffe JSShrier CO'Neil MEichler EEKrentz ADYeh LPrinten MRanganathan VShulman LHBrewster SJZhang HNguyen ANZha CDelaporte JO'Brien KColeman KJuarez APHirshman AIstephanous DSchoonover GNewman ODeMarco LRichardson HBahl EGhaziuddin MSchultz RTWainer ALSchweers KACasseus MCamba ASarris MMallardi MDMcCarthy CKim ADuBois MBuescher CXu SXHepburn SCutri MKoza MCorrea DCurrin MOrtiz CGonring KPopp MAButler MEChung WKLawson NTaylor CMMartin CLHirst KPolanco JLampert EHeyman MStamps DLechniak HAndrus AAdams AHauf BMastel SZhou XXiao SSimon AMichaels SSwanson ASrishyla DBooker SAlessandri MBrown AEsler ACarpenter LPramparo TTallbull ASimon LCarpenter SJorgenson AWang JCasten LBrooks ELesher LBirdwell SWang TGanesan SHolbrook ARutter TBaraghoshi GHuang-Storms LYHojlo MLaw JKJou RMichaelson JJWasserburg LColombi CFeliciano PYang WSShocklee ADHo THeydemann PBoland SCoughlin MReal KRodriguez NFatemi ALong NEldred SMadi NHooks GMarchenko OBaalman KBeeson LGong JLittlefield SGeschwind DHBeeson JRobertson BEKoomar TOrobio JPalmer SLicona SGhina HRambeck DKitaygorodsky AHarvey WTCoppola LBrown JArriaga IWarren ZEShikov RfalseIntegrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes.To capture the full spectrum of genetic risk for autism, we performed a two-stage analysis of rare de novo and inherited coding variants in 42,607 autism cases, including 35,130 new cases recruited online by SPARK. We identified 60 genes with exome-wide significance (P < 2.5 × 10^-6), including five new risk genes (NAV3, ITSN1, MARK2, SCAF1 and HNRNPUL2). The association of NAV3 with autism risk is primarily driven by rare inherited loss-of-function (LoF) variants, with an estimated relative risk of 4, consistent with moderate effect. Autistic individuals with LoF variants in the four moderate-risk genes (NAV3, ITSN1, SCAF1 and HNRNPUL2; n = 95) have less cognitive impairment than 129 autistic individuals with LoF variants in highly penetrant genes (CHD8, SCN2A, ADNP, FOXP1 and S2022-01-01T00:00:00Z2022 Sep2025-04-19T00:29:38.211Z2025-04-07T11:34:16.173ZS-EPMC94705343598215910.1038/s41588-022-01148-2