biostudies-literatureKaplanis JCancer Research UKMedical Research CouncilDutch Research Council (NWO)Bowel Cancer UKNational Institute for Health Research (NIHR)Wellcome Trust757-762https://www.ebi.ac.uk/biostudies/studies/S-EPMC7116826biostudies-literatureUnknown586(7831)De novo mutations in protein-coding genes are a well-established cause of developmental disorders¹. However, genes known to be associated with developmental disorders account for only a minority of the observed excess of such de novo mutations^1,2. Here, to identify previously undescribed genes associated with developmental disorders, we integrate healthcare and research exome-sequence data from 31,058 parent-offspring trios of individuals with developmental disorders, and develop a simulation-based statistical test to identify gene-specific enrichment of de novo mutations. We identified 285 genes that were significantly associated with developmental disorders, including 28 that had not previously been robustly associated with developmental disorders. Although we detecNatureEvidence for 28 genetic disorders discovered by combining healthcare and research data.PMC7116826HICF-1009-003MC_UU_00007/3NF-SI-0515-10035NF-SI-0510-10282917-17-3532177718PG0019McNerlan SKeelagher RWright RWilliams NMohammed STischkowitz MWright MSwale AWilliams DDouglas ACallaway AGardiner CBorras SShears DZwolinski SBrewer CPaterson JEason JWoods GMolenda ATobias EClowes VJewell RTemple IKLester TGibbons RRetterer KLynch SKaplanis JCooper-Charles LLongman CFisher RFaravelli FFlinter FRosser ESaggar ALow KCarmichael JSansbury FWakeling EDabir TJones ELachlan KTurner CBradley TRuddy DHoward EOwens MBeleza AYau SHurst JCoates ABrunner HGMcLean JDonnelly DKini ULampe AGallone GJenkins LDixit AMorton JRoss ASarkar ABourn DGreen ABerg JWellesley DSuri MKraus AMiedzybrodzka ZIrving MBradley LKumar VKAAbbs SVarghese VSide LMutch SArmstrong RClement EO'Driscoll MMcQuaid SReavey EKinning EBaptista JTennant SParker MPrescott KHunt DOsio DDobbie AJarvis JRagge NEllis IBusby LArvai KJSamocha KEFirth HVProcter AHomfray TShaw-Smith CIslam LDunn CJones WReijnders MRFMcWilliam CIzatt LCastle BBradshaw KBernhard BDanecek PClasper SRaymond LMcEntagart MJuusola JMagee AFitzPatrick DRCanham NJackson AScott RTooley MHewitt SJackson EJohnson DHolden SComerford JMcMullan DBennett CDouzgou SYeung APottinger CWeber AMarks KNemeth ALim DZhang ZAzam TGoudie DWilloughby JMcConnell VMavrak EDean JReid EMoore DYntema HGClayton-Smith JMartincorena IBodek SLelieveld SHGardner EJWilson LClark CCooper NDeciphering Developmental Disorders StudyVissers LELMButler RStewart HJin HFoulds NHobson EMontgomery TChandler KLees MStewart AStewart FSandford RKerr BCilliers DBurn JHellens SCorrin SKivuva ESearle CNorman AMHumphreys MMcGowan RGhali NPorteous MRoworth WBriggs TOng KRGilissen CMcCann EKharbanda MHenderson AHurles MEVogt JThomson JMercer CMurday VShannon NAllen ZTurton SJosifova DShort PJBanka SCole TSplitt MDeshpande CBalasubramanian MWiel LTysoe CNewbury-Ecob RPrice SCox HRoberts ELoughlin SAlbaba SLahiri NMetcalfe KMorrison PJClarke ASampson JRankin JLangley CHuang NBaker DNaik SMullaney BPfundt RCrosby CBrady ABrooks CWright CFStraub VGreenhalgh LBaralle DDaniels SSimonic IBreen CHaines RDavidson RRea GPoulton JBarrett JCGaunt LWhiteford MQuarrell OPilz DCassidy EJde Boer ETurnpenny PRobert LPark SMMugalaasi HTorene RIHills ADonaldson ABarnicoat AHarrison RMansour SRyten MStinton VScurr IBurkitt-Wright EMcKee SSheridan EHolder SHolder MKamath AEberhardt RYJoss SMale AMorrogh DVasudevan PIbitoye RSmithson SSharif ADonnai DCleary ESmith AMcRae JFBlair EBaple ELam WCampbell JBlyth MTatton-Brown KElmslie FMartin HCWilkie ALord JFry AfalseEvidence for 28 genetic disorders discovered by combining healthcare and research data.De novo mutations in protein-coding genes are a well-established cause of developmental disorders¹. However, genes known to be associated with developmental disorders account for only a minority of the observed excess of such de novo mutations^1,2. Here, to identify previously undescribed genes associated with developmental disorders, we integrate healthcare and research exome-sequence data from 31,058 parent-offspring trios of individuals with developmental disorders, and develop a simulation-based statistical test to identify gene-specific enrichment of de novo mutations. We identified 285 genes that were significantly associated with developmental disorders, including 28 that had not previously been robustly associated with developmental disorders. Although we detec2020-01-01T00:00:00Z2020 Oct2026-04-18T01:22:42.74Z2021-02-28T08:15:48ZS-EPMC71168263305719410.1038/s41586-020-2832-5