biostudies-literatureTaylor JCSwiss National Science FoundationCancer Research UKBritish Heart FoundationEuropean Research CouncilAction Medical ResearchMedical Research CouncilNational Institute for Health Research (NIHR)Wellcome TrustAcademy of Medical SciencesBiotechnology and Biological Sciences Research Council717-726https://www.ebi.ac.uk/biostudies/studies/S-EPMC4601524biostudies-literatureUnknown47(7)To assess factors influencing the success of whole-genome sequencing for mainstream clinical diagnosis, we sequenced 217 individuals from 156 independent cases or families across a broad spectrum of disorders in whom previous screening had identified no pathogenic variants. We quantified the number of candidate variants identified using different strategies for variant calling, filtering, annotation and prioritization. We found that jointly calling variants across samples, filtering against both local and external databases, deploying multiple annotation tools and using familial transmission above biological plausibility contributed to accuracy. Overall, we identified disease-causing variants in 21% of cases, with the proportion increasing to 34% (23/68) for mendelian disorders and 57% (8/Nature geneticsFactors influencing success of clinical genome sequencing across a broad spectrum of disorders.PMC4601524091182NF-SI-0514-10091305608G1000801bMC_UU_12009/1090532MC_U137961145MC_UU_12010/6281824102974/Z/13/ZG1000801j093329MC_UU_12010/3G1000801cBB/I02593X/1MR/L009609/1G1000467MC_UU_12010/7AMS-SGCL11-Petousi100308L009609095688/Z/11/ZG9825289MC_UC_12010/3CL-2013-13-003MR/M006824/1G0900747 910701239049RG/12/16/29939100308/Z/12/ZNF-SI-0508-1023509568816459102731090532/Z/09/ZAMS-SGCL13-Bull095552146490310030MC_U1051741972063NIHR-RP-R3-12-026MC_UU_12009/11095552/Z/11/ZMC_UP_1502/3MR/L001411/1G0900747102731/Z/13/ZG1000801Taylor JCHatton EHastings RBentley DFlint JRobson KHughes LTaylor JWright BWhyte MPLunter GRusso AMcMullin MFYau CWilkie AOWatkins HLangman CBento CKrohn JPetousi NWitty LFiddy SGreger IHMcCarthy DKanapin ABuck DFugger LUhlig HHPagnamenta APugh CQuek LDendrou CDonnelly PHoward MNesbit MAKini USimmons AKingsbury ZOrmondroyd EPercy MKnight JCGreen AGoriely ASchuh ADavenport EEHumphray SCraft JDevuyst OAricescu ARRatcliffe PJBell JIGrocock RThakker RVSilverman ESahgal NCais OLise SPatel SYPiret SEHill ADahan Kvan Schouwenburg PAOturai ABHolmes CCornall RMurray LSorensen PSCazier JBWall SABecq JNemeth AHPopitsch NFenwick ALCario HMcGowan SJHiggs DPowrie FPolanco-Echeverry GHumburg PNutt DTomlinson IBuckle VJMiller KABeeson DVyas PChapel HTwigg SRGruszczyk AVMcVean GJohnson DBull KTrebes ABignell PBabbs CKarpe FGilbert RDAttar MBlair EPiazza PSweeney EAllan CLonie LCopley RRBroxholme JLuck JVyse TRobbins PAMartin HCRimmer ALamble SfalseFactors influencing success of clinical genome sequencing across a broad spectrum of disorders.To assess factors influencing the success of whole-genome sequencing for mainstream clinical diagnosis, we sequenced 217 individuals from 156 independent cases or families across a broad spectrum of disorders in whom previous screening had identified no pathogenic variants. We quantified the number of candidate variants identified using different strategies for variant calling, filtering, annotation and prioritization. We found that jointly calling variants across samples, filtering against both local and external databases, deploying multiple annotation tools and using familial transmission above biological plausibility contributed to accuracy. Overall, we identified disease-causing variants in 21% of cases, with the proportion increasing to 34% (23/68) for mendelian disorders and 57% (8/2015-01-01T00:00:00Z2015 Jul2026-05-04T14:06:40.765Z2019-03-27T01:59:54ZS-EPMC46015242598513810.1038/ng.3304