biostudies-literatureSeaby EGNIMH NIH HHSGerald Kerkut Charitable TrustNational Institute for Health Research (NIHR)NHGRI NIH HHSNational Institute of Mental HealthNational Human Genome Research InstituteWellcome Trust351-362https://www.ebi.ac.uk/biostudies/studies/S-EPMC9950176biostudies-literatureUnknown142(3)<h4>Background</h4>Genome sequencing was first offered clinically in the UK through the 100,000 Genomes Project (100KGP). Analysis was restricted to predefined gene panels associated with the patient's phenotype. However, panels rely on clearly characterised phenotypes and risk missing diagnoses outside of the panel(s) applied. We propose a complementary method to rapidly identify pathogenic variants, including those missed by 100KGP methods.<h4>Methods</h4>The Loss-of-function Observed/Expected Upper-bound Fraction (LOEUF) score quantifies gene constraint, with low scores correlated with haploinsufficiency. We applied DeNovoLOEUF, a filtering strategy to sequencing data from 13,949 rare disease trios in the 100KGP, by filtering for rare, de novo, loss-of-function variants in disease genesHuman geneticsTargeting de novo loss-of-function variants in constrained disease genes improves diagnostic rates in the 100,000 Genomes Project.PMC9950176U41 HG006834U24 HG011450RP-2016-07-011U01 MH119689UM1 HG008900Savage KTaylor Tavares ALBevers RFowler TRehm HLChan GCWilliams EThomas NSPullinger JLopez FJMaleady-Crowe FBaralle DLahnstein LHubbard TJPEnnis SWelland MJMinneci FStuckey ASieghart AGenomics England ConsortiumCaulfield MJHamblin AMueller MO'Donovan PAmbrose JCScott RHTucci AMoutsianas LBleda MLeigh SEAPatch CThomas ERABrittain HJones LJSeaby EGArumugam PKasperaviciute DHenderson SPereira MBRogers TBoardman-Pretty FMcEntagart MKayikci MThompson SRMurugaesu NLeong IUSKousathanas AWitkowska KTanguy MSmith SCJackson RGiess ARendon ASosinsky AO'Donnell-Luria APerez-Gil DNeed ACSawant KBoustred CRSiddiq AOdhams CAWebb ARahim TWood SMfalseTargeting de novo loss-of-function variants in constrained disease genes improves diagnostic rates in the 100,000 Genomes Project.<h4>Background</h4>Genome sequencing was first offered clinically in the UK through the 100,000 Genomes Project (100KGP). Analysis was restricted to predefined gene panels associated with the patient's phenotype. However, panels rely on clearly characterised phenotypes and risk missing diagnoses outside of the panel(s) applied. We propose a complementary method to rapidly identify pathogenic variants, including those missed by 100KGP methods.<h4>Methods</h4>The Loss-of-function Observed/Expected Upper-bound Fraction (LOEUF) score quantifies gene constraint, with low scores correlated with haploinsufficiency. We applied DeNovoLOEUF, a filtering strategy to sequencing data from 13,949 rare disease trios in the 100KGP, by filtering for rare, de novo, loss-of-function variants in disease genes2023-01-01T00:00:00Z2023 Mar2026-05-16T03:14:55.148Z2025-02-18T23:44:18.07ZS-EPMC99501763647740910.1007/s00439-022-02509-x