Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality.
Asmundur OddssonPatrick SulemGardar SveinbjörnssonGudny Anna ArnadottirValgerdur SteinthorsdottirGisli Hreinn HalldorssonBjarni A AtlasonGudjon R OskarssonHannes HelgasonHenriette Svarre NielsenDavid WestergaardJuha M KarjalainenHildigunnur KatrinardottirRun FridriksdottirBrynjar Orn JenssonVinicius TraganteEgil FerkingstadHákon JónssonSigurjon A GudjonssonDoruk BeyterKristjan Helgi Swerford MooreHelga B ThordardottirSnaedis KristmundsdottirOlafur A StefanssonSolbritt Rantapää DahlqvistIda Elken SonderbyMaria DidriksenPernilla StridhJan HaavikLaufey TryggvadottirOleksandr FreiG Bragi WaltersIngrid KockumHenrik HjalgrimThorunn Asta OlafsdottirGeir SelbaekMette NygaardChristian ErikstrupThorsten BrodersenSaedis SaevarsdottirTomas OlssonKaspar Rene NielsenAsgeir HaraldssonMie Topholm BruunThomas Folkmann Hansennull nullThora SteingrimsdottirRikke Louise JacobsenRolv Terje LieSrdjan DjurovicLars AlfredssonAitzkoa Lopez de Lapuente PortillaSoren BrunakPall MelstedBjarni V HalldórssonJona SaemundsdottirOlafur Th MagnussonLeonid PadyukovKarina BanasikThorunn RafnarJohan AsklingLars KlareskogOle Birger Vesterager PedersenGisli MassonKaroline Alexandra HavdahlBjörn NilssonOle Andreas AndreassenMark DalySisse Rye OstrowskiIngileif JónsdóttirHreinn StefanssonHilma HólmAgnar HelgasonUnnur ThorsteinsdottirKári StefánssonDaníel F GuðbjartssonPublished in: Nature communications (2023)
Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. To explore genetic causes of recessive lethality, we searched for sequence variants with deficit of homozygosity among 1.52 million individuals from six European populations. In this study, we identified 25 genes harboring protein-altering sequence variants with a strong deficit of homozygosity (10% or less of predicted homozygotes). Sequence variants in 12 of the genes cause Mendelian disease under a recessive mode of inheritance, two under a dominant mode, but variants in the remaining 11 have not been reported to cause disease. Sequence variants with a strong deficit of homozygosity are over-represented among genes essential for growth of human cell lines and genes orthologous to mouse genes known to affect viability. The function of these genes gives insight into the genetics of intrauterine lethality. We also identified 1077 genes with homozygous predicted loss-of-function genotypes not previously described, bringing the total set of genes completely knocked out in humans to 4785.