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Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality

2023; Nature Portfolio; Volume: 14; Issue: 1 Linguagem: Inglês

10.1038/s41467-023-38951-2

2041-1723

Ásmundur Oddsson, Patrick Sulem, Garðar Sveinbjörnsson, Gudny A. Arnadottir, Valgerður Steinthórsdóttir, Gísli H. Halldórsson, Bjarni A. Atlason, Gudjon R. Oskarsson, Hannes Helgason, Henriette Svarre Nielsen, David Westergaard, Juha Karjalainen, Hildigunnur Katrínardóttir, Rún Friðriksdóttir, Brynjar Ö. Jensson, Vinicius Tragante, Egil Ferkingstad, Hákon Jónsson, Sigurjón A. Guðjónsson, Doruk Beyter, Kristjan H. S. Moore, Helga B. Thordardottir, Snædís Kristmundsdóttir, Ólafur Andri Stefánsson, Solbritt Rantapää‐Dahlqvist, Ida E. Sønderby, Maria Didriksen, Pernilla Stridh, Jan Haavik, Laufey Tryggvadóttír, Oleksandr Frei, G. Bragi Walters, Ingrid Kockum, Henrik Hjalgrim, Thorunn A. Olafsdottir, Geir Selbæk, Mette Nyegaard, Christian Erikstrup, Thorsten Brodersen, Saedís Saevarsdóttir, Tomas Olsson, Kaspar René Nielsen, Ásgeir Haraldsson, Mie Topholm Bruun, Thomas Hansen, Søren Brunak, Kasper Nielsen, Mie Topholm Brun, Hreinn Stefánsson, Unnur Þorsteinsdóttir, Þóra Steingrímsdóttir, Rikke Louise Jacobsen, Rolv T. Lie, Srdjan Djurovic, Lars Alfredsson, Aitzkoa Lopez de Lapuente Portilla, Søren Brunak, Páll Melsted, Bjarni V. Halldórsson, Jona Saemundsdottir, Ólafur Þ. Magnússon, Leonid Padyukov, Karina Banasik, Þórunn Rafnar, Johan Askling, Lars Klareskog, Ole Birger Pedersen, Gísli Másson, Alexandra Havdahl, Björn Nilsson, Ole A. Andreassen, Mark J. Daly, Sisse Rye Ostrowski, Ingileif Jónsdóttir, Hreinn Stefánsson, Hilma Hólm, Agnar Helgason, Unnur Þorsteinsdóttir, Kári Stéfansson, Daníel F. Guðbjartsson,

Nutrition, Genetics, and Disease

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.