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We estimated the genome-wide contribution of recessive coding variation in 6040 families from the Deciphering Developmental Disorders study. The proportion of cases attributable to recessive coding variants was 3.6% in patients of European ancestry, compared with 50% explained by de novo coding mutations. It was higher (31%) in patients with Pakistani ancestry, owing to elevated autozygosity. Half of this recessive burden is attributable to known genes. We identified two genes not previously associated with recessive developmental disorders, KDM5B and EIF3F, and functionally validated them with mouse and cellular models. Our results suggest that recessive coding variants account for a small fraction of currently undiagnosed nonconsanguineous individuals, and that the role of noncoding variants, incomplete penetrance, and polygenic mechanisms need further exploration.

Original publication

DOI

10.1126/science.aar6731

Type

Journal article

Journal

Science

Publication Date

07/12/2018

Volume

362

Pages

1161 - 1164

Keywords

Animals, Developmental Disabilities, Disease Models, Animal, Eukaryotic Initiation Factor-3, Europe, Genes, Recessive, Genetic Code, Genetic Variation, Genome-Wide Association Study, Humans, Jumonji Domain-Containing Histone Demethylases, Mice, Nuclear Proteins, Pakistan, Penetrance, Phylogeny, Repressor Proteins