Rare genetic variants in genes and loci linked to dominant monogenic developmental disorders cause milder related phenotypes in the general population

• DOI: 10.1016/j.ajhg.2022.05.011
• Publication Date: 2022-06-13T14:30:23Z
• Authors: Rebecca Kingdom; Marcus Tuke; Andrew Wood; Robin N. Beaumont; Timothy M. Frayling; Michael N. Weedon; Caroline F. Wright
• Keywords: Penetrance; Exome

Many rare monogenic diseases are known to be caused by deleterious variants in thousands of genes, however the same can also found people without associated clinical phenotypes. The penetrance these is generally unknown wider population, as they typically identified small cohorts affected individuals and families with highly penetrant variants. Here, we investigated phenotypic effect rare, potentially genes loci where similar cause developmental disorders (DDs) a large population cohort. We used UK Biobank investigate phenotypes protein-truncating missense 599 monoallelic DDG2P using whole-exome-sequencing data from ∼200,000 copy-number overlapping DD SNP-array ∼500,000 individuals. that likely had mild DD-related phenotype, including lower fluid intelligence, slower reaction times, numeric memory scores, longer pairs matching times compared rest They were shorter, higher BMI, significant socioeconomic disadvantages: less employed or able work income deprivation index. Our findings suggest many routinely tested within pediatric genetics have intermediate may lifelong sub-clinical general adult population.