Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes.

ABSTRACT: Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless,

SUBMITTER: Goodrich JK 

PROVIDER: S-EPMC8190084 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature