Dissecting the Reduced Penetrance of Putative Loss-of-Function Variants in Population-Scale Biobanks.

ABSTRACT: Loss-of-function variants (LoFs) disrupt the activity of their impacted gene. They are often associated with clinical phenotypes, including autosomal dominant diseases driven by haploinsufficiency. Recent analyses using biobanks have suggested that LoF penetrance for some haploinsufficient disorders may be low, an observation that has important implications for population genomic screening. However, biobanks are also rife with missing data, and the reliability of these findings remains uncertain. Here, we examine the penetrance of putative LoFs (pLoFs) using a cohort of ≈24,000 carriers derived from two population-scale biobanks: the UK Biobank and the All of Us Research Program. We investigate several possible etiologies for reduced pLoF penetrance, including biobank recruitment biases, a

SUBMITTER: Blair DR 

PROVIDER: S-EPMC11469360 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature