Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts.

ABSTRACT: The true prevalence and penetrance of monogenic disease variants are often not known because of clinical-referral ascertainment bias. We comprehensively assess the penetrance and prevalence of pathogenic variants in HNF1A, HNF4A, and GCK that account for >80% of monogenic diabetes. We analyzed clinical and genetic data from 1,742 clinically referred probands, 2,194 family members, clinically unselected individuals from a US health system-based cohort (n = 132,194), and a UK population-based cohort (n = 198,748). We show that one in 1,500 individuals harbor a pathogenic variant in one of these genes. The penetrance of diabetes for HNF1A and HNF4A pathogenic variants was substantially lower in the clinically unselected individuals compared to clinically referred probands and was dependent on

SUBMITTER: Mirshahi UL 

PROVIDER: S-EPMC9674944 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature