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

Autor:	Mirshahi UL; Geisinger Clinic, Geisinger Health System, Danville, PA, USA., Colclough K; Molecular Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK., Wright CF; Institute of Biomedical and Clinical Science, College of Medicine and Health, University of Exeter, Exeter, UK., Wood AR; Institute of Biomedical and Clinical Science, College of Medicine and Health, University of Exeter, Exeter, UK., Beaumont RN; Institute of Biomedical and Clinical Science, College of Medicine and Health, University of Exeter, Exeter, UK., Tyrrell J; Institute of Biomedical and Clinical Science, College of Medicine and Health, University of Exeter, Exeter, UK., Laver TW; Institute of Biomedical and Clinical Science, College of Medicine and Health, University of Exeter, Exeter, UK., Stahl R; Geisinger Clinic, Geisinger Health System, Danville, PA, USA., Golden A; Geisinger Clinic, Geisinger Health System, Danville, PA, USA., Goehringer JM; Geisinger Clinic, Geisinger Health System, Danville, PA, USA., Frayling TF; Institute of Biomedical and Clinical Science, College of Medicine and Health, University of Exeter, Exeter, UK., Hattersley AT; Institute of Biomedical and Clinical Science, College of Medicine and Health, University of Exeter, Exeter, UK., Carey DJ; Geisinger Clinic, Geisinger Health System, Danville, PA, USA., Weedon MN; Institute of Biomedical and Clinical Science, College of Medicine and Health, University of Exeter, Exeter, UK. Electronic address: m.n.weedon@exeter.ac.uk., Patel KA; Institute of Biomedical and Clinical Science, College of Medicine and Health, University of Exeter, Exeter, UK. Electronic address: k.a.patel@exeter.ac.uk.
Jazyk:	angličtina
Zdroj:	American journal of human genetics [Am J Hum Genet] 2022 Nov 03; Vol. 109 (11), pp. 2018-2028. Date of Electronic Publication: 2022 Oct 17.
DOI:	10.1016/j.ajhg.2022.09.014
Abstrakt:	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 the setting (32% in the population, 49% in the health system cohort, 86% in a family member, and 98% in probands for HNF1A). The relative risk of diabetes was similar across the clinically unselected cohorts highlighting the role of environment/other genetic factors. Surprisingly, the penetrance of pathogenic GCK variants was similar across all cohorts (89%-97%). We highlight that pathogenic variants in HNF1A, HNF4A, and GCK are not ultra-rare in the population. For HNF1A and HNF4A, we need to tailor genetic interpretation and counseling based on the setting in which a pathogenic monogenic variant was identified. GCK is an exception with near-complete penetrance in all settings. This along with the clinical implication of diagnosis makes it an excellent candidate for the American College of Medical Genetics secondary gene list. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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