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

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 cl...

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Autores principales: Mirshahi, Uyenlinh L, Colclough, Kevin, Wright, Caroline F, Wood, Andrew R, Beaumont, Robin N, Tyrrell, Jessica, Laver, Thomas W, Stahl, Richard, Golden, Alicia, Goehringer, Jessica M, Frayling, Timothy F, Hattersley, Andrew T, Carey, David J, Weedon, Michael N, Patel, Kashyap A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9674944/
https://www.ncbi.nlm.nih.gov/pubmed/36257325
http://dx.doi.org/10.1016/j.ajhg.2022.09.014
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author Mirshahi, Uyenlinh L
Colclough, Kevin
Wright, Caroline F
Wood, Andrew R
Beaumont, Robin N
Tyrrell, Jessica
Laver, Thomas W
Stahl, Richard
Golden, Alicia
Goehringer, Jessica M
Frayling, Timothy F
Hattersley, Andrew T
Carey, David J
Weedon, Michael N
Patel, Kashyap A
author_facet Mirshahi, Uyenlinh L
Colclough, Kevin
Wright, Caroline F
Wood, Andrew R
Beaumont, Robin N
Tyrrell, Jessica
Laver, Thomas W
Stahl, Richard
Golden, Alicia
Goehringer, Jessica M
Frayling, Timothy F
Hattersley, Andrew T
Carey, David J
Weedon, Michael N
Patel, Kashyap A
author_sort Mirshahi, Uyenlinh L
collection PubMed
description 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.
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spelling pubmed-96749442022-11-20 Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts Mirshahi, Uyenlinh L Colclough, Kevin Wright, Caroline F Wood, Andrew R Beaumont, Robin N Tyrrell, Jessica Laver, Thomas W Stahl, Richard Golden, Alicia Goehringer, Jessica M Frayling, Timothy F Hattersley, Andrew T Carey, David J Weedon, Michael N Patel, Kashyap A Am J Hum Genet Article 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. Elsevier 2022-11-03 2022-10-17 /pmc/articles/PMC9674944/ /pubmed/36257325 http://dx.doi.org/10.1016/j.ajhg.2022.09.014 Text en © 2022 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Mirshahi, Uyenlinh L
Colclough, Kevin
Wright, Caroline F
Wood, Andrew R
Beaumont, Robin N
Tyrrell, Jessica
Laver, Thomas W
Stahl, Richard
Golden, Alicia
Goehringer, Jessica M
Frayling, Timothy F
Hattersley, Andrew T
Carey, David J
Weedon, Michael N
Patel, Kashyap A
Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts
title Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts
title_full Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts
title_fullStr Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts
title_full_unstemmed Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts
title_short Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts
title_sort reduced penetrance of mody-associated hnf1a/hnf4a variants but not gck variants in clinically unselected cohorts
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9674944/
https://www.ncbi.nlm.nih.gov/pubmed/36257325
http://dx.doi.org/10.1016/j.ajhg.2022.09.014
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