The penetrance of rare variants in cardiomyopathy-associated genes: A cross-sectional approach to estimating penetrance for secondary findings.

Female Male Humans Adult Penetrance Cardiomyopathies / genetics Cardiomyopathy, Hypertrophic Cardiomyopathy, Dilated / genetics Gene Frequency
cardiomyopathy penetrance prevalence secondary findings

Journal

American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475

Informations de publication

Date de publication:
07 09 2023
Historique:
received: 15 03 2023
revised: 21 07 2023
accepted: 04 08 2023
medline: 11 9 2023
pubmed: 1 9 2023
entrez: 31 8 2023
Statut: ppublish

Résumé

Understanding the penetrance of pathogenic variants identified as secondary findings (SFs) is of paramount importance with the growing availability of genetic testing. We estimated penetrance through large-scale analyses of individuals referred for diagnostic sequencing for hypertrophic cardiomyopathy (HCM; 10,400 affected individuals, 1,332 variants) and dilated cardiomyopathy (DCM; 2,564 affected individuals, 663 variants), using a cross-sectional approach comparing allele frequencies against reference populations (293,226 participants from UK Biobank and gnomAD). We generated updated prevalence estimates for HCM (1:543) and DCM (1:220). In aggregate, the penetrance by late adulthood of rare, pathogenic variants (23% for HCM, 35% for DCM) and likely pathogenic variants (7% for HCM, 10% for DCM) was substantial for dominant cardiomyopathy (CM). Penetrance was significantly higher for variant subgroups annotated as loss of function or ultra-rare and for males compared to females for variants in HCM-associated genes. We estimated variant-specific penetrance for 316 recurrent variants most likely to be identified as SFs (found in 51% of HCM- and 17% of DCM-affected individuals). 49 variants were observed at least ten times (14% of affected individuals) in HCM-associated genes. Median penetrance was 14.6% (±14.4% SD). We explore estimates of penetrance by age, sex, and ancestry and simulate the impact of including future cohorts. This dataset reports penetrance of individual variants at scale and will inform the management of individuals undergoing genetic screening for SFs. While most variants had low penetrance and the costs and harms of screening are unclear, some individuals with highly penetrant variants may benefit from SFs.

Identifiants

DOI: 10.1016/j.ajhg.2023.08.003 PMID: 37652022 PMC: PMC10502871
pubmed: 37652022
pii: S0002-9297(23)00279-3
doi: 10.1016/j.ajhg.2023.08.003
pmc: PMC10502871
pii:
doi:

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1482-1495

Subventions

Organisme : Medical Research Council
ID : MC-A658-5TY00
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Organisme : British Heart Foundation
ID : BBC/F/21/220106
Pays : United Kingdom
Organisme : British Heart Foundation
ID : FS/IPBSRF/22/27059
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UP_1605/13
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RG/19/6/34387
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 107469/Z/15/Z
Pays : United Kingdom
Organisme : British Heart Foundation
ID : RE/18/4/34215
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 200990/A/16/Z
Pays : United Kingdom

Informations de copyright

Copyright © 2023. Published by Elsevier Inc.

Déclaration de conflit d'intérêts

Declaration of interests J.S.W. has consulted for MyoKardia, Inc., Foresite Labs, and Pfizer. A.H. now works for AstraZeneca, UK. D.P.O. has consulted for Bayer. L.B. has consulted for Roche. D.G.M. is a paid advisor to GlaxoSmithKline, Insitro, Variant Bio, and Overtone Therapeutics and has received research support from AbbVie, Astellas, Biogen, BioMarin, Eisai, Merck, Pfizer, and Sanofi-Genzyme; none of these activities are directly related to the work presented here. E.M. is the owner of Mazalytics LLC, Boston, Massachusetts, USA.

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Auteurs

Kathryn A McGurk (KA)

National Heart and Lung Institute, Imperial College London, London, UK; MRC London Institute of Medical Sciences, Imperial College London, London, UK.

Xiaolei Zhang (X)

National Heart and Lung Institute, Imperial College London, London, UK.

Pantazis Theotokis (P)

National Heart and Lung Institute, Imperial College London, London, UK; MRC London Institute of Medical Sciences, Imperial College London, London, UK.

Kate Thomson (K)

Division of Cardiovascular Medicine, Radcliffe Department of Medicine and the Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

Andrew Harper (A)

Division of Cardiovascular Medicine, Radcliffe Department of Medicine and the Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

Rachel J Buchan (RJ)

National Heart and Lung Institute, Imperial College London, London, UK; MRC London Institute of Medical Sciences, Imperial College London, London, UK; Royal Brompton & Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, UK.

Erica Mazaika (E)

National Heart and Lung Institute, Imperial College London, London, UK.

Elizabeth Ormondroyd (E)

Division of Cardiovascular Medicine, Radcliffe Department of Medicine and the Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

William T Wright (WT)

Northern Ireland Regional Genetics Centre, Belfast Health and Social Care Trust, Belfast City Hospital, Belfast, Northern Ireland, UK.

Daniela Macaya (D)

GeneDx LLC, Gaithersburg, MD, USA.

Chee Jian Pua (CJ)

National Heart Research Institute Singapore and Duke-National University of Singapore, Singapore, Singapore.

Birgit Funke (B)

Laboratory for Molecular Medicine, Partners Healthcare Center for Personalized Genetic Medicine, Boston, MA, USA.

Daniel G MacArthur (DG)

Centre for Population Genomics, Garvan Institute of Medical Research and UNSW, Sydney, NSW, Australia; Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, VIC, Australia.

Sanjay K Prasad (SK)

National Heart and Lung Institute, Imperial College London, London, UK; Royal Brompton & Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, UK.

Stuart A Cook (SA)

MRC London Institute of Medical Sciences, Imperial College London, London, UK; National Heart Research Institute Singapore and Duke-National University of Singapore, Singapore, Singapore.

Mona Allouba (M)

National Heart and Lung Institute, Imperial College London, London, UK; Aswan Heart Centre, Aswan, Egypt.

Yasmine Aguib (Y)

National Heart and Lung Institute, Imperial College London, London, UK; Aswan Heart Centre, Aswan, Egypt.

Magdi H Yacoub (MH)

National Heart and Lung Institute, Imperial College London, London, UK; Royal Brompton & Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, UK; Aswan Heart Centre, Aswan, Egypt.

Declan P O'Regan (DP)

MRC London Institute of Medical Sciences, Imperial College London, London, UK.

Paul J R Barton (PJR)

National Heart and Lung Institute, Imperial College London, London, UK; MRC London Institute of Medical Sciences, Imperial College London, London, UK; Royal Brompton & Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, UK.

Hugh Watkins (H)

Division of Cardiovascular Medicine, Radcliffe Department of Medicine and the Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

Leonardo Bottolo (L)

Department of Medical Genetics, University of Cambridge, Cambridge, UK; The Alan Turing Institute, London, UK; MRC Biostatistics Unit, University of Cambridge, Cambridge, UK.

James S Ware (JS)

National Heart and Lung Institute, Imperial College London, London, UK; MRC London Institute of Medical Sciences, Imperial College London, London, UK; Royal Brompton & Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, UK. Electronic address: j.ware@imperial.ac.uk.

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