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Phenotypic expression and outcomes in individuals with rare genetic variants of hypertrophic cardiomyopathy

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Title: Phenotypic expression and outcomes in individuals with rare genetic variants of hypertrophic cardiomyopathy
Authors: Simoes Monteiro de Marvao, A
McGurk, K
Zheng, S
Thanaj, M
Bai, W
Duan, J
Biffi, C
Mazzarotto, F
Statton, B
Dawes, T
Savioli, N
Halliday, B
Xu, X
Buchan, R
Baksi, A
Quinlan, M
Tokarczuk, P
Tayal, U
Francis, C
Whiffin, N
Theotokis, A
Zhang, X
Jang, M
Berry, A
Pantazis, A
Barton, P
Rueckert, D
Prasad, S
Walsh, R
Ho, C
Cook, S
Ware, J
O'Regan, D
Item Type: Journal Article
Abstract: Background: Hypertrophic cardiomyopathy (HCM) is caused by rare variants in sarcomereencoding genes, but little is known about the clinical significance of these variants in the general population. Objectives: To compare lifetime outcomes and cardiovascular phenotypes according to the presence of rare variants in sarcomere-encoding genes amongst middle-aged adults. Methods: We analysed whole exome sequencing and cardiac magnetic resonance (CMR) imaging in UK Biobank participants stratified by sarcomere-encoding variant status. Results: The prevalence of rare variants (allele frequency <0.00004) in HCM-associated sarcomere-encoding genes in 200,584 participants was 2.9% (n=5,712; 1 in 35), and the prevalence of variants pathogenic or likely pathogenic for HCM (SARC-HCM-P/LP) was 0.25% (n=493, 1 in 407). SARC-HCM-P/LP variants were associated with increased risk of death or major adverse cardiac events compared to controls (HR 1.69, 95% CI 1.38 to 2.07, p<0.001), mainly due to heart failure endpoints (HR 4.23, 95% CI 3.07 to 5.83, p<0.001). In 21,322 participants with CMR, SARC-HCM-P/LP were associated with asymmetric increase in left ventricular maximum wall thickness (10.9±2.7 vs 9.4±1.6 mm, p<0.001) but hypertrophy (≥13mm) was only present in 18.4% (n=9/49, 95% CI 9 to 32%). SARC-HCMP/LP were still associated with heart failure after adjustment for wall thickness (HR 6.74, 95% CI 2.43 to 18.7, p<0.001). Conclusions: In this population of middle-aged adults, SARC-HCM-P/LP variants have low aggregate penetrance for overt HCM but are associated with increased risk of adverse cardiovascular outcomes and an attenuated cardiomyopathic phenotype. Although absolute event rates are low, identification of these variants may enhance risk stratification beyond familial disease.
Issue Date: 14-Sep-2021
Date of Acceptance: 6-Jul-2021
URI: http://hdl.handle.net/10044/1/90815
DOI: 10.1016/j.jacc.2021.07.017
ISSN: 0735-1097
Publisher: Elsevier
Start Page: 1097
End Page: 1110
Journal / Book Title: Journal of the American College of Cardiology
Volume: 78
Issue: 11
Copyright Statement: © 2021 THE AUTHORS. PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN COLLEGE OF CARDIOLOGY FO UNDATION. THIS IS AN OPEN ACCESS ARTICLE UNDER THE CC BY LICENSE ( http://creativecommons.org/licenses/by/4.0/ ) .
Sponsor/Funder: The Academy of Medical Sciences
Imperial College Healthcare NHS Trust- BRC Funding
British Heart Foundation
Imperial College Healthcare NHS Trust- BRC Funding
British Heart Foundation
British Heart Foundation
Wellcome Trust
National Heart & Lung Institute Foundation
Engineering & Physical Science Research Council (EPSRC)
Mason Medical Research Foundation
The Academy of Medical Sciences
Funder's Grant Number: nil
RDC04
NH/17/1/32725
RDB02
RE/18/4/34215
RG/19/6/34387
107469/Z/15/Z
N/A
EP/P001009/1
N/A
SGL015/1006
Keywords: Science & Technology
Life Sciences & Biomedicine
Cardiac & Cardiovascular Systems
Cardiovascular System & Cardiology
deep learning
genetics
hypertrophic cardiomyopathy
penetrance
cardiovascular magnetic resonance
MEDICAL GENETICS
AMERICAN-COLLEGE
CLINICAL EXOME
DIAGNOSIS
RISK
RECOMMENDATIONS
GUIDELINES
DISEASE
BURDEN
cardiovascular magnetic resonance
deep learning
genetics
hypertrophic cardiomyopathy
penetrance
1102 Cardiorespiratory Medicine and Haematology
1117 Public Health and Health Services
Cardiovascular System & Hematology
Publication Status: Published
Online Publication Date: 2021-09-06
Appears in Collections:Computing
National Heart and Lung Institute
Institute of Clinical Sciences
Faculty of Medicine
Department of Brain Sciences
Faculty of Engineering



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