Phenotypic expression and outcomes in individuals with rare genetic variants of hypertrophic cardiomyopathy
File(s)
Published version
Author(s)
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.
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.
Date Issued
2021-09-14
Date Acceptance
2021-07-06
Citation
Journal of the American College of Cardiology, 2021, 78 (11), pp.1097-1110
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/ ) .
COLLEGE OF CARDIOLOGY FO UNDATION. THIS IS AN OPEN ACCESS ARTICLE UNDER
THE CC BY LICENSE ( http://creativecommons.org/licenses/by/4.0/ ) .
License URL
Sponsor
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
Identifier
https://www.sciencedirect.com/science/article/pii/S0735109721056953?via%3Dihub
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
Subjects
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
Date Publish Online
2021-09-06