Phenotypic Expression and Outcomes in Individuals With Rare Genetic Variants of Hypertrophic Cardiomyopathy
De Marvao A, Mcgurk KA, Zheng SL, Thanaj M, Bai W, Duan J, Biffi C, Mazzarotto F, Statton B, Dawes TJW, Savioli N, Halliday BP, Xu X, Buchan RJ, Baksi AJ, Quinlan M, Tokarczuk P, Tayal U, Francis C, Whiffin N, Theotokis P, Zhang X, Jang M, Berry A, Pantazis A, Barton PJR, Rueckert D, Prasad SK, Walsh R, Ho CY, Cook SA, Ware JS, O'Regan DP (2021)
Publication Type: Journal article
Publication year: 2021
Journal
Book Volume: 78
Pages Range: 1097-1110
Journal Issue: 11
DOI: 10.1016/j.jacc.2021.07.017
Abstract
Background: Hypertrophic cardiomyopathy (HCM) is caused by rare variants in sarcomere-encoding genes, but little is known about the clinical significance of these variants in the general population. Objectives: The goal of this study was to compare lifetime outcomes and cardiovascular phenotypes according to the presence of rare variants in sarcomere-encoding genes among middle-aged adults. Methods: This study analyzed whole exome sequencing and cardiac magnetic resonance imaging in UK Biobank participants stratified according to 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 an increased risk of death or major adverse cardiac events compared with controls (hazard ratio: 1.69; 95% confidence interval [CI]: 1.38-2.07; P < 0.001), mainly due to heart failure endpoints (hazard ratio: 4.23; 95% CI: 3.07-5.83; P < 0.001). In 21,322 participants with both cardiac magnetic resonance imaging and whole exome sequencing, SARC-HCM-P/LP variants were associated with an asymmetric increase in left ventricular maximum wall thickness (10.9 ± 2.7 mm vs 9.4 ± 1.6 mm; P < 0.001), but hypertrophy (≥13 mm) was only present in 18.4% (n = 9 of 49; 95% CI: 9%-32%). SARC-HCM-P/LP variants were still associated with heart failure after adjustment for wall thickness (hazard ratio: 6.74; 95% CI: 2.43-18.7; 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 an 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.
Involved external institutions
Imperial College London / The Imperial College of Science, Technology and Medicine
United Kingdom (GB)
Amsterdam University Medical Centers (Amsterdam UMC) / Amsterdam Universitair Medische Centra
Netherlands (NL)
Brigham and Women's Hospital (BWH)
United States (USA) (US)
United Kingdom (GB)
Amsterdam University Medical Centers (Amsterdam UMC) / Amsterdam Universitair Medische Centra
Netherlands (NL)
Brigham and Women's Hospital (BWH)
United States (USA) (US)
How to cite
APA:
De Marvao, A., Mcgurk, K.A., Zheng, S.L., Thanaj, M., Bai, W., Duan, J.,... O'Regan, D.P. (2021). Phenotypic Expression and Outcomes in Individuals With Rare Genetic Variants of Hypertrophic Cardiomyopathy. Journal of the American College of Cardiology, 78(11), 1097-1110. https://dx.doi.org/10.1016/j.jacc.2021.07.017
MLA:
De Marvao, Antonio, et al. "Phenotypic Expression and Outcomes in Individuals With Rare Genetic Variants of Hypertrophic Cardiomyopathy." Journal of the American College of Cardiology 78.11 (2021): 1097-1110.
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