Preprint: Outcomes and phenotypic expression of rare variants in hypertrophic cardiomyopathy genes amongst UK Biobank participants

Antonio de Marvao, Kathryn A. McGurk, Sean L. Zheng, Marjola Thanaj, Wenjia Bai, Jinming Duan, Carlo Biffi, Francesco Mazzarotto, Ben Statton, Timothy J.W. Dawes, Nicolò Savioli, Brian P. Halliday, Xiao Xu, Rachel J. Buchan, A John Baksi, Marina Quinlan, Paweł Tokarczuk, Upasana Tayal, Catherine Francis, Nicola Whiffin, Pantazis I. Theotokis, Xiaolei Zhang, Mikyung Jang, Alaine Berry, Antonis Pantazis, Paul J.R. Barton, Daniel Rueckert, Sanjay K. Prasad, Roddy Walsh, Carolyn Y. Ho, Stuart A. Cook, James S. Ware and Declan P. O’Regan 2021. Preprint: Outcomes and phenotypic expression of rare variants in hypertrophic cardiomyopathy genes amongst UK Biobank participants. medRxiv. https://doi.org/10.1101/2021.01.21.21249470

TitlePreprint: Outcomes and phenotypic expression of rare variants in hypertrophic cardiomyopathy genes amongst UK Biobank participants
AuthorsAntonio de Marvao, Kathryn A. McGurk, Sean L. Zheng, Marjola Thanaj, Wenjia Bai, Jinming Duan, Carlo Biffi, Francesco Mazzarotto, Ben Statton, Timothy J.W. Dawes, Nicolò Savioli, Brian P. Halliday, Xiao Xu, Rachel J. Buchan, A John Baksi, Marina Quinlan, Paweł Tokarczuk, Upasana Tayal, Catherine Francis, Nicola Whiffin, Pantazis I. Theotokis, Xiaolei Zhang, Mikyung Jang, Alaine Berry, Antonis Pantazis, Paul J.R. Barton, Daniel Rueckert, Sanjay K. Prasad, Roddy Walsh, Carolyn Y. Ho, Stuart A. Cook, James S. Ware and Declan P. O’Regan
Description

Now published in Journal of the American College of Cardiology 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.

Methods We compared outcomes and cardiovascular phenotypes in UK Biobank participants with whole exome sequencing 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=5,727; 1 in 35), of which 0.24% (n=474, 1 in 423) were pathogenic or likely pathogenic variants (SARC-P/LP). SARC-P/LP variants were associated with increased risk of death or major adverse cardiac events compared to controls (HR 1.68, 95% CI 1.37-2.06, p<0.001), mainly due to heart failure (HR 4.40, 95% CI 3.22-6.02, p<0.001) and arrhythmia (HR 1.55, 95% CI 1.18-2.03, p=0.002). In 21,322 participants with cardiac magnetic resonance imaging, SARC-P/LP were associated with increased left ventricular maximum wall thickness (10.9±2.7 vs 9.4±1.6 mm, p<0.001) and concentric remodelling (mass/volume ratio: 0.63±0.12 vs 0.58±0.09 g/mL, p<0.001), but hypertrophy (≥13mm) was only present in 16% (n=7/43, 95% CI 7-31%). Other rare sarcomere-encoding variants had a weak effect on wall thickness (9.5±1.7 vs 9.4±1.6 mm, p=0.002) with no combined excess cardiovascular risk (HR 1.00 95% CI 0.92-1.08, p=0.9).

Conclusions In the general population, SARC-P/LP variants have low aggregate penetrance for overt HCM but are associated with an increased risk of adverse cardiovascular outcomes and a sub-clinical cardiomyopathic phenotype. In contrast, rare sarcomeric variants that do not meet criteria to be classified as P/LP appear to have minimal clinical impact.

Year2021
Output mediaMedRxiv preprint
PublishermedRxiv
Publication dates
Published online26 Jan 2021
Digital Object Identifier (DOI)https://doi.org/10.1101/2021.01.21.21249470
Web address (URL)https://doi.org/10.1101/2021.01.21.21249470

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