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

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 WhiffinPantazis 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, Declan P O'Regan

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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.

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.

This study analyzed whole exome sequencing and cardiac magnetic resonance imaging in UK Biobank participants stratified according to sarcomere-encoding variant status.

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).

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.
Original languageEnglish
Pages (from-to)1097-1110
JournalJournal of the American College of Cardiology
Issue number11
Early online date6 Sept 2021
Publication statusPublished - 14 Sept 2021


  • cardiovascular magnetic resonance
  • deep learning
  • genetics
  • hypertrophic cardiomyopathy
  • penetrance

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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