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Updated: Oct 20, 2025

Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
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Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model

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Phenotypic Expression and Outcomes in Individuals With Rare Genetic Variants of Hypertrophic Cardiomyopathy

Antonio de Marvao1, Kathryn A McGurk2, Sean L Zheng3

  • 1MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, London, United Kingdom.

Journal of the American College of Cardiology
|September 10, 2021
PubMed

Insights

Rare variants in sarcomere-encoding genes (SARC-HCM-P/LP) are linked to increased cardiovascular risks and heart failure in middle-aged adults, even without overt hypertrophic cardiomyopathy (HCM). These findings may improve risk stratification beyond familial disease.

Area of Science:

  • Cardiovascular Genetics
  • Genomics
  • Precision Medicine

Background:

  • Hypertrophic cardiomyopathy (HCM) is primarily caused by rare variants in sarcomere-encoding genes.
  • The clinical significance of these genetic variants in the general population remains largely unknown.

Purpose of the Study:

  • To compare lifetime outcomes and cardiovascular phenotypes in middle-aged adults based on the presence of rare sarcomere-encoding gene variants.
  • To investigate the clinical impact of SARC-HCM-P/LP variants in a large, population-based cohort.

Main Methods:

  • Analysis of whole exome sequencing data from 200,584 UK Biobank participants.
  • Stratification of participants based on sarcomere-encoding variant status.
  • Cardiac magnetic resonance imaging (CMR) data analyzed in a subset of 21,322 participants.

Main Results:

  • Prevalence of SARC-HCM-P/LP variants was 0.25% (1 in 407).
  • SARC-HCM-P/LP variants were associated with increased risk of death or major adverse cardiac events (HR: 1.69) and heart failure (HR: 4.23).
  • Variants were linked to increased left ventricular wall thickness, but overt HCM was rare (18.4%); heart failure risk remained elevated even after adjusting for wall thickness.

Conclusions:

  • SARC-HCM-P/LP variants exhibit low penetrance for overt HCM but increase cardiovascular risk and attenuate the cardiomyopathic phenotype.
  • Identification of these variants can enhance cardiovascular risk stratification beyond known familial disease.
  • These findings highlight the importance of genetic screening for sarcomere-encoding variants in broader populations.
Abstract

Keywords:
cardiovascular magnetic resonancedeep learninggeneticshypertrophic cardiomyopathypenetrance

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