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Updated: Jun 5, 2025

Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
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Low Penetrance Sarcomere Variants Contribute to Additive Risk in Hypertrophic Cardiomyopathy.

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|December 5, 2024
PubMed
Summary

Low penetrance sarcomere variants (LowSVs) are common and contribute to hypertrophic cardiomyopathy (HCM) risk. Combined with pathogenic variants, LowSVs significantly increase HCM severity and influence age-related cardiac remodeling.

Keywords:
cardiomyopathiescardiomyopathy, hypertrophicgenetic variationinduced pluripotent stem cellspenetrancesarcomeres

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Area of Science:

  • Cardiovascular Genetics
  • Human Genetics
  • Molecular Cardiology

Background:

  • Hypertrophic cardiomyopathy (HCM) traditionally viewed as monogenic, caused by rare, highly penetrant sarcomere variants.
  • Polygenic contributions are increasingly recognized, but low penetrance sarcomere variants (LowSVs) remain understudied.
  • LowSVs are common, intermediate frequency variants with moderate effect sizes, hypothesized to influence HCM risk and severity.

Purpose of the Study:

  • Systematically investigate the role of LowSVs in hypertrophic cardiomyopathy (HCM).
  • Define LowSVs based on population frequency and enrichment in HCM patients.
  • Assess the association of LowSVs with disease severity, clinical outcomes, and HCM-adjacent traits.

Main Methods:

  • Identified LowSVs from the Sarcomeric Human Cardiomyopathy Registry (SHaRe) using defined frequency and enrichment criteria.
  • Analyzed LowSV association with HCM severity and outcomes.
  • Assessed functional impact of selected LowSVs using patient-derived cardiomyocytes.
  • Correlated LowSVs with HCM-adjacent traits in the general population using UK Biobank data.

Main Results:

  • Identified 12 LowSVs, collectively common in the general population (1:350) and enriched in HCM patients.
  • Isolated LowSVs associated with later HCM diagnosis and fewer adverse events.
  • LowSVs combined with pathogenic variants significantly increased morbidity (HR 5.4) compared to single pathogenic variants (HR 2.0).
  • Validated intermediate functional impact for specific LowSVs (MYBPC3, TNNT2).
  • Five LowSVs associated with HCM-adjacent traits in the general population without overt HCM.

Conclusions:

  • Established LowSVs as a distinct class of common, low penetrance variants influencing HCM.
  • Isolated LowSVs contribute to milder HCM phenotypes.
  • Combined effects of LowSVs and pathogenic variants significantly exacerbate HCM severity.
  • LowSVs contribute to cardiac remodeling even in the absence of overt HCM.