Related Experiment Video

Updated: May 27, 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

Published on: August 8, 2022

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Genes Associated With Hypertrophic Cardiomyopathy: A Reappraisal by the ClinGen Hereditary Cardiovascular Disease

Sophie Hespe1, Amber Waddell2, Babken Asatryan3

  • 1Genomics and Inherited Disease Program, Garvan Institute of Medical Research, and UNSW Sydney, Sydney, New South Wales, Australia.

Journal of the American College of Cardiology
|February 19, 2025
PubMed

Insights

This study reappraised hypertrophic cardiomyopathy (HCM) genes, upgrading 3 and downgrading 9. It identified 29 genes with definitive, strong, or moderate evidence for causing HCM or left ventricular hypertrophy.

Area of Science:

  • Genetics
  • Cardiology
  • Molecular Biology

Background:

  • Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac condition with significant genetic causes.
  • Previous gene curation in 2019 identified 57 HCM-associated genes, but further evaluation is needed due to genetic heterogeneity.

Purpose of the Study:

  • To reappraise the clinical validity of previously curated and newly identified genes associated with HCM.
  • To update the classification of gene-disease relationships for HCM and related syndromic conditions involving left ventricular hypertrophy.

Main Methods:

  • Utilized the Clinical Genome Resource systematic gene curation framework.
  • Reclassified 31 previously curated genes and evaluated 5 new potential HCM-associated genes.
  • Conducted twice-monthly calls with the Hereditary Cardiovascular Disease (HCVD) Gene Curation Expert Panel (GCEP) comprising 29 experts from 21 institutions.

Main Results:

  • Seventeen of 31 recurated genes changed classification, with 3 clinically relevant upgrades, including TNNC1 as a definitive sarcomere gene.
  • Two genes were curated for multiple inheritance patterns (TRIM63, ALPK3), and CSRP3 was classified for semidominant inheritance.
  • Nine genes were downgraded to disputed, and 5 newly reported HCM genes were classified (RPS6KB1, RBM20, KLHL24, MT-TI, FHOD3).

Conclusions:

  • Identified 29 genes with definitive, strong, or moderate evidence for causing HCM or isolated left ventricular hypertrophy.
  • The updated gene classifications provide crucial information for genetic testing and clinical reporting of HCM.
  • This systematic reappraisal enhances understanding of the genetic landscape of HCM and related cardiovascular conditions.
Abstract

Keywords:
genetic testinghypertrophic cardiomyopathysarcomerevariant classification

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