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Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes

Jodie Ingles1,2, Jennifer Goldstein3, Courtney Thaxton3

  • 1Agnes Ginges Centre for Molecular Cardiology at Centenary Institute and Faculty of Medicine and Health, The University of Sydney, University of Sydney, Australia (J.I., C.S.).

Circulation. Genomic and Precision Medicine
|January 26, 2019
PubMed

Insights

Genetic testing for hypertrophic cardiomyopathy (HCM) often includes genes with questionable links to the disease. Validating these gene-disease associations is crucial for accurate diagnosis and improved patient care.

Area of Science:

  • Genetics
  • Cardiology
  • Molecular Biology

Background:

  • Genetic testing for hypertrophic cardiomyopathy (HCM) is vital for patient care.
  • Current genetic panels often include genes with unproven associations to HCM.
  • Accurate classification of HCM genes and variants is critical to prevent misdiagnosis.

Purpose of the Study:

  • To systematically assess the validity of genes reported to cause HCM.
  • To evaluate gene-disease associations using established criteria.
  • To review variant classifications in ClinVar for HCM-associated genes.

Main Methods:

  • A systematic approach was used to evaluate gene-disease associations for isolated HCM and related syndromes.
  • Genes were categorized based on the strength of evidence for disease causation (definitive, strong, moderate, limited, no evidence).
  • Current variant classifications for HCM in ClinVar were reviewed.

Main Results:

  • Of 33 HCM genes, only 8 (24%) had definitive evidence of causation; 3 had moderate evidence, and 22 had limited or no evidence.
  • 12 of 24 syndromic genes were definitively associated with isolated left ventricular hypertrophy.
  • 31% of 4191 HCM variants in ClinVar were in genes with limited or no evidence of disease association.

Conclusions:

  • Most genes commonly tested for HCM lack strong evidence of disease causation.
  • Systematic curation of HCM genes is essential for accurate variant reporting.
  • Ensuring gene validity improves outcomes for families affected by HCM.
Abstract

Keywords:
genetic testingheart failuresyndromeuncertainty

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