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ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel: Reappraisal of Genes associated with

Sophie Hespe1, Amber Waddell2, Babken Asatryan3

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

Medrxiv : the Preprint Server for Health Sciences
|August 12, 2024
PubMed

Insights

This study reappraised hypertrophic cardiomyopathy (HCM) genes, reclassifying 17 genes and identifying 5 new potential HCM-associated genes. The findings confirm 29 genes definitively linked to HCM, improving genetic diagnosis for this inherited cardiac condition.

Area of Science:

  • Cardiovascular Genetics
  • Human Genetics
  • Molecular Cardiology

Background:

  • Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac condition (~1 in 500 prevalence) with significant genetic heterogeneity.
  • Previous systematic evaluations of HCM-associated genes were published in 2019, identifying 57 genes.
  • The ClinGen Hereditary Cardiovascular Disorders Gene Curation Expert Panel (HCVD-GCEP) reappraises the clinical validity of known and potential HCM genes.

Purpose of the Study:

  • To re-evaluate the clinical validity of previously curated and newly identified genes associated with hypertrophic cardiomyopathy (HCM).
  • To systematically classify gene-disease relationships for HCM and related syndromic conditions involving left ventricular hypertrophy.
  • To update the evidence base for genetic testing and reporting in HCM.

Main Methods:

  • Utilized the ClinGen systematic gene curation framework to re-classify gene-disease relationships for HCM.
  • Included previously curated genes (if classification was not definitive or curation was >2-3 years old) and new genes with literature assertions.
  • Conducted twice-monthly calls with the HCVD-GCEP (29 experts from 21 institutions, 6 countries) to review and classify gene evidence.

Main Results:

  • Thirty-one genes were re-curated, and 5 new potential HCM-associated genes were evaluated.
  • Seventeen (55%) re-curated genes changed classification; 3 genes were upgraded (e.g., TNNC1 to definitive HCM association), and 9 were downgraded to disputed.
  • Five new genes were curated (RPS6KB1, RBM20, KLHL24, MT-TI, FHOD3), with FHOD3 achieving definitive HCM association. TRIM63 and ALPK3 were curated for multiple inheritance patterns.

Conclusions:

  • A total of 29 genes now have definitive, strong, or moderate evidence supporting their causation of HCM or isolated left ventricular hypertrophy (LVH).
  • This reappraisal includes sarcomere, sarcomere-associated, and syndromic conditions contributing to HCM.
  • The updated classifications provide a more robust foundation for clinical genetic testing and interpretation in HCM.
Abstract

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