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

Journal article

S. Hespe, Amber Waddell, B. Asatryan, Emma H Owens, C. Thaxton, Mhy-Lanie Adduru, Kailyn Anderson, Emily E. Brown, L. Hoffman-Andrews, Elizabeth Jordan, Katherine Josephs, Megan Mayers, Stacey Peters, F. Stafford, R. Bagnall, L. Bronicki, B. Callewaert, C. Chahal, C. James, O. Jarinova, A. Landstrom, E. M. McNally, B. Murray, L. Muiño-Mosquera, Victoria N. Parikh, Chloe Reuter, R. Walsh, Bess Wayburn, J. Ware, Jodie Ingles
Journal of the American College of Cardiology, 2025

Semantic Scholar DOI PubMedCentral PubMed

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APA Click to copy
Hespe, S., Waddell, A., Asatryan, B., Owens, E. H., Thaxton, C., Adduru, M.-L., … Ingles, J. (2025). ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel: Reappraisal of Genes associated with Hypertrophic Cardiomyopathy. Journal of the American College of Cardiology.

Chicago/Turabian Click to copy
Hespe, S., Amber Waddell, B. Asatryan, Emma H Owens, C. Thaxton, Mhy-Lanie Adduru, Kailyn Anderson, et al. “ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel: Reappraisal of Genes Associated with Hypertrophic Cardiomyopathy.” Journal of the American College of Cardiology (2025).

MLA Click to copy
Hespe, S., et al. “ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel: Reappraisal of Genes Associated with Hypertrophic Cardiomyopathy.” Journal of the American College of Cardiology, 2025.

BibTeX Click to copy

@article{s2025a,
  title = {ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel: Reappraisal of Genes associated with Hypertrophic Cardiomyopathy},
  year = {2025},
  journal = {Journal of the American College of Cardiology},
  author = {Hespe, S. and Waddell, Amber and Asatryan, B. and Owens, Emma H and Thaxton, C. and Adduru, Mhy-Lanie and Anderson, Kailyn and Brown, Emily E. and Hoffman-Andrews, L. and Jordan, Elizabeth and Josephs, Katherine and Mayers, Megan and Peters, Stacey and Stafford, F. and Bagnall, R. and Bronicki, L. and Callewaert, B. and Chahal, C. and James, C. and Jarinova, O. and Landstrom, A. and McNally, E. M. and Murray, B. and Muiño-Mosquera, L. and Parikh, Victoria N. and Reuter, Chloe and Walsh, R. and Wayburn, Bess and Ware, J. and Ingles, Jodie}
}

Abstract

Background: Hypertrophic cardiomyopathy (HCM) is an inherited cardiac condition affecting ~1 in 500 and exhibits marked genetic heterogeneity. Previously published in 2019, 57 HCM-associated genes were curated providing the first systematic evaluation of gene-disease validity. Objectives: Here we report work by the ClinGen Hereditary Cardiovascular Disorders Gene Curation Expert Panel (HCVD-GCEP) to reappraise the clinical validity of previously curated and new putative HCM genes. Methods: The ClinGen systematic gene curation framework was used to re-classify the gene-disease relationships for HCM and related syndromic entities involving left ventricular hypertrophy. Genes previously curated were included if their classification was not definitive, and if the time since curation was >2–3 years. New genes with literature assertions for HCM were included for initial evaluation. Existing genes were curated for new inheritance patterns where evidence existed. Curations were presented on twice monthly calls, with the HCVD-GCEP composed of 29 individuals from 21 institutions across 6 countries. Results: Thirty-one genes were re-curated and an additional 5 new potential HCM-associated genes were curated. Among the re-curated genes, 17 (55%) genes changed classification: 1 limited and 4 disputed (from no known disease relationship), 9 disputed (from limited), and 3 definitive (from moderate). Among these, 3 (10%) genes had a clinically relevant upgrade, including TNNC1, a 9th sarcomere gene with definitive HCM association. With new evidence, two genes were curated for multiple inheritance patterns (TRIM63, disputed for autosomal dominant but moderate for autosomal recessive; ALPK3, strong for autosomal dominant and definitive for recessive). CSRP3 was curated for a semi-dominant mode of inheritance (definitive). Nine (29%) genes were downgraded to disputed, further discouraging clinical reporting of variants in these genes. Five genes recently reported to cause HCM were curated: RPS6KB1 and RBM20 (limited), KLHL24 and MT-TI (moderate), and FHOD3 (definitive). Conclusions: We report 29 genes with definitive, strong or moderate evidence of causation for HCM or isolated LVH, including sarcomere, sarcomere-associated and syndromic conditions.