Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes

Jodie Ingles, Jennifer Goldstein, Courtney Thaxton, Colleen Caleshu, Edward W Corty, Stephanie B Crowley, Kristen Dougherty, Steven M Harrison, Jennifer McGlaughon, Laura V Milko, Ana Morales, Bryce A Seifert, Natasha Strande, Kate Thomson, J Peter van Tintelen, Kathleen Wallace, Roddy Walsh, Quinn Wells, Nicola Whiffin, Leora WitkowskiChristopher Semsarian, James S Ware, Ray E Hershberger, Birgit Funke

Research output: Contribution to journalArticleAcademicpeer-review


BACKGROUND: Genetic testing for families with hypertrophic cardiomyopathy (HCM) provides a significant opportunity to improve care. Recent trends to increase gene panel sizes often mean variants in genes with questionable association are reported to patients. Classification of HCM genes and variants is critical, as misclassification can lead to genetic misdiagnosis. We show the validity of previously reported HCM genes using an established method for evaluating gene-disease associations.

METHODS: A systematic approach was used to assess the validity of reported gene-disease associations, including associations with isolated HCM and syndromes including left ventricular hypertrophy (LVH). Genes were categorized as having definitive, strong, moderate, limited or no evidence of disease causation. We also reviewed current variant classifications for HCM in ClinVar, a publicly available variant resource.

RESULTS: Fifty-seven genes were selected for curation based on their frequent inclusion in HCM testing and prior association reports. Of 33 HCM genes, only 8 (24%) were categorized as definitive ( MYBPC3, MYH7, TNNT2, TNNI3, TPM1, ACTC1, MYL2, MYL3); 3 had moderate evidence ( CSRP3, TNNC1, JPH2; 33%); and 22 (66%) had limited (n=16) or no evidence (n=6). There were 12 of 24 syndromic genes definitively associated with isolated LVH. Of 4191 HCM variants in ClinVar, 31% were in genes with limited or no evidence of disease association.

CONCLUSIONS: The majority of genes previously reported as causative of HCM and commonly included in diagnostic tests have limited or no evidence of disease association. Systematically curated HCM genes are essential to guide appropriate reporting of variants and ensure best possible outcomes for HCM families.

Original languageEnglish
Article numbere002460
Pages (from-to)57-64
Number of pages8
JournalCirculation. Genomic and precision medicine
Issue number2
Early online date25 Jan 2019
Publication statusPublished - Feb 2019
Externally publishedYes


  • genetic testing
  • heart failure
  • syndrome
  • uncertainty


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