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. 2019 Feb;12(2):e002460.
doi: 10.1161/CIRCGEN.119.002460.

Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes

Jodie Ingles  1   2 , Jennifer Goldstein  3 , Courtney Thaxton  3 , Colleen Caleshu  4 , Edward W Corty  3 , Stephanie B Crowley  3 , Kristen Dougherty  5 , Steven M Harrison  6 , Jennifer McGlaughon  3 , Laura V Milko  3 , Ana Morales  7 , Bryce A Seifert  3 , Natasha Strande  3 , Kate Thomson  8 , J Peter van Tintelen  9 , Kathleen Wallace  3 , Roddy Walsh  10   11 , Quinn Wells  12 , Nicola Whiffin  10   11 , Leora Witkowski  13 , Christopher Semsarian  1   2 , James S Ware  10   11 , Ray E Hershberger  7   14 , Birgit Funke  13
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Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes

Jodie Ingles et al. Circ Genom Precis Med. 2019 Feb.

Abstract

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. 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, and MYL3); 3 had moderate evidence ( CSRP3, TNNC1, and 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 left ventricular hypertrophy. 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 the best possible outcomes for HCM families.

Keywords: genetic testing; heart failure; syndrome; uncertainty.

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Figures

Figure 1.
Figure 1.
Hypertrophic cardiomyopathy gene-disease classifications showing genetic, experimental, and overall scores and classification.
Figure 2.
Figure 2.
Number of ClinVar assertions for hypertrophic cardiomyopathy (HCM) phenotype, grouped by gene classifications. LV indicates left ventricle.
See this image and copyright information in PMC

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