Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes.

Ingles J1, Goldstein J2, Thaxton C3, Caleshu C4, Corty EW5, Crowley SB6, Dougherty K7, Harrison SM8, McGlaughon J9, Milko LV10, Morales A11, Seifert BA9, Strande N12, Thomson K13, van Tintelen JP14, Wallace K15, Walsh R16, Wells Q17, Whiffin N16, Witkowski L18, Semsarian C19, Ware JS20, Hershberger RE21, Funke B22.

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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 (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.