Abstract
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. 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. 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. 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.
Highlights
Genetic testing for families with hypertrophic cardiomyopathy (HCM) provides a significant opportunity to improve care
There is potential for HCM genetic testing to add significant value to family management, nonjudicious use has potential for harm including variant misclassification and genetic misdiagnosis.[9]
Of 328 gene panels identified in the National Center for Biotechnology Information Genetic Testing Regis-Impact of Including HCM Candidate Genes in Diagnostic Gene Panels
Summary
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. All data and materials have been made publicly available on the ClinGen website https://www.clinicalgenome.org/working-groups/clinical-domain/cardiovascular-clinical-domainworking-group/hypertrophic-cardiomyopathy-gene-ep/ and can be accessed at URL in the Data Supplement. Try, 24 were included (Table I in the Data Supplement; 20 panels identified as HCM panels and 4 cardiomyopathy panels). There were 162 unique genes represented across all panels (Figure II in the Data Supplement; Table II in the Data Supplement). Twenty-six of the 57 genes had prior reported association with HCM in Online Mendelian Inheritance in Man (http://www.omim/org; Tables VI and VII in the Data Supplement)
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