Evaluating the clinical validity of hypertrophic cardiomyopathy genes
Circulation: Genomic and Precision Medicine, 2019•Am Heart Assoc
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 …
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 …
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.
Am Heart Assoc
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