Evaluating the clinical validity of hypertrophic cardiomyopathy genes

Title: Evaluating the clinical validity of hypertrophic cardiomyopathy genes
Authors: Ingles, J
Goldstein, J
Thaxton, C
Caleshu, C
Corty, EW
Crowley, SB
Dougherty, K
Harrison, SM
McGlaughon, J
Milko, LV
Morales, A
Seifert, BA
Strande, N
Thomson, K
Van Tintelen, JP
Wallace, K
Walsh, R
Wells, Q
Whiffin, N
Witkowski, L
Semsarian, C
Ware, JS
Hershberger, RE
Funke, B
Item Type: Journal Article
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.
Issue Date: 2-Apr-2019
Date of Acceptance: 18-Jan-2019
URI: http://hdl.handle.net/10044/1/74196
DOI: https://doi.org/10.1161/CIRCULATIONAHA.119.040626
ISSN: 0009-7322
Publisher: American Heart Association
Start Page: 1745
End Page: 1745
Journal / Book Title: Circulation
Volume: 139
Issue: 14
Copyright Statement: © 2019 American Heart Association, Inc.
Sponsor/Funder: Wellcome Trust
Funder's Grant Number: 107469/Z/15/Z
Keywords: Science & Technology
Life Sciences & Biomedicine
Cardiac & Cardiovascular Systems
Peripheral Vascular Disease
Cardiovascular System & Cardiology
Science & Technology
Life Sciences & Biomedicine
Cardiac & Cardiovascular Systems
Peripheral Vascular Disease
Cardiovascular System & Cardiology
Cardiovascular System & Hematology
1103 Clinical Sciences
1102 Cardiorespiratory Medicine and Haematology
1117 Public Health and Health Services
Publication Status: Published
Open Access location: https://doi.org/10.1161/CIRCULATIONAHA.119.040626
Appears in Collections:Institute of Clinical Sciences