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Evaluating the clinical validity of hypertrophic cardiomyopathy genes

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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
Peter van Tintelen, J
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: 1-Feb-2019
Date of Acceptance: 18-Jan-2019
URI: http://hdl.handle.net/10044/1/67173
DOI: https://dx.doi.org/10.1161/CIRCGEN.119.002460
ISSN: 1942-325X
Publisher: American Heart Association
Journal / Book Title: Circulation: Cardiovascular Genetics
Volume: 12
Issue: 2
Copyright Statement: © 2019 The Authors. Circulation: Genomic and Precision Medicine is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.
Sponsor/Funder: Wellcome Trust
Funder's Grant Number: 107469/Z/15/Z
Keywords: genetic testing
heart failure
syndrome
uncertainty
Publication Status: Published
Appears in Collections:Institute of Clinical Sciences