TY - JOUR
T1 - Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes
AU - Ingles, Jodie
AU - Goldstein, Jennifer
AU - Thaxton, Courtney
AU - Caleshu, Colleen
AU - Corty, Edward W
AU - Crowley, Stephanie B
AU - Dougherty, Kristen
AU - Harrison, Steven M
AU - McGlaughon, Jennifer
AU - Milko, Laura V
AU - Morales, Ana
AU - Seifert, Bryce A
AU - Strande, Natasha
AU - Thomson, Kate
AU - van Tintelen, J Peter
AU - Wallace, Kathleen
AU - Walsh, Roddy
AU - Wells, Quinn
AU - Whiffin, Nicola
AU - Witkowski, Leora
AU - Semsarian, Christopher
AU - Ware, James S
AU - Hershberger, Ray E
AU - Funke, Birgit
N1 - Funding Information:
Dr Ingles is the recipient of a National Heart Foundation of Australia Future Leader Fellowship (number 100833). Dr van Tintelen acknowledges the support from the Netherlands Cardiovascular Research Initiative, an initiative with support of the Dutch Heart Foundation (CVON2014-40 DOSIS). K. Thomson is funded by a National Institute for Health Research (NIHR) and Health Education England Healthcare Science Doctoral Research Fellowship (NIHR-HCS-D13-04-006). Dr Semsarian is the recipient of a National Health and Medical Research Council Practitioner Fellowship (number 1059156). Dr Hershberger and A. Morales were supported by ClinGen subcontracts (National Human Genome Research Institute [NHGRI]; NHGRI HG007437 and NHGRI 1U41HG009650). We are very grateful to the NHGRI for funding this work (grant number U01HG007437-04, U41HG009650, and U41HG006834.). This study was supported by the Wellcome Trust (107469/Z/15/Z); Medical Research Council (UK); NIHR Royal Brompton Biomedical Research Unit; and NIHR Imperial Biomedical Research Centre.
Publisher Copyright:
© 2019 American Heart Association, Inc.
Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2019/2
Y1 - 2019/2
N2 - 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.
AB - 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.
KW - genetic testing
KW - heart failure
KW - syndrome
KW - uncertainty
UR - http://www.scopus.com/inward/record.url?scp=85061855740&partnerID=8YFLogxK
U2 - 10.1161/CIRCGEN.119.002460
DO - 10.1161/CIRCGEN.119.002460
M3 - Article
C2 - 30681346
SN - 2574-8300
VL - 12
SP - 57
EP - 64
JO - Circulation. Genomic and precision medicine
JF - Circulation. Genomic and precision medicine
IS - 2
M1 - e002460
ER -