Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes

Jodie Ingles^{1

2}, Jennifer Goldstein³, Courtney Thaxton³, Colleen Caleshu⁴, Edward W Corty³, Stephanie B Crowley³, Kristen Dougherty⁵, Steven M Harrison⁶, Jennifer McGlaughon³, Laura V Milko³, Ana Morales⁷, Bryce A Seifert³, Natasha Strande³, Kate Thomson⁸, J Peter van Tintelen⁹, Kathleen Wallace³, Roddy Walsh^{10

11}, Quinn Wells¹², Nicola Whiffin^{10

11}, Leora Witkowski¹³, Christopher Semsarian^{1

2}, James S Ware^{10

11}, Ray E Hershberger^{7

14}, Birgit Funke¹³

Affiliations

¹ Agnes Ginges Centre for Molecular Cardiology at Centenary Institute and Faculty of Medicine and Health, The University of Sydney, University of Sydney, Australia (J.I., C.S.).
² Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia (J.I., C.S.).
³ Department of Genetics, UNC Chapel Hill, NC (J.G., C.T., E.W.C., S.B.C., J.M., L.V.M., B.A.S., N.S., K.W.).
⁴ Stanford Center for Inherited Cardiovascular Disease, Stanford University, CA (C.C.).
⁵ Eastern Virginia Medical School, Norfolk, VA (K.D.).
⁶ Laboratory for Molecular Medicine, Partners Healthcare, Harvard Medical School, Cambridge, MA (S.M.H.).
⁷ Division of Human Genetics, Davis Heart and Lung Research Institute (A.M., R.E.H.).
⁸ Oxford Medical Genetics Laboratory, United Kingdom (K.T.).
⁹ Department of Clinical Genetics, Amsterdam University Medical Centers, University of Amsterdam, Cardiovascular Sciences, The Netherlands (J.P.v.T.).
¹⁰ National Heart and Lung Institute & MRC London Institute of Medical Sciences, Imperial College London, United Kingdom (R.W., N.W., J.S.W.).
¹¹ Cardiovascular Research Centre at Royal Brompton & Harefield Hospitals NHS Trust, London, United Kingdom (R.W., N.W., J.S.W.).
¹² Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (Q.W.).
¹³ Department of Pathology, Harvard Medical School/Massachusetts General Hospital, Boston (L.W., B.F.).
¹⁴ Division of Cardiovascular Medicine, The Ohio State University, Columbus (R.E.H.).

PMID: 30681346
PMCID: PMC6410971
DOI: 10.1161/CIRCGEN.119.002460

Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes

Jodie Ingles et al. Circ Genom Precis Med. 2019 Feb.

. 2019 Feb;12(2):e002460.

doi: 10.1161/CIRCGEN.119.002460.

Authors

Affiliations

¹ Agnes Ginges Centre for Molecular Cardiology at Centenary Institute and Faculty of Medicine and Health, The University of Sydney, University of Sydney, Australia (J.I., C.S.).
² Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia (J.I., C.S.).
³ Department of Genetics, UNC Chapel Hill, NC (J.G., C.T., E.W.C., S.B.C., J.M., L.V.M., B.A.S., N.S., K.W.).
⁴ Stanford Center for Inherited Cardiovascular Disease, Stanford University, CA (C.C.).
⁵ Eastern Virginia Medical School, Norfolk, VA (K.D.).
⁶ Laboratory for Molecular Medicine, Partners Healthcare, Harvard Medical School, Cambridge, MA (S.M.H.).
⁷ Division of Human Genetics, Davis Heart and Lung Research Institute (A.M., R.E.H.).
⁸ Oxford Medical Genetics Laboratory, United Kingdom (K.T.).
⁹ Department of Clinical Genetics, Amsterdam University Medical Centers, University of Amsterdam, Cardiovascular Sciences, The Netherlands (J.P.v.T.).
¹⁰ National Heart and Lung Institute & MRC London Institute of Medical Sciences, Imperial College London, United Kingdom (R.W., N.W., J.S.W.).
¹¹ Cardiovascular Research Centre at Royal Brompton & Harefield Hospitals NHS Trust, London, United Kingdom (R.W., N.W., J.S.W.).
¹² Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (Q.W.).
¹³ Department of Pathology, Harvard Medical School/Massachusetts General Hospital, Boston (L.W., B.F.).
¹⁴ Division of Cardiovascular Medicine, The Ohio State University, Columbus (R.E.H.).

PMID: 30681346
PMCID: PMC6410971
DOI: 10.1161/CIRCGEN.119.002460

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.

Keywords: genetic testing; heart failure; syndrome; uncertainty.

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Figures

**Figure 1.**
**Hypertrophic cardiomyopathy gene-disease classifications showing genetic, experimental, and overall scores and classification.**

**Figure 2.**
**Number of ClinVar assertions for hypertrophic cardiomyopathy (HCM) phenotype, grouped by gene classifications.** LV indicates left ventricle.

See this image and copyright information in PMC

References

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Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes

Affiliations

Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Research Materials

Miscellaneous