Evidence-Based Assessment of Genes in Dilated Cardiomyopathy

DOI Web Site 3 Citations 44 References Open Access
  • Elizabeth Jordan
    Division of Human Genetics (E.J., L.P., T.A., R.E.H.), Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus.
  • Laiken Peterson
    Division of Human Genetics (E.J., L.P., T.A., R.E.H.), Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus.
  • Tomohiko Ai
    Division of Human Genetics (E.J., L.P., T.A., R.E.H.), Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus.
  • Babken Asatryan
    Department for Cardiology, Inselspital, Bern University Hospital, University of Bern, Switzerland (B.A.).
  • Lucas Bronicki
    Department of Genetics, Children’s Hospital of Eastern Ontario, Ottawa, Canada (L.B., O.J.).
  • Emily Brown
    Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD (E.B., C.A.J., B.M.).
  • Rudy Celeghin
    Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padua, Italy (R.C., K.P.).
  • Matthew Edwards
    Clinical Genetics and Genomics Laboratory, Royal Brompton and Harefield NHS Foundation Trust, London, United Kingdom (M.E.).
  • Judy Fan
    Department of Medicine, University of California, Los Angeles (J.F., J. Wang).
  • Jodie Ingles
    Cardio Genomics Program at Centenary Institute, University of Sydney, Australia (J.I.).
  • Cynthia A. James
    Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD (E.B., C.A.J., B.M.).
  • Olga Jarinova
    Department of Genetics, Children’s Hospital of Eastern Ontario, Ottawa, Canada (L.B., O.J.).
  • Renee Johnson
    Victor Chang Cardiac Research Institute, Sydney, Australia (R.J.).
  • Daniel P. Judge
    Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston (D.P.J.).
  • Najim Lahrouchi
    Department of Clinical and Experimental Cardiology, Heart Centre, Amsterdam Cardiovascular Sciences, Amsterdam Universitair Medische Centra, University of Amsterdam, the Netherlands (N.L., R.W.).
  • Ronald H. Lekanne Deprez
    Department of Clinical Genetics, Amsterdam University Medical Center location Academic Medical Center, the Netherlands (R.H.L.D.).
  • R. Thomas Lumbers
    Institute of Health Informatics, University College London, London, UK (R.T.L.).
  • Francesco Mazzarotto
    Cardiovascular Research Center, Royal Brompton and Harefield Hospitals, National Health Service Foundation Trust, London, United Kingdom (F.M., J. Ware).
  • Argelia Medeiros Domingo
    Swiss DNAlysis Cardiogenetics, Dübendorf, Switzerland (A.M.D.).
  • Rebecca L. Miller
    Cardiovascular Genomics Center, Inova Heart and Vascular Institute, Falls Church, VA (R.L.M., P. Shah).
  • Ana Morales
    Invitae Corp, San Francisco, CA (A.M.).
  • Brittney Murray
    Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD (E.B., C.A.J., B.M.).
  • Stacey Peters
    Department of Cardiology and Genomic Medicine, Royal Melbourne Hospital, Australia (S.P.).
  • Kalliopi Pilichou
    Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padua, Italy (R.C., K.P.).
  • Alexandros Protonotarios
    Centre for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, London, United Kingdom (A.P., P. Syrris).
  • Christopher Semsarian
    Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, University of Sydney, Australia (C.S.).
  • Palak Shah
    Cardiovascular Genomics Center, Inova Heart and Vascular Institute, Falls Church, VA (R.L.M., P. Shah).
  • Petros Syrris
    Centre for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, London, United Kingdom (A.P., P. Syrris).
  • Courtney Thaxton
    Department of Genetics, University of North Carolina, Chapel Hill (C.T.).
  • J. Peter van Tintelen
    Department of Genetics, University Medical Center Utrecht, University of Utrecht, The Netherlands (J.P.v.T.).
  • Roddy Walsh
    Department of Clinical and Experimental Cardiology, Heart Centre, Amsterdam Cardiovascular Sciences, Amsterdam Universitair Medische Centra, University of Amsterdam, the Netherlands (N.L., R.W.).
  • Jessica Wang
    Department of Medicine, University of California, Los Angeles (J.F., J. Wang).
  • James Ware
    Cardiovascular Research Center, Royal Brompton and Harefield Hospitals, National Health Service Foundation Trust, London, United Kingdom (F.M., J. Ware).
  • Ray E. Hershberger
    Division of Human Genetics (E.J., L.P., T.A., R.E.H.), Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus.

Description

<jats:sec> <jats:title>Background:</jats:title> <jats:p>Each of the cardiomyopathies, classically categorized as hypertrophic cardiomyopathy, dilated cardiomyopathy (DCM), and arrhythmogenic right ventricular cardiomyopathy, has a signature genetic theme. Hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy are largely understood as genetic diseases of sarcomere or desmosome proteins, respectively. In contrast, >250 genes spanning >10 gene ontologies have been implicated in DCM, representing a complex and diverse genetic architecture. To clarify this, a systematic curation of evidence to establish the relationship of genes with DCM was conducted.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods:</jats:title> <jats:p>An international panel with clinical and scientific expertise in DCM genetics evaluated evidence supporting monogenic relationships of genes with idiopathic DCM. The panel used the Clinical Genome Resource semiquantitative gene-disease clinical validity classification framework with modifications for DCM genetics to classify genes into categories on the basis of the strength of currently available evidence. Representation of DCM genes on clinically available genetic testing panels was evaluated.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p> Fifty-one genes with human genetic evidence were curated. Twelve genes (23%) from 8 gene ontologies were classified as having definitive ( <jats:italic>BAG3</jats:italic> , <jats:italic>DES</jats:italic> , <jats:italic>FLNC</jats:italic> , <jats:italic>LMNA</jats:italic> , <jats:italic>MYH7</jats:italic> , <jats:italic>PLN</jats:italic> , <jats:italic>RBM20</jats:italic> , <jats:italic>SCN5A</jats:italic> , <jats:italic>TNNC1</jats:italic> , <jats:italic>TNNT2</jats:italic> , <jats:italic>TTN</jats:italic> ) or strong ( <jats:italic>DSP</jats:italic> ) evidence. Seven genes (14%; <jats:italic>ACTC1</jats:italic> , <jats:italic>ACTN2</jats:italic> , <jats:italic>JPH2</jats:italic> , <jats:italic>NEXN</jats:italic> , <jats:italic>TNNI3</jats:italic> , <jats:italic>TPM1</jats:italic> , <jats:italic>VCL</jats:italic> ) including 2 additional ontologies were classified as moderate evidence; these genes are likely to emerge as strong or definitive with additional evidence. Of these 19 genes, 6 were similarly classified for hypertrophic cardiomyopathy and 3 for arrhythmogenic right ventricular cardiomyopathy. Of the remaining 32 genes (63%), 25 (49%) had limited evidence, 4 (8%) were disputed, 2 (4%) had no disease relationship, and 1 (2%) was supported by animal model data only. Of the 16 evaluated clinical genetic testing panels, most definitive genes were included, but panels also included numerous genes with minimal human evidence. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>In the curation of 51 genes, 19 had high evidence (12 definitive/strong, 7 moderate). It is notable that these 19 genes explain only a minority of cases, leaving the remainder of DCM genetic architecture incompletely addressed. Clinical genetic testing panels include most high-evidence genes; however, genes lacking robust evidence are also commonly included. We recommend that high-evidence DCM genes be used for clinical practice and that caution be exercised in the interpretation of variants in variable-evidence DCM genes.</jats:p> </jats:sec>

Journal

  • Circulation

    Circulation 144 (1), 7-19, 2021-07-06

    Ovid Technologies (Wolters Kluwer Health)

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