International Evidence Based Reappraisal of Genes Associated With Arrhythmogenic Right Ventricular Cardiomyopathy Using the Clinical Genome Resource Framework

DOI Web Site 被引用文献3件
  • Cynthia A. James
    Division of Cardiology, Department of Medicine, Johns Hopkins Hospital, Baltimore, MD (C.A.J., B.M., E.B.).
  • Jan D.H. Jongbloed
    Department of Genetics, University of Groningen, University Medical Center Groningen, the Netherlands (J.D.H.J.).
  • Ray E. Hershberger
    Division of Cardiovascular Medicine, Department of Internal Medicine (R.E.H., E.J.), Ohio State University, Columbus.
  • Ana Morales
    Division of Human Genetics, Department of Internal Medicine (R.E.H., A.M.), Ohio State University, Columbus.
  • Daniel P. Judge
    Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston (D.P.J.).
  • Petros Syrris
    Centre for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, United Kingdom (P.S., A.P.).
  • Kalliopi Pilichou
    Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padua, Italy (K.P., R.C.).
  • Argelia Medeiros Domingo
    Department for Cardiology, Inselspital, Bern University Hospital, University of Bern, Switzerland (A.M.D., B.A.).
  • Brittney Murray
    Division of Cardiology, Department of Medicine, Johns Hopkins Hospital, Baltimore, MD (C.A.J., B.M., E.B.).
  • Julia Cadrin-Tourigny
    Cardiovascular Genetics Centre, Montreal Heart Institute, Université de Montréal, Canada (J.C.-T.).
  • Ronald Lekanne Deprez
    Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, the Netherlands (R.L.D., J.P.v.T.).
  • Rudy Celeghin
    Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padua, Italy (K.P., R.C.).
  • Alexandros Protonotarios
    Centre for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, United Kingdom (P.S., A.P.).
  • Babken Asatryan
    Department for Cardiology, Inselspital, Bern University Hospital, University of Bern, Switzerland (A.M.D., B.A.).
  • Emily Brown
    Division of Cardiology, Department of Medicine, Johns Hopkins Hospital, Baltimore, MD (C.A.J., B.M., E.B.).
  • Elizabeth Jordan
    Division of Cardiovascular Medicine, Department of Internal Medicine (R.E.H., E.J.), Ohio State University, Columbus.
  • Jennifer McGlaughon
    Department of Genetics, University of North Carolina, Chapel Hill (J.M., C.T., C.L.K.).
  • Courtney Thaxton
    Department of Genetics, University of North Carolina, Chapel Hill (J.M., C.T., C.L.K.).
  • C. Lisa Kurtz
    Department of Genetics, University of North Carolina, Chapel Hill (J.M., C.T., C.L.K.).
  • J. Peter van Tintelen
    Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, the Netherlands (R.L.D., J.P.v.T.).

説明

<jats:sec> <jats:title>Background:</jats:title> <jats:p>Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disease characterized by ventricular arrhythmias and progressive ventricular dysfunction. Genetic testing is recommended, and a pathogenic variant in an ARVC-associated gene is a major criterion for diagnosis according to the 2010 Task Force Criteria. As incorrect attribution of a gene to ARVC can contribute to misdiagnosis, we assembled an international multidisciplinary ARVC Clinical Genome Resource Gene Curation Expert Panel to reappraise all reported ARVC genes.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods:</jats:title> <jats:p>Following a comprehensive literature search, six 2-member teams conducted blinded independent curation of reported ARVC genes using the semiquantitative Clinical Genome Resource framework.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p> Of 26 reported ARVC genes, only 6 ( <jats:italic>PKP2</jats:italic> , <jats:italic>DSP</jats:italic> , <jats:italic>DSG2</jats:italic> , <jats:italic>DSC2</jats:italic> , <jats:italic>JUP</jats:italic> , and <jats:italic>TMEM43</jats:italic> ) had strong evidence and were classified as definitive for ARVC causation. There was moderate evidence for 2 genes, <jats:italic>DES</jats:italic> and <jats:italic>PLN</jats:italic> . The remaining 18 genes had limited or no evidence. <jats:italic>RYR2</jats:italic> was refuted as an ARVC gene since clinical data and model systems exhibited a catecholaminergic polymorphic ventricular tachycardia phenotype. In ClinVar, only 5 pathogenic/likely pathogenic variants (1.1%) in limited evidence genes had been reported in ARVC cases in contrast to 450 desmosome gene variants (97.4%). </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p> Using the Clinical Genome Resource approach to gene-disease curation, only 8 genes ( <jats:italic>PKP2</jats:italic> , <jats:italic>DSP</jats:italic> , <jats:italic>DSG2</jats:italic> , <jats:italic>DSC2</jats:italic> , <jats:italic>JUP</jats:italic> , <jats:italic>TMEM43</jats:italic> , <jats:italic>PLN</jats:italic> , and <jats:italic>DES</jats:italic> ) had definitive or moderate evidence for ARVC, and these genes accounted for nearly all pathogenic/likely pathogenic ARVC variants in ClinVar. Therefore, only pathogenic/likely pathogenic variants in these 8 genes should yield a major criterion for ARVC diagnosis. Pathogenic/likely pathogenic variants identified in other genes in a patient should prompt further phenotyping as variants in many of these genes are associated with other cardiovascular conditions. </jats:p> </jats:sec>

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