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Mechanisms of Disease: molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy

Nature Clinical Practice Cardiovascular Medicine volume 5, pages 258–267 (2008)Cite this article

Abstract

Arrhythmogenic right ventricular dysplasia/cardiomyopathy is an inherited cardiomyopathy estimated to affect approximately 1 in 5,000 individuals. Cardinal manifestations include right ventricular enlargement and dysfunction, fibrofatty replacement of myocytes in the right ventricle, characteristic electrocardiographic abnormalities, and ventricular arrhythmia most commonly arising from the right ventricle. The disease is frequently familial and typically involves autosomal dominant transmission with low penetrance and variable expressivity. Approximately 50% of symptomatic individuals harbor a mutation in one of the five major components of the cardiac desmosome. Nevertheless, other genetic modifiers and environmental factors complicate the clinical management of mutation carriers as well as counseling of their relatives. This Review summarizes the known genetic mutations associated with arrhythmogenic right ventricular dysplasia/cardiomyopathy, describes possible origins of recurrent mutations, presents theories on the pathogenesis of disease following a mutation, and discusses the current issues surrounding clinical use of genetic analysis in the assessment of individuals with this condition.

Key Points

  • Mutation in genes encoding any of the five major components of the cardiac desmosome—PKP2 (encoding plakophilin-2), DSG2 (encoding desmoglein-2), DSP (encoding desmoplakin), DSC2 (encoding desmocollin-2), and JUP (encoding junctional plakoglobin)—can result in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C)

  • Approximately 50% of individuals with ARVD/C who have undergone full sequence analysis of these desmosome genes have a single heterozygous mutation identified, though a few cases of individuals with homozygous or compound heterozygous mutations have also been described

  • ARVD/C segregates in families with both incomplete penetrance and variable expressivity; clinical screening of family members is recommended, particularly among those recognized to share a genetic predisposition to ARVD/C

  • Owing to the age-dependent onset of ARVD/C, repeat clinical screening is recommended at 2- to 3-year intervals from the age of 12 years in the absence of a known mutation, to help target family members at highest risk; in families with earlier onset disease or sudden cardiac death in children, earlier clinical screening should be performed

  • With the recent emergence of clinical genetic testing for ARVD/C, genetic counseling is strongly advised for individuals with ARVD/C and their family members

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Figure 1: The cardiac desmosome and proposed roles of the desmosome in (A) supporting structural stability through cell–cell adhesion, (B) regulating transcription of genes involved in adipogenesis and apoptosis, and maintaining proper electrical conductivity through regulation of (C) gap junctions and (D) calcium homeostasis.
Figure 2: Schematic of the five desmosomal proteins in which ARVD/C mutations have been identified and published.
Figure 3: Tallies of the types of unique mutations found in each of the five desmosomal genes mutated in arrhythmogenic right ventricular dysplasia/cardiomyopathy.

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Acknowledgements

The authors wish to acknowledge funding from the National Institutes of Health (HL088072 to DPJ) and the France-Merrick Foundation. We would also like to acknowledge the Johns Hopkins ARVD Program (http://www.arvd.com) which is supported by the Bogle Foundation, the Campanella family, and the Wilmerding Endowments. Désirée Lie, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

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Authors and Affiliations

  1. MM Awad is an MD-PhD Candidate at the Johns Hopkins University School of Medicine and the Johns Hopkins University Cellular and Molecular Medicine program, Baltimore, MD, USA.,

    Mark M Awad

  2. H Calkins is a Professor of Medicine at the Johns Hopkins University School of Medicine and Director of the Electrophysiology Laboratory at the Johns Hopkins Hospital, Baltimore, MD, USA.,

    Hugh Calkins

  3. DP Judge is Assistant Professor of Medicine at the Johns Hopkins University School of Medicine and Medical Director of the Center for Inherited Heart Disease at Johns Hopkins Hospital, Baltimore, MD, USA.,

    Daniel P Judge

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Correspondence to Daniel P Judge.

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Awad, M., Calkins, H. & Judge, D. Mechanisms of Disease: molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Nat Rev Cardiol 5, 258–267 (2008). https://doi.org/10.1038/ncpcardio1182

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