The Primary Arrhythmia Syndromes: Same Mutation, Different Manifestations. Are We Starting to Understand Why?

Authors

  • BRENDON P. SCICLUNA B.A., M.Sc.,

    1. Heart Failure Research Center, Department of Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands
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  • ARTHUR W. WILDE M.D., Ph.D.,

    1. Heart Failure Research Center, Department of Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands
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  • CONNIE R. BEZZINA Ph.D.

    1. Heart Failure Research Center, Department of Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands
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Errata

This article is corrected by:

  1. Errata: Erratum Volume 19, Issue 7, 774, Article first published online: 25 July 2008

  • C.R. Bezzina and A.A. Wilde are supported by funding from the Dutch Heart Foundation (grants: 2003B195 and 2003T302), funds from the Interuniversity Cardiology Institute of the Netherlands (ICIN project 27), and by a Leducq Foundation Transatlantic Network of Excellence award (Alliance Against Sudden Cardiac Death). C.R. Bezzina is an Established Investigator of the Dutch Heart Foundation (2005T024).

  • Manuscript received 11 October 2007; Revised manuscript received 7 November 2007; Accepted for publication 16 November 2007.

  • Section Editor: Silvia G. Priori, M.D., Ph.D.

Address for correspondence: Connie R. Bezzina, Ph.D., Heart Failure Research Center, Department of Experimental Cardiology, Academic Medical Center, Room K2-120, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands. Fax: +31-20-6975458; E-mail: c.r.bezzina@amc.uva.nl

Abstract

The discovery of pathogenic mutations primarily in genes encoding cardiac ion-channel proteins underlying the primary cardiac arrhythmia syndromes has had a remarkable impact on the management of these disorders, especially in patients with the long-QT syndrome. The availability of a genetic diagnostic test has added an important diagnostic tool, providing new opportunities for patient management such as early (presymptomatic) identification and treatment of patients at risk of developing fatal arrhythmias, risk stratification, and installation of gene-specific therapy. However, the fact that the identification of the causal mutation within a family allows diagnosis in other family members independently from the ECG features and arrhythmic manifestations quickly led to the recognition that extensive variability in clinical manifestations (e.g., extent of ECG abnormality and/or symptomatology) may be observed among family members carrying an identical mutation in a single ion channel gene. It is commonly held that this clinical variability stems from interactions between environmental and genetic modifiers with the particular pathogenic mutation. This Molecular Perspectives article reviews current knowledge on these modifiers of disease expression in the cardiac arrhythmia syndromes with particular reference to genetic modifiers.

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