Desmoplakin truncations and arrhythmogenic left ventricular cardiomyopathy: characterizing a phenotype

Europace. 2014 Dec;16(12):1838-46. doi: 10.1093/europace/euu128. Epub 2014 Jun 17.

Abstract

Aims: Risk stratification for sudden death in arrhythmogenic right ventricular cardiomyopathy (ARVC) is challenging in clinical practice. We lack recommendations for the risk stratification of exclusive left-sided phenotypes. The aim of this study was to investigate genotype-phenotype correlations in patients carrying a novel DSP c.1339C>T, and to review the literature on the clinical expression and the outcomes in patients with DSP truncating mutations.

Methods and results: Genetic screening of the DSP gene was performed in 47 consecutive patients with a phenotype of either an ARVC (n = 24) or an idiopathic dilated cardiomyopathy (DCM), who presented with ventricular arrhythmias or a family history of sudden death (n = 23) (aged 40 ± 19 years, 62% males). Three unrelated probands with DCM were found to be carriers of a novel mutation (c.1339C>T). Cascade family screening led to the identification of 15 relatives who are carriers. Penetrance in c.1339C>T carriers was 83%. Sustained ventricular tachycardia was the first clinical manifestation in six patients and nine patients were diagnosed with left ventricular impairment (two had overt severe disease and seven had a mild dysfunction). Cardiac magnetic resonance revealed left ventricular involvement in nine cases and biventricular disease in three patients. Extensive fibrotic patterns in six and non-compaction phenotype in five patients were the hallmark in imaging.

Conclusion: DSP c.1339C>T is associated with an aggressive clinical phenotype of left-dominant arrhythmogenic cardiomyopathy and left ventricular non-compaction. Truncating mutations in desmoplakin are consistently associated with aggressive phenotypes and must be considered as a risk factor of sudden death. Since ventricular tachycardia occurs even in the absence of severe systolic dysfunction, an implantable cardioverter-defibrillator should be indicated promptly.

Keywords: Arrhythmogenic cardiomyopathy; Desmoplakin; Dilated cardiomyopathy; Implantable cardioverter-defibrillator; Sudden death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Arrhythmogenic Right Ventricular Dysplasia / epidemiology*
  • Arrhythmogenic Right Ventricular Dysplasia / genetics*
  • Desmoplakins / genetics*
  • Female
  • Genetic Predisposition to Disease / epidemiology*
  • Genetic Predisposition to Disease / genetics*
  • Genetic Testing
  • Heterozygote
  • Humans
  • Incidence
  • Male
  • Mutation / genetics
  • Polymorphism, Single Nucleotide / genetics
  • Risk Factors
  • Spain / epidemiology
  • Ventricular Dysfunction, Left / epidemiology*
  • Ventricular Dysfunction, Left / genetics*

Substances

  • Desmoplakins