Desmoplakin truncations and arrhythmogenic left ventricular cardiomyopathy: Characterizing a phenotype

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 studywas to investigate genotype-phenotype correlations in patients carrying a novelDSP 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 carrierswas 83%. Sustained ventricular tachycardia was the first clinical manifestation in six patients and nine patientswere 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. Published on behalf of the European Society of Cardiology. All rights reserved.