DSP p.(Thr2104Glnfs*12) variant presents variably with early onset severe arrhythmias and left ventricular cardiomyopathy

Abstract

Background: Dilated cardiomyopathy (DCM) is a condition characterized by dilatation and systolic dysfunction of the left ventricle in the absence of severe coronary artery disease or abnormal loading conditions. Mutations in the titin (TTN) and lamin A/C (LMNA) genes are the two most significant contributors in familial DCM. Previously mutations in the desmoplakin (DSP) gene have been associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) and more recently with DCM.

Methods: We describe the cardiac phenotype related to a DSP mutation which was identified in ten unrelated Finnish index patients using next-generation sequencing. Sanger sequencing was used to verify the presence of this DSP variant in the probands' relatives. Medical records were obtained, and clinical evaluation was performed.

Results: We identified DSP c.6310delA, p.(Thr2104Glnfs*12) variant in 17 individuals of which 11 (65%) fulfilled the DCM diagnostic criteria. This pathogenic variant presented with left ventricular dilatation, dysfunction and major ventricular arrhythmias. Two patients showed late gadolinium enhancement (LGE) and myocardial edema on cardiac magnetic resonance imaging (MRI) that may suggest inflammatory process at myocardium.

Conclusions: The patients diagnosed with DCM showed an arrhythmogenic phenotype as well as SCD at young age supporting the recently proposed concept of arrhythmogenic cardiomyopathy. This study also demonstrates relatively low penetrance of truncating DSP variant in the probands' family members by the age of 40. Further studies are needed to elucidate the possible relations between myocardial inflammation and pathogenic DSP variants.

Keywords: Arrhythmogenic cardiomyopathy; Cardiomyopathies; DSP; Dilated cardiomyopathy; Mutation; desmoplakin.

Fig. 1

Pedigrees of six families affected with the DSP c.6310delA, p.(Thr2104Glnfs*12) variant. Squares represent men and circles women. Black-filled symbols represent individuals who fulfill DCM diagnostic criteria. Grey symbol represents individual who was considered affected. Arrows indicate index patients. Carriers of the DSP p.(Thr2104Glnfs*12) variant are marked in symbols with bolded outlines. Genotypes: +/− heterozygous for the DSP p.(Thr2104Glnfs*12), −/− wild type allele, * TTN p.(Val33411Thrfs*32). Year of birth, left ventricular ejection fraction and end-diastolic diameter and other clinical features listed below the symbols. LVEF left ventricular ejection fraction (%); LVEDD left ventricular end-diastolic diameter (mm). Pacemaker/Cardiac transplant: + indicates yes, − indicates no. ECG (electrocardiogram) - SR indicates sinus rhythm; (p)L/RBBB (partial) left/right bundle branch block; LAHB left anterior hemiblock. Arrhythmias - VT for ventricular tachycardia; VES for ventricular extrasystoles; AF for atrial fibrillation; NA not available. ProBNP pro b-type natriuretic peptide, ** BNP b-type natriuretic peptide