Nonischemic left ventricular scar: sporadic or familial? Screen the genes, scan the mutation carriers.

A 20-year-old soccer player died suddenly while watching a game with friends at home. At annual preparticipation screening, ECG was normal with consequent sport eligibility (Figure 1A). History for juvenile sudden death and hyper-trophic cardiomyopathy was reported on the mother's side of the family. Postmortem examination of the heart showed normal dimensions (weight, 347 g; wall thicknesses of left ventricle [LV] and septum 13 mm and right ventricle [RV], 3 mm), in the absence of aneurysms or chamber dilatation; a subepicardial scar-like grey rim was evident in the anterolat-eral and posterior LV free wall and in the septum (Figure 1B). Coronary arteries had a normal origin and course, with patent lumen. Histological examination revealed extensive subepi-cardial and intramural fibrous replacement with scarce fatty tissue infiltration, involving the entire LV circumference and the septum (Figure 1C). Right ventricular involvement was only focally detected, in the anterior wall. The features were in keeping with either chronic myocarditis or left-dominant arrhythmogenic cardiomyopathy (AC). At postmortem, molecular pathology investigation by poly-merase chain reaction ruled out the presence of viral genomes in the myocardium. Genetic testing of all AC-related genes was performed on DNA isolated from frozen tissue sample. A heterozygous nonsense mutation of desmoplakin (DSP) at position c.448C>T in exon 4, resulting in a premature stop codon and truncation (Arg150X) at the N-terminal domain of the protein, was detected in the proband (Figure 2A). All family members underwent genetic screening that identified the same DSP mutation in the 54-year-old father and the 19-year-old sister (Figure 2B). Interestingly, the father appeared to be the first mutation carrier in the family, suggesting a dominant de novo mutation. The 54-year-old asymptomatic father showed low QRS voltages and a single premature ventricular complex (PVC) with a left bundle branch block (LBBB) pattern at 12-lead ECG (Figure 3A); signal-averaged ECG was positive at 2 filters (40 and 80 Hz); 1 Minor Task Force Criterion-TFC 2010). Echocardiography was normal, whereas cine cardiac magnetic resonance (CMR) showed anterolateral RV dyski-nesia (1 Minor TFC 1994; 1 Movie I in the online-only Data Supplement); LV posterolateral late enhancement (LE) was evident on contrast enhanced (CE)–CMR (Figure 3B). The 19-year-old sister has been followed-up since the age of 9 for idiopathic ventricular arrhythmias (PVCs with an LBBB pattern) discovered at preparticipation screening. Pharmacological therapy was undertaken with solatol (50 mg ×2). Low QRS voltage, inverted T wave in lead V1, incomplete right bundle branch …