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Background Variants of the desmosomal protein desmoplakin are associated with arrhythmogenic cardiomyopathy, an important cause of ventricular arrhythmias in children and young adults. Disease penetrance of desmoplakin variants is incomplete and variant carriers may display noncardiac, dermatologic phenotypes. We describe a novel cardiac phenotype associated with a truncating desmoplakin variant, likely causing mechanical instability of myocardial desmosomes. Methods and Results In 2 young brothers with recurrent myocarditis triggered by physical exercise, screening of 218 cardiomyopathy‐related genes identified the heterozygous truncating variant p.Arg1458Ter in desmoplakin. Screening for infections yielded no evidence of viral or nonviral infections. Myosin and troponin I autoantibodies were detected at high titers. Immunohistology failed to detect any residual DSP protein in endomyocardial biopsies, and none of the histologic criteria of arrhythmogenic cardiomyopathy were fulfilled. Cardiac magnetic resonance imaging revealed no features associated with right ventricular arrhythmogenic cardiomyopathy, but multifocal subepicardial late gadolinium enhancement was present in the left ventricles of both brothers. Screening of adult cardiomyopathy cohorts for truncating variants identified the rare genetic variants p.Gln307Ter, p.Tyr1391Ter, and p.Tyr1512Ter, suggesting that over subsequent decades critical genetic/exogenous modifiers drive pathogenesis from desmoplakin truncations toward different end points. Conclusions The described novel phenotype of familial recurrent myocarditis associated with a desmoplakin truncation in adolescents likely represents a serendipitously revealed subtype of arrhythmogenic cardiomyopathy. It may be caused by a distinctive adverse effect of the variant desmoplakin upon the mechanical stability of myocardial desmosomes. Variant screening is advisable to allow early detection of patients with similar phenotypes.

Background Cardiomyopathies are heterogeneous diseases with clinical presentations varying from asymptomatic to life‐threatening events, including severe heart failure and sudden cardiac death. The role of underlying genetic and disease‐modulating factors in children and adolescents is relatively unknown. In this prospective study, in‐depth phenotypic and genetic characterization of pediatric patients with primary cardiomyopathy and their first‐degree family members (FMs) was performed. Outcome was assessed to identify clinical risk factors. Methods and Results Sixty index patients with primary cardiomyopathy (median age: 7.8 years) and 124 FMs were enrolled in the RIKADA (Risk Stratification in Children and Adolescents with Primary Cardiomyopathy) study. Family screening included cardiac workup and genetic testing. Using cardiologic screening, we identified 17 FMs with cardiomyopathies and 30 FMs with suspected cardiomyopathies. Adverse events appeared in 32% of index patients and were more common in those with lower body surface area (P=0.019), increased NT‐proBNP (N‐terminal pro–brain natriuretic peptide; P