Background: Idiopathic dilated cardiomyopathy is a familial disorder in 25% to 50% of patients, but the genetic basis in the majority of cases remains unknown. Genes encoding desmosomal proteins, currently regarded as synonymous with another disorder, arrhythmogenic right ventricular cardiomyopathy, are known to cause left ventricular dysfunction, but their importance in unselected patients with unequivocal dilated cardiomyopathy is unknown. The objective of this study was to determine the prevalence of mutations in 5 desmosomal protein genes in patients with dilated cardiomyopathy.
Methods and results: We studied 100 unrelated patients with idiopathic dilated cardiomyopathy consecutively referred to a dedicated cardiomyopathy unit. Patients underwent clinical evaluation, ECG, echocardiography, exercise testing, 24-hour ambulatory ECG monitoring, and mutation screening of 5 genes implicated in arrhythmogenic right ventricular cardiomyopathy: plakoglobin, desmoplakin, plakophilin-2, desmoglein-2, and desmocollin-2. Of the 100 patients (mean age at evaluation, 46.8+/-13.8 years; range, 17.0 to 72.8 years; male sex, 63%), 5 were found to carry pathogenic desmosomal protein gene mutations. An additional 13 patients had sequence variants of uncertain pathogenic significance and were excluded from further comparative analysis. Patients harboring desmosomal gene mutations had a phenotype indistinguishable from the 82 noncarriers, with the exception of exercise-induced ventricular ectopy, which was more frequent in the desmosomal mutation carriers (P=0.033). None of the 5 carriers of desmosomal mutations fulfilled current diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy, but 1 had fibrofatty change in the left ventricle at autopsy.
Conclusions: Heart failure caused by a dilated, poorly contracting left ventricle and arrhythmogenic right ventricular cardiomyopathy have been considered distinct clinicopathologic entities. This study suggests that both clinical presentations can be caused by mutations in desmosomal protein genes.