Four cardiomyopathy patients with a heterozygous DSG2 p.Arg119Ter variant

DSG2, encoding desmoglein-2, is one of the causative genes of arrhythmogenic cardiomyopathy. We previously identified a homozygous DSG2 p.Arg119Ter stop-gain variant in a patient with juvenile-onset cardiomyopathy and advanced biventricular heart failure. However, the pathological significance and prevalence of the heterozygous DSG2 p.Arg119Ter variant remains uncertain. Here, we identified four unrelated patients with cardiomyopathy with heterozygous DSG2 p.Arg119Ter variants among 808 patients with nonischemic cardiomyopathy; the allele frequency was 0.0037, which is more than 50-fold greater than that reported in the general Japanese population. These patients were clinically diagnosed with arrhythmogenic right ventricular cardiomyopathy (Pt-1), dilated cardiomyopathy (DCM) after ventricular septum defect closure surgery (Pt-2), DCM (Pt-3), and end-stage hypertrophic cardiomyopathy (Pt-4). The patients also exhibited reduced left ventricular contractile function and varying clinical courses. Genetic analysis identified additional possible causative variants, DSG2 p.Arg292Cys in Pt-1 and BAG3 p.His166SerfsTer6 in Pt-3. Immunohistochemical analysis of endomyocardial biopsy samples revealed that the expression of not only desmoglein-2 but also desmoplakin was markedly reduced. Transmission electron microscopy revealed pale and fragmented desmosomes and widened gaps between intercalated discs in the myocardium. A microforce test using human cardiomyocytes differentiated from induced pluripotent stem cells (iPSC-CMs) demonstrated reduced contractility in iPSC-CMs carrying a heterozygous truncating variant in DSG2. These data suggest that the DSG2 p.Arg119Ter variant is concealed in patients with cardiomyopathy with heart failure, and desmosome impairment may be a latent exacerbating factor of contractile dysfunction and disease progression.