Different prognosis of ARVC patients between DSG2 and PKP2 variant carriers

Abstract Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy mainly caused by desmosomal gene variants. In Europe and North America, pathogenic variants in PKP2 were identified in most of the ARVC patients. On the other hand, we have reported that the genetic backgrounds of ARVC in Japanese were different from those in European; pathogenic variants in DSG2 were predominant in Japanese. Genotype-phenotype correlations, however, have not been clarified yet. Purpose In this study, we aimed to examine whether the genotype affect the phenotype and outcome in Japanese ARVC patients. Methods and results This study included 167 Japanese ARVC patients who received genetic testing (128 males [77%]). Their median age at diagnosis was 44 [24–55] years old and median follow-up duration was 10 [4–21] years. We found 90 patients with pathogenic variants: 52 in DSG2 (31%), 30 in PKP2 (18%), 3 in DSP (1.8%), 1 in DSC (0.6%), 1 in JUP (0.6%) and 3 in DES (1.8%). The age of the first sustained ventricular arrhythmia (SVT) were older in the patients with DSG2 than those with PKP2 variants (48±15 years vs. 35±15 years, P=0.008) but younger in DSG2 variant carriers at the first hospitalization for heart failure (41 [22–61] years vs. 67 [61–74] years, P=0.03). The left ventricular ejection fractions of DSG2 variant carriers were significantly lower at diagnosis than that of PKP2 (52 [41–60] % vs. 61 [56–66] %, P=0.002). Kaplan-Meier survival curve for lethal arrhythmic events including SVT, ventricular fibrillation and sudden death revealed that the event rate of DSG2 variant carriers was significantly lower than that of PKP2 (log-rank test, P=0.02) (Fig. 1). Among 11 patients who had both SVT and hospitalizations for HF, 7 PKP2 variant carriers had SVT first, then, hospitalized for HF (48 [35–53] years and 67 [55–71] years, P=0.02). Contrary, the clinical course of 4 DSG2 variants carriers were different from those with PKP2 (54 [40–68] years for SVT and 65 [56–70, P=0.1] years for HF) (Fig. 2). Conclusion The patients with DSG2, which is the major causative gene for ARVC in Japanese, show different phenotype and outcome from those with PKP2. We should examine the effect of variants on the prognosis of ARVC patients in more large population including various ethnics. Funding Acknowledgement Type of funding sources: None.