Background Previous studies suggested that genetic status affects the clinical course of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) patients. The aim of this study was to compare the outcome of desmoglein‐2 (DSG2) mutation carriers to those who carry the plakophilin‐2 (PKP2) mutation, the most common ARVC/D‐associated gene. Methods and results Consecutive ARVC/D patients carrying a pathogenic mutation in PKP2 or DSG2 were selected from a national ARVC/D registry. The cumulative freedom from sustained ventricular arrhythmia and cardiac transplantation/death from heart failure (HF) during follow‐up was assessed, compared between PKP2 and DSG2, and predictors for ventricular arrhythmia and HF events determined. Overall, 118 patients from 78 families were included: 27 (23%) carried a DSG2 mutation and 91 (77%) a PKP2 mutation. There were no significant differences between DSG2 and PKP2 mutation carriers concerning gender, proband status, age at diagnosis, T‐wave inversion, or right ventricular dysfunction at baseline. DSG2 patients displayed more frequent epsilon wave (37% vs. 17%, P = 0.048) and left ventricular dysfunction at diagnosis (54% vs. 10%, P < 0.001). During a median follow‐up of 5.6 years (2.5–16), DSG2 and PKP2 mutation carriers displayed a similar risk of sustained ventricular arrhythmia (log‐rank P = 0.20), but DSG2 mutation carriers were at higher risk of transplantation/HF‐related death (log‐rank P < 0.001). The presence of a DSG2 mutation vs. PKP2 mutation was a predictor of transplantation/HF‐related death in univariate Cox analysis (P = 0.0005). Conclusions In this multicentre cohort, DSG2 mutation carriers were found to be at high risk of end‐stage HF compared to PKP2 mutation carriers, supporting careful haemodynamic monitoring of these patients. The benefit of early HF treatment needs to be assessed in DSG2 carriers.

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