In this study, both PKP2-deficient human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and a cardiac-specific knock-out, Pkp2-cKO, mouse model were utilized to identify the molecular, structural, and functional signatures that recapitulate human ARVC clinical phenotypes. Here, PKP2 is linked to arrhythmogenic right ventricular cardiomyopathy.