Case Report: Contrasting phenotypes of arrhythmogenic cardiomyopathy: classic desmosomal ARVC and a RIT1-related phenocopy

Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is most commonly associated with pathogenic variants in desmosomal genes. However, ARVC-like phenotypes may also arise from non-desmosomal genetic backgrounds, creating diagnostic challenges and raising the concept of phenocopies. Case summary We describe two contrasting cases of arrhythmogenic cardiomyopathy. Case 1 is a middle-aged man presenting with atrial fibrillation and imaging evidence of right ventricular (RV) fatty infiltration, repolarization abnormalities, and positive signal-averaged electrocardiogram (ECG) , in whom a pathogenic RIT1 variant was identified without desmosomal mutations. This case was interpreted as a RASopathy-associated arrhythmogenic cardiomyopathy phenocopy. Case 2 is a woman with severe RV dysfunction, ventricular arrhythmia burden, characteristic ECG findings, a strong family history of sudden cardiac death, and a likely pathogenic DSG2 variant, fulfilling multiple major Task Force Criteria for classic ARVC and requiring implantable cardioverter-defibrillator implantation. Discussion These cases highlight the genetic and phenotypic heterogeneity of ARVC and emphasize the importance of multimodality imaging and extended genetic testing to distinguish classic desmosomal disease from phenocopies.