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: 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.