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

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.

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.

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.