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

## TL;DR

This case report compares two different types of arrhythmogenic cardiomyopathy, one caused by a desmosomal gene and the other by a RIT1 variant, highlighting the need for thorough genetic and imaging assessments.

## Contribution

The paper presents two distinct cases that illustrate the genetic and phenotypic diversity of ARVC, including a RIT1-related phenocopy.

## Key findings

- A RIT1 variant was identified in a patient with ARVC-like symptoms but no desmosomal mutations.
- A DSG2 variant was found in a patient with classic ARVC features and a strong family history of sudden cardiac death.
- Multimodality imaging and genetic testing are essential to differentiate classic ARVC from phenocopies.

## Abstract

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.