Phenotypic spectrum and prognostic stratification in desmoglein-2-associated arrhythmogenic cardiomyopathy: Results from a pooled analysis

BACKGROUND: Increasing knowledge of genotype-phenotype correlations in arrhythmogenic cardiomyopathy (ACM) is leading to more refined diagnostic and risk stratification strategies, encompassing both arrhythmic outcomes and heart failure (HF) progression. Desmoglein-2 (DSG2) mutations represent a clinically relevant genetic subset, taking into consideration both their relative prevalence and their association with severe phenotypic expression. OBJECTIVE: We aimed to provide a comprehensive characterization of DSG2-associated ACM in terms of clinical presentation, phenotypic expression, and predictors of adverse outcomes. METHODS: Clinical and genetic data from patients carrying pathogenic or likely pathogenic DSG2 variants were pooled with individual-level data extracted from previously published series. Demographic features, clinical history, phenotypic expression, and outcome measures during follow-up were harmonized and analyzed. RESULTS: The final cohort included 202 patients, 64.8% males and 60.9% probands. Life-threatening ventricular arrhythmias (LTVAs) were the most common clinical presentation (25.8%). Most of the patients exhibited a right-dominant (38.1%) or biventricular (31.2%) phenotype. After a median follow-up of 92.8 months, 35.3% of patients experienced LTVAs, and 10.9% developed HF. Patients with LTVAs had more severe right ventricular dysfunction, whereas those developing HF exhibited biventricular involvement. Probands exhibit a more severe phenotype in comparison to first-degree relatives, with a trend toward a higher rate of major adverse cardiovascular events (MACEs). Non-sustained ventricular tachycardia on Holter monitoring was the only independent predictor of MACE. CONCLUSION: DSG2-related ACM is characterized by a high arrhythmic burden, both at clinical onset and during follow-up. HF development is associated with biventricular involvement, and non-sustained ventricular tachycardia represents an independent predictor of MACE, supporting its role in early risk stratification.