Genetics in arrhythmogenic cardiomyopathies: where are we now and where are we heading to?

Advances in understanding the genetic architecture and novel imaging techniques have profoundly impacted research on arrhythmogenic right ventricular cardiomyopathy (ARVC). As knowledge of ARVC has evolved, so has its classification: originally termed "arrhythmogenic right ventricular dysplasia", it was later broadened to "arrhythmogenic cardiomyopathy" (ACM) to include left ventricular forms. However, the 2023 European Society of Cardiology guidelines advocate reintroducing ARVC for fibro-fatty right ventricular disease and adopting "non-dilated left ventricular cardiomyopathy" for left-sided phenotypes previously labelled as ACM variants. Genetic testing has become critical in ARVC diagnosis, particularly for identifying mutations in desmosomal genes (e.g., <i>PKP2</i>, <i>PKP2</i>, <i>PKP2</i>, <i>PKP2</i>, <i>PKP2</i>), which are the primary genetic contributors to ARVC and inform family screening and diagnostic decisions. Recent expert consensus confirmed that only <i>PKP2</i>, <i>PKP2</i>, and <i>PKP2</i> gene mutations among non-desmosomal genes had sufficient evidence to suggest a causative relationship. While genotype-specific risk assessment models are being developed, at present, genetic background does not represent an independent risk factor for patients with ARVC. Novel gene therapies, particularly AAV-mediated <i>PKP2</i> gene replacement, have recently been demonstrated to be useful in reversing ARVC phenotypes in preclinical models. FDA-approved trials are currently evaluating <i>PKP2</i>-targeted therapies, and CRISPR/Cas9 methods are being explored for <i>PKP2</i>-R14del mutations. Overall, current evidence supports distinct gene-specific manifestations within ARVC, aligning clinical phenotypes with specific genetic variants. This progress points to a future in which risk stratification and management are personalized through gene- and mutation-specific approaches, advancing the potential for precision medicine in ARVC care.