Cardiac ryanodinopathies: integrating phenotypes, genotypes, mechanisms, and the latest evidence

Introduction Cardiac ryanodinopathies represent a heterogeneous group of inherited arrhythmia syndromes caused primarily by pathogenic variants in RYR2, the gene encoding the cardiac ryanodine receptor (RyR2). Increasing recognition of these disorders has expanded the clinical and genetic spectrum, revealing diverse phenotypes and complex underlying mechanisms. Objectives To summarize current knowledge on the phenotypic presentations, genetic landscape, and pathophysiological mechanisms of cardiac ryanodinopathies, and to provide updated insights from recent clinical and experimental studies. Methods A narrative synthesis of contemporary evidence was performed, integrating data from clinical cohorts, molecular genetic analyses, and experimental models to characterize phenotype–genotype correlations and mechanistic and clinical insights related to RyR2 dysfunction. Results Pathogenic RYR2 variants—typically autosomal dominant include gain-of-function destabilize RyR2 and promote diastolic sarcoplasmic reticulum calcium leak, precipitating delayed afterdepolarizations and triggered arrhythmias, leading to the well-known catecholaminergic polymorphic ventricular tachycardia (CPVT) syndrome. Loss-of-function variants, though less frequent, have been associated with unique electrophysiological profiles and overlapping clinical presentations, leading to the novel calcium release deficiency syndrome (CRDS). Recent evidence highlights the role of the calcium overload-induced calcium release mechanism as the underlying pathophysiological factor leading to malignant ventricular arrhythmias. Latest evidence points to disease-specific management strategies for CRDS and highlights a potential novel clinical diagnostic tool. Conclusions Cardiac ryanodinopathies encompass a broad spectrum of phenotypes driven by diverse RYR2 variants and mechanistic perturbations in intracellular calcium handling, with phenotypes ranging from CPVT to CRDS. Improved genetic characterization and mechanistic understanding have refined diagnostic pathways and opened avenues for targeted therapeutic strategies. Continued integration of molecular, functional, and clinical data is essential to optimize risk stratification and personalize management in affected patients.