CASQ2 encodes calsequestrin 2, a high-capacity calcium-binding protein that sequesters approximately 60 Ca2+ ions within the sarcoplasmic reticulum of cardiac muscle 1. It regulates calcium release through the ryanodine receptor 2 (RYR2), playing a critical role in excitation-contraction coupling and maintaining intracellular calcium homeostasis 1. CASQ2 mutations impair calcium handling by reducing the protein's calcium-binding capacity and altering its aggregation state, which increases the opening probability of the RYR2 calcium release channel 2. This pathological mechanism leads to excessive diastolic calcium release, generating delayed afterdepolarizations that trigger arrhythmias 1. CASQ2 mutations cause catecholaminergic polymorphic ventricular tachycardia (CPVT-2), a stress-induced arrhythmogenic disorder characterized by bidirectional and polymorphic ventricular tachycardia, syncope, and sudden cardiac death in young patients 31. Current therapeutic approaches include β-blockers, flecainide, and left cardiac sympathetic denervation, with emerging strategies targeting calcium handling through SK channel enhancement and gene therapy 14. Disease modeling using human cardiac organoids derived from CASQ2-mutant pluripotent stem cells recapitulates the pro-arrhythmia phenotype, enabling drug discovery platforms 5.