To enhance CRDS insight through international cooperation. In the multicenter observational trial, individuals with unexplained life-threatening arrhythmic events and an ultrarare RyR2 mutation were identified. The effects of excitotoxicity-related variants were investigated in HEK293 cells treated with caffeine to determine their functional impact. The researchers reviewed data from September 1, 2012, to March 6, 2021, and analyzed it from August 9, 2015, to March 6, 2021.RyR2 variants found in putative CRDS cases and the clinical syndrome(s) that follow. The deletion of 4 genes (p.E4451del, p.F4499C, p.V4606E, and p.R4608Q) was identified in affected individuals with CRDS (in 4 [67%] male patients and 2 [33%] female patients; median age at presentation, 22 years. Three of the 5 probands with a proven trigger were catecholamine-driven.3 probands with CRDS had no arrhythmias, 1 had a monomorphic couplet, and 2 were unable to have EST (deceased) during the event.No relatives of the decedents had EST test results that were consistent with CPVT.13 relatives were diagnosed with CRDS after screening 3 families, 3 of whom had previous arrhythmic events (23%). While the research, no patients suffered from complex ventricular tachyarrhythmias. Among the 19 CRDS cases confirmed thus far, 10 had at least one life-threatening occurrence at presentation and during a median follow-up of 7 (IQR, 6-18) years. In conclusion, the mechanism of LBLPS-like ventricular fibrillation episodes in dogs is unexplored. Two of the 3 device-detected ventricular fibrillation episodes were induced by a random LBLPS-like sequence. In 16 of 17 surviving patients (94%), β-blockers were administered. Three of 16 patients reported on β-blocker therapy had breakthrough events (19%). The research suggested that calcium-release deficiency syndrome caused by RyR2 loss-of-function variants is mechanistically and phenotypically distinct from CPVT. A spontaneous LBLPS-like sequence of ectopy might cause ventricular fibrillation, but CRDS is difficult to detect clinically. The report’s findings emphasized the importance of improved diagnostic tools and therapies for the emerging problem.