B-PO04-022 CLINICAL AND FUNCTIONAL CHARACTERIZATION OF RYR2 VARIANTS IMPLICATED IN CALCIUM RELEASE DEFICIENCY SYNDROME: AN INTERNATIONAL MULTICENTER STUDY

Calcium release deficiency syndrome (CRDS), caused by loss of function (LOF) RYR2 variants, is a recently recognized condition. CRDS patients are vulnerable to VT/VF, but have lacked provocable ventricular ectopy characteristic of CPVT during exercise stress testing (EST). To identify novel cases of CRDS through clinical and functional characterization. We identified probands with rare RYR2 variants and unexplained VT/VF despite extensive phenotyping. Variants were expressed in HEK293 cells and subjected to caffeine stimulation to determine functional impact. Of 11 probands assessed, 7 had RYR2 LOF variants in the C-terminus based on response to caffeine stimulation, consistent with CRDS. During EST, 2 CRDS probands had no arrhythmias, 2 had monomorphic arrhythmia, and 3 were unable to undergo EST (2 deceased, 1 disabled). The LOF variant was found in 14 relatives, for a total of 21 CRDS cases among 26 patients in the cohort (81%) (Fig). Four had atrial arrhythmias (19%). Eleven (52%) CRDS patients had ≥1 life threatening event at presentation or over 6 yrs (IQR 10-37) of follow up. All but one occurred while taking a β-blocker, and 53% were not adrenergic triggered. β-blockers were used in 89%. CRDS caused by RYR2 LOF variants is often mistaken for CPVT. The combination of a rare RYR2 C-terminus variant, unexplained VT/VF, and EST not diagnostic of typical CPVT should raise suspicion for CRDS. Notably, unlike CPVT, CRDS is not reliably triggered by adrenergic stimuli, β-blockers appear less effective, and the EST is non-specific, making diagnosis nearly impossible prior to a fatal or near-fatal event.