Abstract 12296: Clinical and Functional Genetic Characterization of the Role of Cardiac Calcium Channel Variants in the Early Repolarization Syndrome

Abstract

Introduction: Early repolarization syndrome (ERS) is an inherited sudden cardiac death syndrome. Hypothesis: In this study we test the role of genetic variants in cardiac calcium channel genes in the pathogenesis of ERS and probes the underlying mechanisms. Methods: PCR-based next-generation sequencing was carried out using a targeted gene approach. Unrelated ERS probands carrying calcium channel variants were evaluated clinically and compared with matched healthy controls. Wild type (WT) and mutant CACNA1C genes were co-expressed with CACNB2b and CACNA2D1 in HEK293 cells and studied using whole-cell patch-clamp and confocal fluorescence microscope . Results: Among 104 ERS probands, 16 carried pathogenic variants in calcium channel genes (32.2±14.6 years old, 87.5% male). The symptoms at diagnosis included syncope (56.3%), ventricular tachycardia/fibrillation (VT/VF, 62.5%), sudden cardiac death (SCD, 56.3%). Three cases (18.8%) had a family history of SCD or syncope. Eight patients (50.0%) had a single calcium gene rare variant. The other half carried rare variants in other ERS susceptible genes. Compared with controls, the heart rate was slower (72.7±8.9 vs. 65.6±16.1 bpm), QTc interval was shorter (408.2±21.4 vs. 386.8±16.9 ms) and Tp-e/QT was longer (0.22±0.05 vs.0.28±0.04) in calcium mutation carriers. Electrophysiological analysis of one mutation, CACNA1C -P817S revealed that the density of I Ca was reduced by approximately 84.6% compared to WT (-3.1±2.5 vs. -20.5±3.6 pA/pF, n=11 and 15, respectively). Heterozygous expression of mutant channels was associated with a 51.3% reduction of I Ca . Steady-state inactivation was shifted to more negative potentials and significantly accelerated. Confocal microscopy revealed trafficking impairment of CACNA1C -P817S (peripheral/central intensity: 0.94±0.1 in WT vs. 0.33±0.1 in P817S, n=10 and 9, respectively). Conclusions: ERS associated with loss of function (LOF) genetic defects in genes encoding the cardiac calcium channel represents a unique clinical entity characterized by decreased heart rate and QTc, as well as increased transmural dispersion of repolarization. In the case of CACNA1C -P817S impaired trafficking of the channel to the membrane contributes to the LOF.