{"doi":"10.3389/fcvm.2021.680819","title":"Clinical and Functional Genetic Characterization of the Role of Cardiac Calcium Channel Variants in the Early Repolarization Syndrome","abstract":"Background: Early repolarization syndrome (ERS) is an inherited sudden cardiac death (SCD) syndrome. The present study investigates the role of genetic variants in cardiac calcium-channel genes in the pathogenesis of ERS and probes the underlying mechanisms. Methods: Polymerase chain reaction–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 coexpressed with CACNB2b and CACNA2D1 in HEK293 cells and studied using whole-cell patch-clamp techniques 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 (62.5%), and 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 beats/min, * p < 0.05), QTc interval was shorter (408.2 ± 21.4 vs. 386.8 ± 16.9 ms, ** p < 0.01), and Tp-e/QT was longer (0.22 ± 0.05 vs. 0.28 ± 0.04, *** p < 0.001) in single calcium mutation carriers. Electrophysiological analysis of one mutation, CACNA1C -P817S (c.2449C>T), revealed that the density of whole-cell calcium current ( I Ca ) was reduced by ~84.61% compared to WT (−3.17 ± 2.53 vs. −20.59 ± 3.60 pA/pF, n = 11 and 15, respectively, ** p < 0.01). Heterozygous expression of mutant channels was associated with a 51.35% reduction of I Ca . Steady-state inactivation was shifted to more negative potentials and significantly accelerated as well. Confocal microscopy revealed trafficking impairment of CACNA1C -P817S (peripheral/central intensity: 0.94 ± 0.10 in WT vs. 0.33 ± 0.12 in P817S, n = 10 and 9, respectively, ** p < 0.01). 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.","journal":"Frontiers in Cardiovascular Medicine","year":2021,"id":191058,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":13,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9053,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":480552,"name":"Héctor Barajas-Martínez","orcid":"0000-0002-2704-3807","position":1,"is_corresponding":false},{"id":755987,"name":"Hao Xia","orcid":"0000-0001-6172-2152","position":2,"is_corresponding":false},{"id":721603,"name":"Zhonghe Zhang","orcid":"0000-0003-4070-0936","position":3,"is_corresponding":false},{"id":755988,"name":"Ganxiao Chen","orcid":"0009-0009-0730-5118","position":4,"is_corresponding":false},{"id":755989,"name":"Bo Yang","orcid":"0000-0002-6365-6061","position":5,"is_corresponding":false},{"id":755990,"name":"Hong Jiang","orcid":"0000-0001-7410-234X","position":6,"is_corresponding":false},{"id":395432,"name":"Charles Antzelevitch","orcid":"0000-0001-7349-1582","position":7,"is_corresponding":false},{"id":430749,"name":"Dan Hu","orcid":"0000-0002-0994-8434","position":8,"is_corresponding":false},{"id":755986,"name":"Xiu Chen","orcid":"0000-0001-9227-6298","position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":null,"created_at":"2026-07-18T23:49:31.121780Z","pmid":"34222376","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}