{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T10:40:32Z","timestamp":1791888032184,"version":"4.3.4"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,6,18]],"date-time":"2021-06-18T00:00:00Z","timestamp":1623974400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> 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.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> Polymerase chain reaction\u2013based 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 <jats:italic>CACNA1C<\/jats:italic> genes were coexpressed with <jats:italic>CACNB2b<\/jats:italic> and <jats:italic>CACNA2D1<\/jats:italic> in HEK293 cells and studied using whole-cell patch-clamp techniques and confocal fluorescence microscope.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> Among 104 ERS probands, 16 carried pathogenic variants in calcium-channel genes (32.2 \u00b1 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 \u00b1 8.9 vs. 65.6 \u00b1 16.1 beats\/min, <jats:sup>*<\/jats:sup><jats:italic>p<\/jats:italic> &amp;lt; 0.05), QTc interval was shorter (408.2 \u00b1 21.4 vs. 386.8 \u00b1 16.9 ms, <jats:sup>**<\/jats:sup><jats:italic>p<\/jats:italic> &amp;lt; 0.01), and Tp-e\/QT was longer (0.22 \u00b1 0.05 vs. 0.28 \u00b1 0.04, <jats:sup>***<\/jats:sup><jats:italic>p<\/jats:italic> &amp;lt; 0.001) in single calcium mutation carriers. Electrophysiological analysis of one mutation, <jats:italic>CACNA1C<\/jats:italic>-P817S (c.2449C&amp;gt;T), revealed that the density of whole-cell calcium current (<jats:italic>I<\/jats:italic><jats:sub>Ca<\/jats:sub>) was reduced by ~84.61% compared to WT (\u22123.17 \u00b1 2.53 vs. \u221220.59 \u00b1 3.60 pA\/pF, <jats:italic>n<\/jats:italic> = 11 and 15, respectively, <jats:sup>**<\/jats:sup><jats:italic>p<\/jats:italic> &amp;lt; 0.01). Heterozygous expression of mutant channels was associated with a 51.35% reduction of <jats:italic>I<\/jats:italic><jats:sub>Ca<\/jats:sub>. Steady-state inactivation was shifted to more negative potentials and significantly accelerated as well. Confocal microscopy revealed trafficking impairment of <jats:italic>CACNA1C<\/jats:italic>-P817S (peripheral\/central intensity: 0.94 \u00b1 0.10 in WT vs. 0.33 \u00b1 0.12 in P817S, <jats:italic>n<\/jats:italic> = 10 and 9, respectively, <jats:sup>**<\/jats:sup><jats:italic>p<\/jats:italic> &amp;lt; 0.01).<\/jats:p><jats:p><jats:bold>Conclusions:<\/jats:bold> 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 <jats:italic>CACNA1C<\/jats:italic>-P817S, impaired trafficking of the channel to the membrane contributes to the LOF.<\/jats:p>","DOI":"10.3389\/fcvm.2021.680819","type":"journal-article","created":{"date-parts":[[2021,6,18]],"date-time":"2021-06-18T04:42:33Z","timestamp":1623991353000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["Clinical and Functional Genetic Characterization of the Role of Cardiac Calcium Channel Variants in the Early Repolarization 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