Distinct features of probands with early repolarization and Brugada Syndromes carrying SCN5A pathogenic variants

Journal article


Zhang, Zhong-He, Barajas-Martínez, Hector, Xia, Hao, Li, Bian, Capra, John A, Clatot, Jerome, Chen, Gan-Xiao, Chen, Xiu, Yang, Bo, Jiang, Hong, Tse, Gary, Aizawa, Yoshiyasu, Gollob, Michael H, Scheinman, Melvin, Antzelevitch, Charles and Hu, Dan 2021. Distinct features of probands with early repolarization and Brugada Syndromes carrying SCN5A pathogenic variants. Journal of the American College of Cardiology. 78 (16), pp. 1603-1617. https://doi.org/S0735-1097(21)06008-3
AuthorsZhang, Zhong-He, Barajas-Martínez, Hector, Xia, Hao, Li, Bian, Capra, John A, Clatot, Jerome, Chen, Gan-Xiao, Chen, Xiu, Yang, Bo, Jiang, Hong, Tse, Gary, Aizawa, Yoshiyasu, Gollob, Michael H, Scheinman, Melvin, Antzelevitch, Charles and Hu, Dan
AbstractTwo major forms of inherited J-wave syndrome (JWS) are recognized: early repolarization syndrome (ERS) and Brugada syndrome (BrS). This study sought to assess the distinct features between patients with ERS and BrS carrying pathogenic variants in SCN5A. Clinical evaluation and next-generation sequencing were performed in 262 probands with BrS and 104 with ERS. Nav1.5 and Kv4.3 channels were studied with the use of patch-clamp techniques. A computational model was used to investigate the protein structure. The SCN5A+ yield in ERS was significantly lower than in BrS (9.62% vs 22.90%; P = 0.004). Patients diagnosed with ERS displayed shorter QRS and QTc than patients with BrS. More than 2 pathogenic SCN5A variants were found in 5 probands. These patients displayed longer PR intervals and QRS duration and experienced more major arrhythmia events (MAE) compared with those carrying only a single pathogenic variant. SCN5A-L1412F, detected in a fever-induced ERS patient, led to total loss of function, destabilized the Nav1.5 structure, and showed a dominant-negative effect, which was accentuated during a febrile state. ERS-related SCN5A-G452C did not alter the inward sodium current (INa) when SCN5A was expressed alone, but when coexpressed with KCND3 it reduced peak INa by 44.52% and increased the transient outward potassium current (Ito) by 106.81%. These findings point to SCN5A as a major susceptibility gene in ERS as much as it is in BrS, whereas the lower SCN5A+ ratio in ERS indicates the difference in underlying electrophysiology. These findings also identify the first case of fever-induced ERS and demonstrate a critical role of Ito in JWS and a higher risk for MAE in JWS probands carrying multiple pathogenic variants in SCN5A. [Abstract copyright: Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.]
KeywordsGenetics; Sudden cardiac death; J-wave syndrome; Sodium channel; Risk stratification
Year2021
JournalJournal of the American College of Cardiology
Journal citation78 (16), pp. 1603-1617
PublisherElsevier
ISSN1558-3597
Digital Object Identifier (DOI)https://doi.org/S0735-1097(21)06008-3
https://doi.org/10.1016/j.jacc.2021.08.024
Official URLhttps://www.sciencedirect.com/science/article/pii/S0735109721060083?via%3Dihub
Publication dates
Online11 Oct 2021
Online19 Oct 2021
Publication process dates
Accepted10 Aug 2021
Deposited16 Jun 2022
Output statusPublished
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