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

Zhang, Zhong-He, Barajas-Martínez, Hector, Xia, Hao, Li, Bian, Capra, John A., Clatot, Jerome, Chen, Gan-Xiao, Chen, Xiu, Yang, Bo, Jiang, Hong, and others. (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. ISSN 0735-1097. E-ISSN 1558-3597. (doi:10.1016/j.jacc.2021.08.024) (The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided) (KAR id:98443)

The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided. (Contact us about this Publication)
Official URL:
https://doi.org/10.1016/j.jacc.2021.08.024

Abstract

Background

Two major forms of inherited J-wave syndrome (JWS) are recognized: early repolarization syndrome (ERS) and Brugada syndrome (BrS).

Objectives

This study sought to assess the distinct features between patients with ERS and BrS carrying pathogenic variants in SCN5A.

Methods

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.

Results

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%.

Conclusions

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.

Item Type: Article
DOI/Identification number: 10.1016/j.jacc.2021.08.024
Uncontrolled keywords: genetics, J-wave syndrome, risk stratification, sodium channel, sudden cardiac death
Subjects: R Medicine
Divisions: Divisions > Division of Natural Sciences > Kent and Medway Medical School
Funders: National Natural Science Foundation of China (https://ror.org/01h0zpd94)
National Institutes of Health (https://ror.org/01cwqze88)
Depositing User: Gary Tse
Date Deposited: 28 Nov 2022 11:38 UTC
Last Modified: 04 Mar 2024 19:23 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/98443 (The current URI for this page, for reference purposes)

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