Original Investigation
Distinct Features of Probands With Early Repolarization and Brugada Syndromes Carrying SCN5A Pathogenic Variants

https://doi.org/10.1016/j.jacc.2021.08.024Get rights and content
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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.

Key Words

genetics
J-wave syndrome
risk stratification
sodium channel
sudden cardiac death

Abbreviations and Acronyms

ARI
activation recovery interval
ASCD
aborted sudden cardiac death
BrS
Brugada syndrome
ECG
electrocardiography
ERP
early repolarization pattern
ERS
early repolarization syndrome
HR
heart rate
INa
inward sodium current
Ito
transient outward potassium current
JWS
J-wave syndrome
MAE
major arrhythmic events
SCD
sudden cardiac death
Tp-e
Tpeak-Tend
VT/VF
ventricular tachycardia/fibrillation
WT
wild-type

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The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.

Drs Zhang and Barajas-Martínez contributed equally as first authors.