Log in to MyACC
SCN5A Pathogenic Variants in Early Repolarization and Brugada Syndromes
Quick Takes
- Patients with early repolarization syndrome are more often male and present at younger ages, but less often carry pathogenic SCN5A genetic variants than those with Brugada syndrome.
- Patients with early repolarization syndrome are more often male and present at younger ages, but less often carry pathogenic SCN5A genetic variants than those with Brugada syndrome.
Study Questions:
What are the distinct features between patients with early repolarization syndrome (ERS) and Brugada syndrome (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.
Results:
The SCN5A+ yield in ERS was significantly lower than in BrS (9.6% vs. 22.9%; p = 0.004). Patients diagnosed with ERS displayed shorter QRS and QTc than patients with BrS. More than two pathogenic SCN5A variants were found in five probands and those patients experienced more major arrhythmia events 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 co-expressed with KCND3, it reduced peak INa by 44.5% and increased the transient outward potassium current (Ito) by 106.8%.
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 J-wave syndrome and a higher risk for major arrhythmia events in J-wave syndrome probands carrying multiple pathogenic variants in SCN5A.
Perspective:
There are two major forms of inherited J-wave syndrome: ERS and BrS. SCN5A is responsible for initiating the cardiac action potential. Loss of function in SCN5A reduces the excitability of myocardial cells and slows impulse conduction throughout the myocardium. This study extends knowledge of the genetics of J-wave syndrome by identifying 10 novel SCN5A variants in ERS and two in BrS. The paper’s findings point to SCN5A as a major susceptibility gene in ERS as it is in BrS, although the yield in ERS is significantly lower than in BrS. This study also identifies the first case of fever-induced ERS, and demonstrates a critical role for Ito in J-wave syndrome.
Clinical Topics: Arrhythmias and Clinical EP, Congenital Heart Disease and Pediatric Cardiology, Dyslipidemia, Implantable Devices, EP Basic Science, Genetic Arrhythmic Conditions, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Congenital Heart Disease, CHD and Pediatrics and Arrhythmias, Lipid Metabolism
Keywords: Action Potentials, Arrhythmias, Cardiac, Brugada Syndrome, Cardiac Electrophysiology, Death, Sudden, Cardiac, Electrocardiography, Genetics, Heart Defects, Congenital, Myocardium, NAV1.5 Voltage-Gated Sodium Channel, Patch-Clamp Techniques, Sodium Channels
< Back to Listings
