Clinical Features of Brugada Syndrome Patients With SCN5A Variants

Area of Science:

• Cardiovascular Genetics
• Electrophysiology
• Genetic Diagnosis

Background:

• SCN5A gene mutations are the most common cause of Brugada syndrome (BrS).
• Interpreting benign or variants of unknown clinical significance (VUS) in SCN5A remains challenging for patient management.
• Genetic testing for BrS requires clear understanding of SCN5A variant pathogenicity.

Purpose of the Study:

• To investigate the association between SCN5A variants and clinical manifestations in Brugada syndrome patients.
• To clarify the clinical significance of SCN5A variants, including VUS, in BrS.
• To identify predictors of cardiac events and symptoms in BrS patients with SCN5A variants.

Main Methods:

• Resequencing of the SCN5A gene in 239 diagnosed Brugada syndrome patients.
• Analysis of SCN5A variants in conjunction with clinical features, 12-lead ECG, and signal-averaged ECG parameters.
• Multivariate analyses to determine independent risk factors for cardiac events and symptoms.

Main Results:

• 84 SCN5A variants identified: 55 benign, 7 pathogenic, 22 VUS.
• Higher proportion of symptomatic patients and higher female incidence observed in patients with SCN5A VUS or pathogenic variants.
• SCN5A pathogenic variants, longer r-J intervals, and fragmented QRS were independently associated with cardiac events.

Conclusions:

• SCN5A pathogenic variants are independent risk factors for cardiac events in BrS.
• While not independent risk factors for cardiac events, SCN5A VUS are associated with increased symptomatic presentation.
• Signal-averaged ECG is crucial for risk stratification of cardiac events in BrS patients with SCN5A VUS.