Brugada syndrome genetics is associated with phenotype severity

Area of Science:

• Cardiology
• Genetics
• Electrophysiology

Background:

• Brugada syndrome (BrS) increases sudden cardiac death risk in young individuals.
• The genotype-phenotype relationship in BrS, particularly involving SCN5A mutations, is not well understood.
• Understanding genetic determinants is crucial for managing BrS risk.

Purpose of the Study:

• To elucidate the genotype-phenotype correlation in Brugada syndrome.
• To investigate the impact of SCN5A mutations on electrophysiological abnormalities.
• To correlate genetic findings with clinical presentation and arrhythmogenic substrate.

Main Methods:

• Genetic testing and epicardial arrhythmogenic substrate (AS) mapping were performed on 200 high-risk Brugada syndrome probands.
• Patients were categorized into SCN5A-positive and SCN5A-negative groups.
• Phenotype characterization included AS mapping, electrogram duration, and non-invasive late potentials.

Main Results:

• SCN5A mutation carriers presented with spontaneous type 1 pattern, aborted cardiac arrest, or VT/VF more frequently.
• SCN5A-positive patients had a larger epicardial AS area and more prolonged electrograms.
• SCN5A mutation presence explained over 26% of the variation in epicardial AS area, acting as the strongest predictor.

Conclusions:

• Genetic background, specifically SCN5A mutations, is a primary determinant of electrophysiological abnormalities in BrS.
• SCN5A mutation carriers exhibit more pronounced epicardial electrical abnormalities and a more aggressive clinical course.
• These findings enhance understanding of genetic factors influencing Brugada syndrome phenotypic variability.