Brugada syndrome genetics is associated with phenotype severity

Abstract

Aims: Brugada syndrome (BrS) is associated with an increased risk of sudden cardiac death due to ventricular tachycardia/fibrillation (VT/VF) in young, otherwise healthy individuals. Despite SCN5A being the most commonly known mutated gene to date, the genotype-phenotype relationship is poorly understood and remains uncertain. This study aimed to elucidate the genotype-phenotype correlation in BrS.

Methods and results: Brugada syndrome probands deemed at high risk of future arrhythmic events underwent genetic testing and phenotype characterization by the means of epicardial arrhythmogenic substrate (AS) mapping, and were divided into two groups according to the presence or absence of SCN5A mutation. Two-hundred probands (160 males, 80%; mean age 42.6 ± 12.2 years) were included in this study. Patients harbouring SCN5A mutations exhibited a spontaneous type 1 pattern and experienced aborted cardiac arrest or spontaneous VT/VF more frequently than the other subjects. SCN5A-positive patients exhibited a larger epicardial AS area, more prolonged electrograms and more frequently observed non-invasive late potentials. The presence of an SCN5A mutation explained >26% of the variation in the epicardial AS area and was the strongest predictor of a large epicardial area.

Conclusion: In BrS, the genetic background is the main determinant for the extent of the electrophysiological abnormalities. SCN5A mutation carriers exhibit more pronounced epicardial electrical abnormalities and a more aggressive clinical presentation. These results contribute to the understanding of the genetic determinants of the BrS phenotypic expression and provide possible explanations for the varying degrees of disease expression.

Keywords: Brugada syndrome; Epicardial arrhythmogenic substrate; Genotype; Phenotype; Predictors; SCN5A.

Figure 1

Exemplary case of an SCN5A carrier with a spontaneous type 1 pattern and abnormal late potentials at the signal-averaged electrocardiogram (top panel). Middle panel shows one of the appropriate shocks by the implantable cardioverter-defibrillators, implanted in primary prevention. The epicardial mapping demonstrated a large area of electrical abnormalities (32.3 cm²), representing the Brugada syndrome arrhythmogenic substrate (purple colour in CARTO map).

Figure 2

Example of a patient negative to the genetic test. Baseline epicardial mapping demonstrated a 4.3 cm² area of abnormal electrograms (top panel), increasing to 10 cm² after ajmaline.

Figure 3

Proportion of variance explained in arrhythmogenic substrate size by each variable included in the linear regression model. The level of statistical significance is also indicated for each variable. SCN5A mutation explained 24.4% of the variance in arrhythmogenic substrate (F  _change = 62.4), spontaneous type 1 pattern 13.6% (F  _change = 42.1), and male gender 5.0% (F  _change = 16.6).

Take-home figure

Brugada syndrome phenotypic expression predictors. (A) Large Brugada syndrome epicardial substrate in a male patient with spontaneous type 1 electrocardiogram pattern experiencing appropriate implantable cardioverter-defibrillator therapy. (B) Specific contribution of each variable (SCN5A mutations, spontaneous type 1 electrocardiogram pattern, and gender), in explaining the variance of the arrhythmogenic substrate. (C) Receiver-operating characteristic curve analysis demonstrating the accuracy of the model for the prediction of a large arrhythmogenic substrate (≥6.3 cm²).