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.

Evaluating the Use of Genetics in Brugada Syndrome Risk Stratification

“…It was also reported that proband status, inducibility toward ventricular arrhythmias (86), arrhythmogenic substrate area, and late potentials (87) were predictors of higher risk. Our group recently proposed the SCN5A genetic status as a prognostic factor for BrS patients (12,88). In particular, SCN5A mutation carriers exhibited more pronounced epicardial electrical abnormalities and a more aggressive clinical presentation.…”

“…However, variants in SCN5A have long been known to not necessarily segregate with BrS (4,11). Recently, patients harboring SCN5A variants were demonstrated to have a worse prognosis (12).…”

The year in cardiovascular medicine 2020: arrhythmias

“…A combined clinical and electrophysiological mapping study showed that SCN5A mutation carriers exhibit more pronounced epicardial electrical abnormalities and a more aggressive clinical presentation than non-carriers. 52 Recent data support the use of drug therapy to manage patients with catecholaminergic polymorphic VT (CPVT). In a provocative paper by Van der Werf et al, 53 no survival benefit from ICDs was shown in young CPVT patients surviving cardiac arrest.…”

The year in cardiovascular medicine 2020: arrhythmias

“…Kombinirano istraživanje kliničkog i elektrofiziološkog mapiranja pokazalo je da nosioci mutacija SCN5A pokazuju izraženije epikardijske električne abnormalnosti i agresivniju kliničku prezentaciju nego nenosioci. 52 Noviji podatci podupiru primjenu terapije lijekovima za zbrinjavanje bolesnika s katekolaminergičnom polimorfnom VT (CPVT). U provokativnom radu Van der Werfa i sur.…”