Brugada syndrome genetics
is associated with phenotype severity
European heart journal
2021 Mar 14;42(11):1082-1090. doi: 10.1093/eurheartj/ehaa942.
PMID: 33221895 PMCID: PMC7955973 DOI: 10.1093/eurheartj/ehaa942
Giuseppe Ciconte, Michelle M Monasky, Vincenzo Santinelli, Emanuele Micaglio, Gabriele Vicedomini, Luigi Anastasia, Gabriele Negro, Valeria Borrelli, Luigi Giannelli, Francesca Santini, Carlo de Innocentiis, Roberto Rondine, Emanuela T Locati, Andrea Bernardini, Beniamino C Mazza, Valerio Mecarocci, Žarko Ćalović, Andrea Ghiroldi, Sara D’Imperio, Sara Benedetti, Chiara Di Resta, Ilaria Rivolta, Giorgio Casari, Enrico Petretto, Carlo Pappone
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.