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Brugada Syndrome Genetics Is Associated With Phenotype Severity
Quick Takes
- Patients with Brugada syndrome who have SCN5A mutations more frequently have type 1 ECG pattern in the right precordial leads and experience aborted cardiac arrest or spontaneous ventricular tachycardia or fibrillation more frequently than those without the mutation.
- SCN5A-positive patients have a larger epicardial arrhythmogenic substrate area, more prolonged local electrograms, and more frequently late potentials on signal-averaged ECG.
Study Questions:
What is the correlation of Brugada syndrome genotypes with phenotypes?
Methods:
Brugada syndrome probands deemed at high risk of future arrhythmic events underwent genetic testing and phenotype characterization by the means of epicardial arrhythmogenic substrate mapping, and were divided into two groups according to the presence or absence of SCN5A mutation.
Results:
There were 200 probands (80% male; mean age, 43 years). Patients with SCN5A mutations more often have a spontaneous type 1 pattern and experience aborted cardiac arrest or spontaneous ventricular tachycardia or fibrillation more frequently than those without the mutation. SCN5A-positive patients also have a larger epicardial arrhythmogenic substrate area, more prolonged local electrograms, and more frequently late potentials on signal-averaged electrocardiography (ECG). The presence of an SCN5A mutation explained >26% of the variation in the epicardial arrhythmogenic substrate area and was the strongest predictor of a large epicardial area.
Conclusions:
In Brugada syndrome, SCN5A mutation is associated with pronounced epicardial electrical abnormalities and a more aggressive clinical presentation.
Perspective:
Despite significant progress in the understanding of the disease since its original description in 1992, much uncertainty remains about the genetics of the syndrome. The strongest evidence for the culprit causative gene exists for SCN5A, but only about 20% of probands have the variants in this gene. Identification of patients at high risk for sudden death has been challenging. The syndrome is associated with discrete arrhythmogenic substrate in the epicardium of the right ventricle. The findings of this study suggest that SCN5A mutation is associated with a larger epicardial scan and more prolonged local ECGs, which may explain a tighter correlation between the SCN5A mutation and clinical outcomes. Much work remains to be done to elucidate the likely polygenic nature of Brugada syndrome to account for its variable expressivity and incomplete penetrance in at-risk individuals.
Clinical Topics: Arrhythmias and Clinical EP, Cardiovascular Care Team, Dyslipidemia, Prevention, Implantable Devices, EP Basic Science, Genetic Arrhythmic Conditions, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Lipid Metabolism
Keywords: Arrhythmias, Cardiac, Brugada Syndrome, Death, Sudden, Electrocardiography, Epicardial Mapping, Genetic Testing, Genotype, Heart Arrest, Mutation, NAV1.5 Voltage-Gated Sodium Channel, Pericardium, Phenotype, Secondary Prevention, Tachycardia, Ventricular, Ventricular Fibrillation
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