Spectrum and Prevalence of Mutations Involving BrS1- Through BrS12-Susceptibility Genes in a Cohort of Unrelated Patients Referred for Brugada Syndrome Genetic Testing: Implications for Genetic Testing

Study Questions:

What is the yield for mutation identification (among 12 susceptibility genes) in patients referred for Brugada syndrome (BrS) genetic testing?


Mutational analysis of BrS1- through BrS12-susceptibility genes was performed in 129 unrelated patients with possible/probable BrS (46 with clinically diagnosed BrS [ECG pattern plus personal/family history of a cardiac event] and 83 with a type 1 BrS ECG pattern only).


Twenty-seven patients (21%) had a putative pathogenic mutation, including 21 patients with an SCN5A mutation, two with a CACNB2B mutation, and one each with a KCNJ8 mutation, a KCND3 mutation, an SCN1Bb mutation, and an HCN4 mutation. The overall mutation yield was 23% in the type 1 BrS ECG pattern-only patients versus 17% in the clinically diagnosed BrS patients, and was significantly greater among men <20 years of age with clinically diagnosed BrS, and among patients who had a prolonged PQ interval.


Putative pathogenic mutations were found in ~20% of a BrS cohort. The yield was similar between patients with only a type 1 BrS ECG pattern and those with clinically established BrS. The yield approaches 40% for SCN5A-mediated BrS (BrS1) when the PQ interval exceeds 200 ms.


BrS is a heritable arrhythmia syndrome associated with increased risk of sudden death due to ventricular arrhythmias. Diagnosis is made by ECG pattern of coved ST elevations in the right precordial leads along with either symptoms, family history of premature sudden cardiac death, or additional relative with typical ECG pattern. This study confirms, in a large cohort of unrelated patients, the relatively common prevalence of SCN5A mutations in BrS patients, and indicates that certain clinical features may direct and increase the yield of genetic testing.

Clinical Topics: Arrhythmias and Clinical EP, Dyslipidemia, Heart Failure and Cardiomyopathies, EP Basic Science, Genetic Arrhythmic Conditions, Lipid Metabolism, Heart Failure and Cardiac Biomarkers

Keywords: NAV1.5 Voltage-Gated Sodium Channel, Mutation, Brugada Syndrome, Prevalence, Death, Biological Markers, Cardiology, Baroreflex, Electrocardiography, Genetic Testing

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