A Double SCN5A Mutation Underlying Asymptomatic Brugada Syndrome

Objective/Background: Patients with the Brugada syndrome who experience syncope or aborted sudden death are at high risk for recurrent lethal arrhythmias. However, the prognosis and the therapeutic approaches in asymptomatic individuals with a Brugada-type ECG (asymptomatic Brugada syndrome) are controversial. Methods/ Results: We genetically screened 30 asymptomatic probands (male 29, female 1; mean age, 47.1 years) exhibiting a spontaneous Brugada-type ECG. Family members of patients with the Brugada syndrome were excluded. Twenty-nine of 30 patients (96.7%) remained free from symptoms for at least three years. One patient (case #1) who had a family history of sudden death died suddenly during sleep. Ventricular fibrillation was induced by programmed electrical stimulation in 14 of 18 subjects (78%), but none of these 18 subjects developed spontaneous ventricular arrhythmias. Genetic screening failed to identify SCN5A mutations in most cases, but demonstrated a novel double missense mutation (K1527R and A1569P) located on the same allele in another asymptomatic subject (case #2). Heterologously expressed mutant Na channels exhibited a negative shift of steady-state inactivation (9.2 mV) and enhanced slow inactivation, suggesting that this individual harbors a subclinical channel dysfunction compatible with symptomatic Brugada syndrome. Conclusions: Asymptomatic individuals with a Brugada-type ECG generally have a better