title: Double SCN5A mutation underlying asymptomatic Brugada syndrome.
abstract: OBJECTIVE
  The purpose of this study was to identify risk markers in patients with Brugada syndrome.
  
  
  BACKGROUND
  Patients with Brugada syndrome who experience syncope or aborted sudden death are at high risk for recurrent lethal arrhythmias. The prognosis and therapeutic approaches in asymptomatic individuals with a Brugada-type ECG (asymptomatic Brugada syndrome) are controversial.
  
  
  METHODS
  We genetically screened 30 asymptomatic probands (29 men and 1 woman; mean age 47.1 years) exhibiting a spontaneous Brugada-type ECG. Family members of patients with Brugada syndrome were excluded from the study.
  
  
  RESULTS
  Twenty-nine of 30 patients (96.7%) remained symptom-free for at least 3 years. One patient (case 1) with 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 this individual harbors a subclinical channel dysfunction compatible with symptomatic Brugada syndrome.
  
  
  CONCLUSIONS
  Asymptomatic individuals with a Brugada-type ECG generally have a better prognosis than their symptomatic counterparts, but a subgroup of these individuals may have a poor prognosis. Severe Na channel dysfunction as a result of SCN5A mutations may not be sufficient to cause symptoms or arrhythmias in patients with Brugada syndrome, suggesting unknown factors or modifier genes influence arrhythmogenesis.
authors.affiliation: Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Hisataka
authors.initials: H
authors.lastname: Yokoi
authors.forename: Naomasa
authors.initials: N
authors.lastname: Makita
authors.forename: Koji
authors.initials: K
authors.lastname: Sasaki
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Takagi
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Okumura
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Nishino
authors.forename: Takeru
authors.initials: T
authors.lastname: Makiyama
authors.forename: Akira
authors.initials: A
authors.lastname: Kitabatake
authors.forename: Minoru
authors.initials: M
authors.lastname: Horie
authors.forename: Ichiro
authors.initials: I
authors.lastname: Watanabe
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsutsui
mesh_terms: D001145:Arrhythmias, Cardiac / Q000235:genetics; D055592:Biophysical Phenomena; D001703:Biophysics; D002037:Bundle-Branch Block / Q000235:genetics*; D004562:Electrocardiography; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D062554:NAV1.5 Voltage-Gated Sodium Channel; D015222:Sodium Channels / Q000235:genetics*; D013577:Syndrome
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels