title: Cardiac sodium channel (SCN5A) variants associated with atrial fibrillation.
abstract: BACKGROUND
  Genetic studies have identified ion channel gene variants in families segregating atrial fibrillation (AF), the most common arrhythmia in clinical practice. Here, we tested the hypothesis that vulnerability to AF is associated with variation in SCN5A, the gene encoding the cardiac sodium channel.
  
  
  RESULTS
  We resequenced the entire SCN5A coding region in 375 subjects with either lone AF (n=118) or AF associated with heart disease (n=257). Controls (n=360) from the same population were then genotyped for the presence of mutations or rare variants identified in the AF cases. In 10 probands (2.7%), 8 novel variants not found in the control population (0%; P=0.001) were identified. All variants affect highly conserved residues in the SCN5A protein. In 6 families with >1 affected member, the novel variant cosegregated with AF. We also identified 11 rare missense variants in 12 probands (3.2%) that have previously been associated with inherited arrhythmia syndromes (eg, congenital long-QT syndrome and Brugada syndrome).
  
  
  CONCLUSIONS
  Mutations or rare variants in SCN5A may predispose patients with or without underlying heart disease to AF. The findings of the present study expand the clinical spectrum of disorders of the cardiac sodium channel to include AF and represent important progress toward molecular phenotyping and directed rather than empirical therapy for this common arrhythmia.
authors: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA. dawood.darbar@vanderbilt.edu
authors: Dawood
authors: D
authors: Darbar
authors: Prince J
authors: PJ
authors: Kannankeril
authors: Brian S
authors: BS
authors: Donahue
authors: Gayle
authors: G
authors: Kucera
authors: Tanya
authors: T
authors: Stubblefield
authors: Jonathan L
authors: JL
authors: Haines
authors: Alfred L
authors: AL
authors: George
authors: Dan M
authors: DM
authors: Roden
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001281:Atrial Fibrillation / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D006331:Heart Diseases / Q000150:complications / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000737:chemistry / Q000235:genetics*; D020125:Mutation, Missense; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010375:Pedigree; D011446:Prospective Studies; D017434:Protein Structure, Tertiary; D012042:Registries; D017422:Sequence Analysis, DNA; D015222:Sodium Channels / Q000737:chemistry / Q000235:genetics*; D013714:Tennessee / Q000453:epidemiology
chemical_list: D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels