title: SCN5A mutations and the role of genetic background in the pathophysiology of Brugada syndrome.
abstract: BACKGROUND
  Mutations in SCN5A are identified in approximately 20% to 30% of probands affected by Brugada syndrome (BrS). However, in familial studies, the relationship between SCN5A mutations and BrS remains poorly understood. The aim of this study was to investigate the association of SCN5A mutations and BrS in a group of large genotyped families.
  
  
  RESULTS
  Families were included if at least 5 family members were carriers of the SCN5A mutation, which was identified in the proband. Thirteen large families composed of 115 mutation carriers were studied. The signature type I ECG was present in 54 mutation carriers (BrS-ECG+; 47%). In 5 families, we found 8 individuals affected by BrS but with a negative genotype (mutation-negative BrS-ECG+). Among these 8 mutation-negative BrS-ECG+ individuals, 3, belonging to 3 different families, had a spontaneous type I ECG, whereas 5 had a type I ECG only after the administration of sodium channel blockers. One of these 8 individuals had also experienced syncope. Mutation carriers had, on average, longer PR and QRS intervals than noncarriers, demonstrating that these mutations exerted functional effects.
  
  
  CONCLUSIONS
  Our results suggest that SCN5A mutations are not directly causal to the occurrence of a BrS-ECG+ and that genetic background may play a powerful role in the pathophysiology of BrS. These findings add further complexity to concepts regarding the causes of BrS, and are consistent with the emerging notion that the pathophysiology of BrS includes various elements beyond mutant sodium channels.
authors.affiliation: INSERM, UMR915, Nantes, France. vincent.probst@chu-nantes.fr
authors.forename: Vincent
authors.initials: V
authors.lastname: Probst
authors.forename: Arthur A M
authors.initials: AA
authors.lastname: Wilde
authors.forename: Julien
authors.initials: J
authors.lastname: Barc
authors.forename: Frederic
authors.initials: F
authors.lastname: Sacher
authors.forename: Dominique
authors.initials: D
authors.lastname: Babuty
authors.forename: Philippe
authors.initials: P
authors.lastname: Mabo
authors.forename: Jacques
authors.initials: J
authors.lastname: Mansourati
authors.forename: Solena
authors.initials: S
authors.lastname: Le Scouarnec
authors.forename: Florence
authors.initials: F
authors.lastname: Kyndt
authors.forename: Cedric
authors.initials: C
authors.lastname: Le Caignec
authors.forename: Pascale
authors.initials: P
authors.lastname: Guicheney
authors.forename: Laetitia
authors.initials: L
authors.lastname: Gouas
authors.forename: Juliette
authors.initials: J
authors.lastname: Albuisson
authors.forename: Paola G
authors.initials: PG
authors.lastname: Meregalli
authors.forename: Hervé
authors.initials: H
authors.lastname: Le Marec
authors.forename: Hanno L
authors.initials: HL
authors.lastname: Tan
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Schott
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D053840:Brugada Syndrome / Q000235:genetics* / Q000503:physiopathology*; D004562:Electrocardiography; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics*; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010375:Pedigree; D012189:Retrospective Studies; D015222:Sodium Channels / Q000235:genetics*; D055815:Young Adult
chemical_list: D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels