SCN5A mutations and the role of genetic background in the pathophysiology of Brugada syndrome.
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.
Probst
Vincent
V
INSERM, UMR915, Nantes, France. vincent.probst@chu-nantes.fr
Wilde
Arthur A M
AA
Barc
Julien
J
Sacher
Frederic
F
Babuty
Dominique
D
Mabo
Philippe
P
Mansourati
Jacques
J
Le Scouarnec
Solena
S
Kyndt
Florence
F
Le Caignec
Cedric
C
Guicheney
Pascale
P
Gouas
Laetitia
L
Albuisson
Juliette
J
Meregalli
Paola G
PG
Le Marec
Hervé
H
Tan
Hanno L
HL
Schott
Jean-Jacques
JJ
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
D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels