TY - JOUR
T1 - SCN5A mutations and the role of genetic background in the pathophysiology of Brugada syndrome
AU - Probst, Vincent
AU - Wilde, Arthur A. M.
AU - Barc, Julien
AU - Sacher, Frederic
AU - Babuty, Dominique
AU - Mabo, Philippe
AU - Mansourati, Jacques
AU - Le Scouarnec, Solena
AU - Kyndt, Florence
AU - Le Caignec, Cedric
AU - Guicheney, Pascale
AU - Gouas, Laetitia
AU - Albuisson, Juliette
AU - Meregalli, Paola G.
AU - Le Marec, Hervé
AU - Tan, Hanno L.
AU - Schott, Jean-Jacques
PY - 2009
Y1 - 2009
N2 - 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. 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. 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
AB - 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. 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. 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
U2 - https://doi.org/10.1161/CIRCGENETICS.109.853374
DO - https://doi.org/10.1161/CIRCGENETICS.109.853374
M3 - Article
C2 - 20031634
SN - 1942-325X
VL - 2
SP - 552
EP - 557
JO - Circulation. Cardiovascular genetics
JF - Circulation. Cardiovascular genetics
IS - 6
ER -