Probst Vincent, Wilde Arthur A M, Barc Julien, Sacher Frederic, Babuty Dominique, Mabo Philippe, Mansourati Jacques, Le Scouarnec Solena, Kyndt Florence, Le Caignec Cedric, Guicheney Pascale, Gouas Laetitia, Albuisson Juliette, Meregalli Paola G, Le Marec Hervé, Tan Hanno L, Schott Jean-Jacques
INSERM, UMR915, Nantes, France.
Circ Cardiovasc Genet. 2009 Dec;2(6):552-7. doi: 10.1161/CIRCGENETICS.109.853374. Epub 2009 Sep 29.
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.
在大约20%至30%的Brugada综合征（BrS）先证者中可检测到SCN5A基因突变。然而，在家族性研究中，SCN5A基因突变与BrS之间的关系仍知之甚少。本研究旨在调查一组大型基因分型家族中SCN5A基因突变与BrS的关联。
如果至少5名家族成员为先证者中检测到的SCN5A基因突变携带者，则纳入该家族。对由115名突变携带者组成的13个大型家族进行了研究。54名突变携带者（BrS-ECG+；47%）出现特征性I型心电图。在5个家族中，我们发现8名个体患有BrS但基因型为阴性（突变阴性的BrS-ECG+）。在这8名突变阴性的BrS-ECG+个体中，3名来自3个不同家族，有自发的I型心电图，而另外5名仅在使用钠通道阻滞剂后出现I型心电图。这8名个体中有1名还曾发生过晕厥。突变携带者的PR间期和QRS间期平均比非携带者长，表明这些突变具有功能效应。
我们的结果表明，SCN5A基因突变并非直接导致BrS-ECG+ 的发生原因，遗传背景可能在BrS的病理生理学中发挥重要作用。这些发现进一步增加了BrS病因概念的复杂性，并且与BrS病理生理学包括突变钠通道以外的多种因素这一新兴观点一致。
