Benito Begoña, Brugada Ramon, Perich Rosa Maria, Lizotte Eric, Cinca Juan, Mont Lluis, Berruezo Antonio, Tolosana José María, Freixa Xavier, Brugada Pedro, Brugada Josep
Cardiovascular Genetics Center, Montreal Heart Institute, University of Montreal, Montreal, Canada.
Heart Rhythm. 2008 Oct;5(10):1434-40. doi: 10.1016/j.hrthm.2008.07.013. Epub 2008 Jul 19.
Type 3 long-QT syndrome (LQT-3) is caused by gain-of-function mutations in the SCN5A encoding the cardiac sodium channel. Familial atrial fibrillation (AF), previously considered a potassium channelopathy, has recently been related to sodium genetic variants, both in isolated forms and in patients with underlying heart disease.
The purpose of this study was to describe the first family associating LQT-3 and AF due to a gain-of-function mutation in SCN5A and assess the usefulness of the sodium blocker flecainide in individuals with both phenotypes.
Complete family screening was performed after identifying a proband showing paroxysmal AF and a long QT interval suggestive of LQT-3. Secondary causes of AF were ruled out in all individuals. Flecainide was used in two patients for LQT-3 diagnosis and therapeutic treatment of AF. Genetic screening was performed by direct sequencing of the exons and exon-intron boundaries of SCN5A.
We identified a three-generation family (eight members), all of them showing long QT intervals. Paroxysmal AF initiated between 20 and 35 years of age in all three adults. The flecainide test led to shortening of the QTc interval. Flecainide was also effective in acutely restoring sinus rhythm. A Y1795C mutation was identified in all members.
This is the first report showing an association of familial AF and LQT-3 due to a mutation in SCN5A. This finding provides further evidence of the role of SCN5A in AF. We also confirm the usefulness of flecainide in this particular complex phenotype, both as a diagnostic tool for LQT-3 and as an acute treatment for AF.
3型长QT综合征（LQT-3）由编码心脏钠通道的SCN5A功能获得性突变引起。家族性心房颤动（AF），以前被认为是一种钾通道病，最近已与钠基因变异相关，包括孤立形式以及患有基础心脏病的患者。
本研究的目的是描述首个因SCN5A功能获得性突变而关联LQT-3和AF的家族，并评估钠通道阻滞剂氟卡尼对具有这两种表型个体的有效性。
在确定一名表现为阵发性AF且QT间期延长提示LQT-3的先证者后，对整个家族进行了全面筛查。排除了所有个体AF的继发原因。两名患者使用氟卡尼进行LQT-3诊断和AF的治疗。通过对SCN5A外显子和外显子-内含子边界进行直接测序进行基因筛查。
我们鉴定出一个三代家族（八名成员），他们均表现出QT间期延长。所有三名成年人在20至35岁之间开始出现阵发性AF。氟卡尼试验导致QTc间期缩短。氟卡尼在急性恢复窦性心律方面也有效。在所有成员中均鉴定出Y1795C突变。
这是第一份显示因SCN5A突变导致家族性AF与LQT-3相关联的报告。这一发现为SCN5A在AF中的作用提供了进一步证据。我们还证实了氟卡尼在这种特殊复杂表型中的有效性，既作为LQT-3的诊断工具，也作为AF的急性治疗方法。
