CLINICAL AND MOLECULAR ANALYSIS OF THE BRUGADA SYNDROME

心律失常会导致相当大的发病率和死亡率。无明显器质性心脏病并伴有右束支传导阻滞(RBBB)和体表心电图右胸导联ST段抬高(STE)的患者可发生室颤和心脏性猝死。这种情况后来被称为Brugada综合征。心脏Na+通道SCN5A的突变最近被证明在三个小家庭中导致Brugada综合征。与大多数室性心律失常一样，Brugada综合征的最佳诊断和治疗方法仍不清楚。我们已经确定了一个有100多名在世成员的家庭，该家庭患有遗传性Brugada综合征，其特征是RBBB/STE EKG模式、室性心律失常和猝死。52个高危家庭成员的EKG确定了10个受影响的和10个可能受影响的以男性为主的个体，其常染色体显性遗传模式以年龄相关的外显性为特征。连锁分析排除SCN5A和其他已知的长QT综合征基因为候选基因。我们推测，另一个心脏离子通道的突变是该家族Brugada综合征的原因。因此，我们建议研究这种疾病的临床和分子特征，这是据报道患有这种疾病的最大家族。无创(负荷测试、信号平均EKG、动态心电图ST段分析、高分辨率体表测绘、倾斜试验和/或药物操作)和有创电生理学研究将与系列EKG进行比较，以检测综合征和预测心律失常。超声心动图和核磁共振将被用来寻找细微的心脏结构异常。引起这种疾病的基因的染色体位置将通过连锁分析来确定。然后将通过候选基因方法或通过定位克隆新的心脏离子通道亚基来确定基因和突变。在过去的两年里，发现心脏K+和Na+通道突变是遗传性心律失常的原因，这一发现引起了人们的极大兴奋。这些疾病虽然非常罕见，但已经为心脏电生理学和促发室性心律失常的机制提供了相当大的洞察力。第二个Brugada综合征基因的鉴定及其引起的临床综合征的特征将进一步深入了解特定离子通道在人类心脏中的作用，促进EKG上ST和T波变化的因素，以及这些因素导致心脏性猝死的机制。

Arrhythmias lead to considerable morbidity and mortality. Ventricular fibrillation and sudden cardiac death can occur in patients without significant structural heart disease in association with a right bundle branch block (RBBB) pattern and ST elevations (STE) in the right precordial leads of the surface EKG. This condition has come to be known as the Brugada syndrome. Mutations of the cardiac Na+ channel SCN5A have recently been shown to cause the Brugada syndrome in three small families. The optimal methods of diagnosis and treatment of the Brugada syndrome, as for most ventricular arrhythmias, remain unclear. We have identified a family with greater than 100 living members that has an inherited form of the Brugada syndrome characterized by a RBBB/STE EKG pattern, ventricular arrhythmias, and sudden death. EKGs of 52 at-risk family members identified 10 affected and 10 probable affected predominantly male individuals with an autosomal dominant inheritance pattern characterized by age- dependent penetrance. SCN5A and the other known long QT syndrome genes were excluded as candidates using linkage analysis. We hypothesize that a mutation of another cardiac ion channel is responsible for the Brugada syndrome in this family. We therefore propose to study the clinical and molecular features of this, the largest family reported with the disorder. Noninvasive (stress testing, signal averaged EKG, Holter monitoring with ST segment analysis, high resolution body surface mapping with tilt table testing and/or pharmacological manipulations) and invasive electrophysiology studies will be compared to serial EKGs for detection syndrome and prediction of arrhythmias. Echocardiography and MRI will be used to search for subtle cardiac structural abnormalities. The chromosomal locus of the gene that causes the disorder will be identified by linkage analysis. The gene and the mutation will then be determined, either by a candidate gene approach or by positionally cloning of a new cardiac ion channel subunit. The identification of cardiac K+ and Na+ channel mutations as the cause of inherited arrhythmias has led to much excitement during the last two years. These disorders, although quite rare, have provided considerable insight into cardiac electrophysiology and the mechanisms that promote ventricular arrhythmias. Identification of a second Brugada syndrome gene and characterization of the clinical syndrome that it causes will provide further insight into the role of specific ion channels in the human heart, the factors which promote ST and T-wave changes on the EKG, and the mechanisms by which these factors lead to sudden cardiac death.