Jongbloed R J, Wilde A A, Geelen J L, Doevendans P, Schaap C, Van Langen I, van Tintelen J P, Cobben J M, Beaufort-Krol G C, Geraedts J P, Smeets H J
Department of Molecular Cell Biology and Genetics, Cardiovascular Research Institute Maastricht, University of Maastricht, The Netherlands.
Hum Mutat. 1999;13(4):301-10. doi: 10.1002/(SICI)1098-1004(1999)13:4<301::AID-HUMU7>3.0.CO;2-V.
Congenital long QT syndrome (cLQTS) is electrocardiographically characterized by a prolonged QT interval and polymorphic ventricular arrhythmias (torsade de pointes). These cardiac arrhythmias may result in recurrent syncopes, seizure, or sudden death. LQTS can occur either as an autosomal dominant (Romano Ward) or as an autosomal recessive disorder (Jervell and Lange-Nielsen syndrome). Mutations in at least five genes have been associated with the LQTS. Four genes, encoding cardiac ion channels, have been identified. The most common forms of LQTS are due to mutations in the potassium-channel genes KCNQ1 and HERG. We have screened 24 Dutch LQTS families for mutations in KCNQ1 and HERG. Fourteen missense mutations were identified. Eight of these missense mutations were novel: three in KCNQ1 and five in HERG. Novel missense mutations in KCNQ1 were Y184S, S373P, and W392R and novel missense mutations in HERG were A558P, R582C, G604S, T613M, and F640L. The KCNQ1 mutation G189R and the HERG mutation R582C were detected in two families. The pathogenicity of the mutations was based on segregation in families, absence in control individuals, the nature of the amino acid substitution, and localization in the protein. Genotype-phenotype studies indicated that auditory stimuli as trigger of cardiac events differentiate LQTS2 and LQTS1. In LQTS1, exercise was the predominant trigger. In addition, a number of asymptomatic gene defect carriers were identified. Asymptomatic carriers are still at risk of the development of life-threatening arrhythmias, underlining the importance of DNA analyses for unequivocal diagnosis of patients with LQTS.
先天性长QT综合征（cLQTS）的心电图特征为QT间期延长和多形性室性心律失常（尖端扭转型室速）。这些心律失常可能导致反复晕厥、癫痫发作或猝死。LQTS可表现为常染色体显性遗传（ Romano Ward综合征）或常染色体隐性遗传疾病（Jervell和Lange-Nielsen综合征）。至少有五个基因的突变与LQTS相关。已鉴定出四个编码心脏离子通道的基因。LQTS最常见的形式是由于钾通道基因KCNQ1和HERG的突变。我们对24个荷兰LQTS家族进行了KCNQ1和HERG突变的筛查。共鉴定出14个错义突变。其中8个错义突变是新发现的：3个在KCNQ1中，5个在HERG中。KCNQ1中的新错义突变是Y184S、S373P和W392R，HERG中的新错义突变是A558P、R582C、G604S、T613M和F640L。在两个家族中检测到KCNQ1突变G189R和HERG突变R582C。突变的致病性基于家族中的分离情况、对照个体中不存在、氨基酸替代的性质以及在蛋白质中的定位。基因型-表型研究表明，听觉刺激作为心脏事件的触发因素可区分LQTS2和LQTS1。在LQTS1中，运动是主要的触发因素。此外，还鉴定出了一些无症状的基因缺陷携带者。无症状携带者仍有发生危及生命的心律失常的风险，这突出了DNA分析对于明确诊断LQTS患者的重要性。
