中文摘要：

目的 采用基因检测和电生理功能分析诊断长QT综合征（LQTS）患者,发现有潜在患病风险的家系成员,以提供临床评估与适当的治疗.方法 采集和分析1例LQTS患儿及所在家系成员的临床资料.同时选择200例具有相同种族背景的健康个体作为正常对照.聚合酶链式反应（PCR）扩增LQTS先证者候选基因KCNQ1、KCNH2和SCN5A外显子及附近上下游序列,直接测序并进行分析.如发现突变,进一步采用全细胞膜片钳技术对该突变进行电生理功能分析,并对其家系成员进行特定突变基因筛查,寻找基因变异及评估其发生心脏性猝死风险.结果 先证者12导联常规心电图初步诊断为LQTS.临床上给予美托洛尔（25 mg、2次/d）治疗,患者服药第3天于午饭时猝死.基因检测发现先证者SCN5A基因上存在一个杂合子错义突变（V411M）,在正常对照组该位点未发现基因突变.与野生型相比,V411M突变型钠通道表现为峰值钠电流[（230.8±27.6） pA/pF比（101.2±10.9）pA/pF,n=10,P＜0.01]及晚钠电流[（156.6±13.6） pA/pF比（95.9±7.9） pA/pF,n=12,P＜0.01]增加.测试脉冲电压在-50 mV时,V411M突变型的钠通道激活数目明显多于野生型（85.0％±7.4％比41.5％±2.6％,P＜0.01）.V411M突变型稳态激活曲线左移,而稳态失活曲线无明显变化.另外,其他家系成员进行SCN5A基因检测发现,先证者母亲、外祖母为无症状突变携带者,给予适当临床评估及长期随访.先证者的同卵双生姐姐及姨妈死于婴儿猝死综合征.结论 首次在国人LQTS患者SCN5A基因上报道一个杂合子错义突变（V411M）.V411 M突变导致钠离子通道蛋白的“功能增强”效应,构成3型LQTS的发病基础.基因检测和电生理功能分析有助于明确LQTS患者及其家系成员的疾病诊断,并提供重要临床评估与治疗,预防心脏性猝死的发生.

英文摘要：

Objectives We identified the long QT syndrome （LQTS） patients,and detected the potential risk of LQTS in family members by using genetic testing and electrophysiological analysis,which helped provide clinical evaluation and appropriate treatment.Methods Detailed clinical characteristics and familiar history were obtained from the whole family members of an idiopathic pediatric LQTS patient.Two hundred healthy subjects with the same ethnic background were recruited as controls.The entire coding sequences of three candidate genes including KCNQ1,KCNH2 and SCN5A were screened for mutations in the proband.The function of the mutation was then explored by whole-cell patch clamp techniques,and the genetic testing and risk assessment of the family members were performed.Results The proband was clinically preliminary diagnosed as LQTS by 12-lead electrocardiogram.On the third day of metoprolol intake （25 mg,bid）,she died suddenly at lunch.One heterozygous missense mutation （SCN5A-V411 M） was identified in this proband,but the mutation was absent in 200 healthy subjects.The electrophysiological analysis indicated that SCN5A-V411M significantly increased the peak current density （（230.8 ± 27.6）pA/ pF vs.（101.2 ± 10.9）pA/pF,n =10,P 〈0.01） and the late sodium current （（156.6 ± 13.6） pA/pF vs.（95.9 ± 7.9） pA/pF,n =12,P 〈 0.01） of sodium channel compared to wide type.The enhanced sodium channel activation with a negative shift in the peak Ⅰ-V relationship was significantly higher by-50 mV than wide type （85.0% ± 7.4% vs.41.5% ± 2.6%,P 〈 0.01）,while the steady-state inactivation curves remained unchanged.Additionally,mother and grandmother of the proband were the silent mutation carriers with no symptoms,who needed the appropriate clinical assessment and follow-up.The proband＇s twin sister and aunt died of sudden infant death syndrome.Conclusions We firstly reported a heterozygote missense mutation （SCN5A-V411M） in this Chinese family.V411M induced ＂gain of function?