长QT综合征的危险度分层

长QT综合征(long QT syndrome,LQTS)最常见的病因为:K~+ 通道基因 KCNQ1(LQT1 位点),KCNH1(LQT2 位点)和 Na~+ 通道基因SCN5A(LQT3 位点)发生突变。该文按照基因型与其他临床变量进行不同层次危险度分析。 方法 评价分析了193个确诊为LQTS的家系,其中104个家系在LQT1位点发生突变,68个家系在LQT2位点发生突变,21个家系在     

发现KCNH2基因上移码突变所致遗传性长QT综合征一例及家系分析

目的应用基因筛查技术对1个遗传性长QT综合征(LQTS)患病家系进行12个已知致病基因的突变分析,明确致病突变。方法在符合伦理要求和获得知情同意的情况下,经过详细的病史采集及临床检查后,采集该家系中7名患者和1名表型正常个体外周血并提取基因组DNA。利用Complete Genomics测序平台对先证者进行全基因组测序,分析已知致病基因:KCNQ1、KCNH2、SCN5A、ANK2、KCNE1、KCNJ2、CACNA1C、CAV3、SCN4B、AKAP9、SNTA1、KCNJ5。对于定位于先证者中的突变,用聚合酶链式反应和直接测序法在家系中其他成员中进行测序,最终确定致病基因突变位点。结果在该家系患者的KCNH2基因上发现1个移码突变c.2400delC(p.Gly800fs*10),在家系内正常成员和正常人群中均未发现该突变。结论在1个中国LQTS家系中发现了一个LQTS相关的KCNH2基因新突变(del D1790)。     

3型长QT综合征基因突变型与表型关系分析

目的 目前已发现至少17个先天性长QT综合征(LQTS)亚型，其中3型长QT综合征(LQT3)检出率为5%～10%,占第三位。该型人数虽不是很多，但由于症状严重、发生猝死的风险高而备受关注。现探讨中国LQT3患者特定突变型与表型的关系。方法 共入组6例2001—2014年诊断为LQT3的先证者。用新一代靶向技术和直接测序法或全外显子测序法检测到SCN5A基因上的突变。对携带特定突变的先证者及其受累亲属进行突变型和表型分析。结果 共检出SCN5A上的5个致病突变(V411M、P1332L、F1473S、R1644H和delD1790)。表型分析显示，多数先证者具有典型的LQT3型心电图(ECG)特点，美西律治疗有效。2例携带V411M突变的无关联先证者均表现为窦性心动过速，且不能被β受体阻滞剂抑制。携带P1332L突变的先证者表现出类似LQT2型的ECG模式，对美西律敏感。1例携带F1473S突变的患者在出生不久即发生了首次心脏事件，美西律无效，2.5岁时发生猝死。携带纯合R1644H突变的患者ECG上表现为基底部宽大的倒置T波，足量美西律治疗后可使ECG完全正常化。另外观察到位于C末端...     

长QT综合征家系KCNQ1 S145L和KCNH2 Y475 C基因新突变

目的研究中国遗传性长QT综合征(LQTS)患者的临床特点及LQTS最常见的基因KCNQ1和KCNH2突变.方法应用聚合酶链反应和测序分析77个遗传性LQTS家系,筛查了LQTS致病基因KCNQ1和KCNH2,观察临床表现和心电图改变.结果77例先证者心电图表现为LQT1者24例、LQT2者42例、LQT3者3例,8例心电图表现不典型.年龄(27.6±16.4)岁.QTc(561±70)ms,发病年龄(17.6±14.7)岁.晕厥触发因素包括运动、情绪激动和铃声刺激等.目前已经发现了4KCNQ1突变和7 KCNH2突变,其中6个为首次发现.结论LQT2为中国最常见的LQTS;本组发现KCNQ1和KCNH2各1个新突变;中国LQTS患者心电图表现和临床特点与欧美LQT患者有所不同.     

Brugada综合征SCN5A基因的三个新突变

目的 研究Brugada综合征相关基因SCN5A突变情况。方法 以4例Brugada综合征患者和9例临床可疑Brugada综合征患者为研究对象,采用聚合酶链反应和双脱氧末端终止测序法对所有患者进行SCNSA基因扫描。对阳性结果者进行家系中其他成员的筛查。结果 在1个Brugada综合征家系发现两个杂合突变,即SCN5A基因第3外显子上发现一错义突变（G283A）,导致代表缬氨酸残基的第95位密码子突变为异亮氨酸残基（V95I）,第28外显子上也发现一错义突变（CA946T）,导致代表丙氨酸的第1649位密码子突变为缬氨酸（A1649V）。在1个临床可疑Brugada综合征家系发现一杂合突变,即SCN5A基因第28外显子缺失3个碱基（TCT）,导致代表苯丙氨酸残基的第1617位密码子缺失（delF1617）。结论 在Brugada综合征患者发现了3个SCN5A基因新突变（V95I、A1649V、delF1617）。     

利用常规心电图鉴别长QT综合征的基因类型

一、引言和背景　　近年来 ,先天性长 QT综合征 ( long QT syn-drome,LQTS)的临床和基础研究在国际上取得了突破性进展。截止目前 ,已从 5个致病基因上鉴定出1 77个基因突变点 ,包括 KVLQTI( LQT1) 42 % ,HERG( LQT2 ) 45% ,SCN5A( LQT3 ) 8% ,KCNE1( LQT5) 3 %和 KCNE2 ( LQT6) 2 % [1] 。LQTS在遗传学上的多样性和复杂性又给临床诊治带来困难。基于目前的技术条件 ,对于一个临床上确诊的 LQTS家系 ,找出其病变基因一般需要 1～ 3年的时间 ,而且费用昂贵 ,其阳性检出率也只有 50 %左右。为了加速实验室的基因检出率…     

长QT综合征发病机制研究新进展

长QT综合征(LQTS)是一种常于青少年发病的遗传性心律失常,迄今为止已发现20个致病基因。其中LQT1~3占约80%,致病基因分别为KCNQ1(IKs)、KCNH2(IKr)、SCN5A(Na),故关于基因筛查专家共识建议只筛查LQT1~3。在3个主要亚型中,目前研究最多的是LQT2。主要涉及的机制有突变导致蛋白转运障碍、无义介导的mRNA衰减、翻译重启造成N端截短蛋白、影响PAS域蛋白折叠及与其他部分的相互关系、全长Kv11.1a异构体转换为C端截短的Kv11.1a-USO等。也探讨了对应这些机制的基因特异性治疗策略。     

6个长QT综合征家系的分子遗传学检测

目的对6个先天性长QT综合征(long QT syndrom e,LQTS)家系成员进行基因检测。方法运用位于KCNH2和SCN5A基因内和临近的短串联重复(short tandem repeat,STR)(D7S1824、D7S2493、D7S483、D3S1298、D3S1767、D3S3521)位点确定染色体单体型。6个家系的所有成员进行单倍型连锁分析,确定基因型。1个家系经直接测序确定其基因型。结果家系1的致病基因位于染色体LQT3位点,而家系2~6的致病基因位于LQT2位点,家系6经直接测序确定该家系的先证者为散发病例,突变基因为KCNH2。确诊LQTS患者22例,其中6例为无症状基因携带者,排除6例可疑患者。结论LQTS的遗传学研究检测不但能确定LQTS基因分型,而且可进行LQTS的症状前诊断。从而为临床的基因靶向治疗提供依据。     

长QT综合征一家系的遗传学定位研究

目的 寻找中国人长QT综合征(LQTS)的遗传易感位点，选择并确立LQTS患者症状前诊断的短串联重复序列(short tandem repeats,STR)和单核苷酸多态性(single nucleotide polymorphism,SNP)，初步建立LQTS遗传学诊断方法。方法 采集一个LQTS家系四代共37个成员，用聚合酶链反应(PCR)方法扩增位于KCNQl、HERG基因内的SNP(K546、K367、H489、和H564)和位于KCNQl、NERG、和SCN5A基因邻近的SIR(DllSl323、DllS2362、DllSl318、D7S636、D7S246l、D7S1824、D3S1298、D3S1767、D3Sll00、D4S1564)，所得产物经6％一10％变性聚丙烯酰胺凝胶电泳后进行等位基因片段长度多态性分析或直接测序。结果 通过单倍体分析排除LQTl、LQT3、和LQT4位点，初步确定该LQTS家系的致病基因位于LQT2位点。NERG基因全部外显于的直接测序结果表明7名患者均出现相同的HERG基因单碱基转换(CGA2587TGA)，与之相对应的编码氨基酸由精氨酸(Arg)突变为终止密码于TGA,即R863X。结论 STR和SNP单倍体分析方法可以有效地区分正常及患病个体，确定LQTS致病基因的位点，可用于LQTS患者的症状前诊断。     

16个先天性长QT综合征先证者临床分析

目的 研究我国西北地区先天性长QT综合征(LQTS)患者的发病、治疗及预后情况.方法 回顾性分析西北地区确诊为LOTS的家系16个.对先证者及其家族成员进行同步6或12导联心电图记录,对先证者的临床情况进行综合分析.结果 先证者发病年龄(19.2±14.8)岁.在20岁以前发病者占59.2%.患者以女性居多,男女比例3:13(18.8%:81.2%).发病症状多以晕厥为主要表现15例(93.7%);症状发作多有明显诱发因素14例(87.5%);根据心电图特点预测LQTS患者的基因型:LQT1占5例(31.2%),LQT2占8例(50.0%),LQT3占2例(12.5%),其余1例(6.3%)心电图特征不明显,无法预测.根据心电图预测LQTS患者的基因型进行了6个家系(2个LQT3,4个LQT)的基因筛查发现了3个KCNH2突变点,基因型和表型的符合率50%.多数患者服用B受体阻滞剂类药物有效;在药物效果不好的患者中,有2例植入起搏器.结论 西北地区LQTS发病情况和临床表现与国外报道基本一致;根据心电图特点对LQTS患者进行的基因分型预测结果显示,我国的LQTS患者可能以LQT2为主,但基因型和表型有一定的差别;β受体阻滞剂可使多数患者的症状得到控制;对β受体阻滞剂疗效不好的患者,植入起搏器可提高疗效.     

中国一家系Brugada综合征相关基因SCN5A突变位点的检测

目的研究一个中国家系Brugada综合征相关基因SCNSA的突变情况。方法收集一个Brugada家系的临床资料,采用聚合酶链反应及直接测序法对该家系进行SCN5A基因突变检测,同时对136例家系外健康对照者的该位点进行单链构象多态性分析。结果在Brugada家系中发现了两个杂合变异,即SCN5A基因第二外显子上发现一个同义变异（A129G）,没有导致氨基酸的改变（A29A）;第26外显子发现一个错义变异（T4492A）,导致代表酪氨酸的1494位密码子突变为天门冬酰胺（Y1494N）。结论在中国人Brugada综合征患者的SCNSA基因上发现了一个已经报道的同义多态位点（A29A）及一个新的错义突变位点（Y1494N）。     

先天性长QT综合征KVLQT1和HERG基因新突变位点的检测

目的：研究中国人先天性长QT综合征（long QT syndrome,LQTS)HERG和KVLQT1的基因突变情况。方法,利用聚合酶链反应和DNA测序对11个LQTS家系HERG跨膜编码区S1－S6和KVLQT1跨膜编码区S2－S6进行基因检测。结果（1）11个LQTS患者在国外已知突变点均无突变;（2）发现4个新的错义突变位点,分别为T1515G（HERG）,C682T,C934T,G983A（KVLQT1）。其对应的氨基酸改变为E505D,R228C,S230L,P312S和R328C。结论：在中国人LQTS患者HERG和KVLQT1上发现了4个新的基因突变位点。     

A novel mutation in SCN5A, delQKP 1507-1509, causing long QT syndrome: role of Q1507 residue in sodium channel inactivation

Inherited long QT syndrome (LQTS) is caused by mutations in six genes including SCN5A, encoding the alpha-subunit of the human cardiac voltage-dependent sodium channel hNa(v)1.5. In LQT3, various mutations in SCN5A were identified, which produce a gain of channel function. The aim of this study was to screen SCN5A for mutations in a family with the LQT3 phenotype and to analyze the consequences of the mutation on the channel function. By polymerase chain reaction-denaturating high performance liquid chromatography-sequencing, we identified a novel deletion in SCN5A, delQKP 1507-1509, in the DIII-DIV linker of the sodium channel. The hNa(v)1.5/delQKP1507-1509, hNa(v)1.5/delQ1507 and hNa(v)1.5/Q1507A mutants were constructed in vitro, mutant channels were expressed in the tsA201 human cell line and studied using the whole-cell configuration of the patch clamp technique. A persistent inward sodium current of 1-1.5% of maximum currents measured at -30 mV in all mutant sodium channels was recorded, which was nearly completely blocked by the sodium-channel blockers tetrodotoxin and lidocaine. The deletion mutants resulted in a significant shift of steady-state activation to more depolarized voltages. The delQ1507 showed a small shift of steady-state inactivation towards more negative potentials, whereas no significant shifts were observed in both steady-state activation and inactivation in Q1507A compared to the wild-type Na(v)1.5 sodium channels. The novel SCN5A mutation, delQKP, induces a residual current as previously shown for other SCN5A mutations causing LQTS. DelQKP shares the deletion of Q1507 with the formerly known delKPQ 1505-1507. Our data suggest that Q1507 plays an important role in fast sodium channel inactivation.     

Homozygous deletion in KVLQT1 associated with Jervell and Lange-Nielsen syndrome

BACKGROUND: Long-QT (LQT) syndrome is a cardiac disorder that causes syncope, seizures, and sudden death from ventricular arrhythmias, specifically torsade de pointes. Both autosomal dominant LQT (Romano-Ward syndrome) and autosomal recessive LQT (Jervell and Lange-Nielsen syndrome, JLNS) have been reported. Heterozygous mutations in 3 potassium channel genes, KVLQT1, KCNE1 (minK), and HERG, and the cardiac sodium channel gene SCN5A cause autosomal dominant LQT. Autosomal recessive LQT, which is associated with deafness, has been found to occur with homozygous mutations in KVLQT1 and KCNE1 in JLNS families in which QTc prolongation was inherited as a dominant trait. METHODS AND RESULTS: An Amish family with clinical evidence of JLNS was analyzed for mutations by use of single-strand conformation polymorphism and DNA sequencing analyses for mutations in all known LQT genes. A novel homozygous 2-bp deletion in the S2 transmembrane segment of KVLQT1 was identified in affected members of this Amish family in which both QTc prolongation and deafness were inherited as recessive traits. This deletion represents a new JLNS-associated mutation in KVLQT1 and has deleterious effects on the KVLQT1 potassium channel, causing a frameshift and the truncation of the KVLQT1 protein. In contrast to previous reports in which LQT was inherited as a clear dominant trait, 2 parents in the JLNS family described here have normal QTc intervals (0.43 and 0.44 seconds, respectively). CONCLUSIONS: A novel homozygous KVLQT1 mutation causes JLNS in an Amish family with deafness that is inherited as an autosomal recessive trait.     

Brugada综合征一家系中2例患者的SCN5A基因突变及意义

目的 观察Brugada综合征一家系中2例患者的SCN5A基因突变情况,并探讨其意义.方法 选择Brugada综合征一家系2例患者,采用直接测序法对其SCN5A基因突变进行检测.结果 该家系中发现1个纯合变异,即SCN5A基因第28外显子上的同义变异（C5457T）,其所编码的1819位天冬氨酸密码子没有发生改变.结论 该Brugada综合征家系2例患者的SCN5A基因上存在1个同义变异,但SCN5A基因不是患者的致病基因.     

Prevalence and spectrum of large deletions or duplications in the major long QT syndrome-susceptibility genes and implications for long QT syndrome genetic testing

Long QT syndrome (LQTS) is a cardiac channelopathy associated with syncope, seizures, and sudden death. Approximately 75% of LQTS is due to mutations in genes encoding for 3 cardiac ion channel α-subunits (LQT1 to LQT3). However, traditional mutational analyses have limited detection capabilities for atypical mutations such as large gene rearrangements. We set out to determine the prevalence and spectrum of large deletions/duplications in the major LQTS-susceptibility genes in unrelated patients who were mutation negative after point mutation analysis of LQT1- to LQT12-susceptibility genes. Forty-two unrelated, clinically strong LQTS patients were analyzed using multiplex ligation-dependent probe amplification, a quantitative fluorescent technique for detecting multiple exon deletions and duplications. The SALSA multiplex ligation-dependent probe amplification LQTS kit from MRC-Holland was used to analyze the 3 major LQTS-associated genes, KCNQ1, KCNH2, and SCN5A, and the 2 minor genes, KCNE1 and KCNE2. Overall, 2 gene rearrangements were found in 2 of 42 unrelated patients (4.8%, confidence interval 1.7 to 11). A deletion of KCNQ1 exon 3 was identified in a 10-year-old Caucasian boy with a corrected QT duration of 660 ms, a personal history of exercise-induced syncope, and a family history of syncope. A deletion of KCNQ1 exon 7 was identified in a 17-year-old Caucasian girl with a corrected QT duration of 480 ms, a personal history of exercise-induced syncope, and a family history of sudden cardiac death. In conclusion, because nearly 5% of patients with genetically elusive LQTS had large genomic rearrangements involving the canonical LQTS-susceptibility genes, reflex genetic testing to investigate genomic rearrangements may be of clinical value.     

Identical twins with long QT syndrome associated with a missense mutation in the S4 region of the HERG

Familial long QT syndrome (LQTS) is caused by mutations in genes encoding ion channels important in determining ventricular repolarization. Mutations in at least five genes have been associated with the LQTS. Fire genes, KCNQ1, HERG, SCN5A, KCNE1, and KCNE2, have been identified. We have identified a missense mutation in the HERG gene in identical twins in a Japanese family with LQTS. The identical twins in our study had QT prolongation and the same missense mutation. However only the proband had a history of syncope. Although many mutations in LQT genes have been reported, there are few reports of twins with LQTS. This is the first report, to our knowledge, of identical twins with a HERG gene mutation.     

国人SCN5A基因新的同义突变位点

目的:研究中国人心原性猝死相关基因SCN5A突变位点.方法:采用聚合酶链反应和DNA测序对1例RQT间期综合征(LQTs)和2例特发性J波患者SCN5A基因进行突变检测.结果:①3例患者在国内、外已知的SCN5A突变位点上,均未发现有突变.②发现1个新的同义突变(T990C),位于钠通道α-亚基的DⅠ区段S5～S6胞外环上.结论:这个新的同义突变可能通过影响门控性钠通道的跨膜电流而与恶性心律失常的发生相关.