遗传性长QT综合征SCN5A基因delD1790新突变

目的研究中国人遗传性长QT综合征3型(LQT3)相关基因SCN5A突变情况。方法以KCNQ1和KC-NH2基因筛查无突变,心电图表现符合LQT3的3例LQTS患者为研究对象,聚合酶链反应和双脱氧末端终止测序法对所有患者进行SCN5A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LQTS家系发现SCN5A基因突变。该家系先证者及其母亲SCN5A基因第28外显子上存在一个杂合突变,即在5368-5370位存在3碱基(GAC)缺失,导致1790位密码子天冬氨酸(Asp)缺失(delD1790)。结论在1个中国LQTS家系发现了一个LQT3相关的SCN5A基因新突变(delD1790)。     

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     

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.     

85例中国人长QT综合征先证者的临床特征及有关基因突变研究现状

目的研究我国长QT综合征(LQTS)病人的临床特征和基因突变特点.方法按照1993年Schwartz等提出的LQTS诊断标准确诊为本病的家系85个,分别来自18个省、市、自治区.其中43个家系由中国离子通道病注册中心的协作成员提供,其余为北京大学人民医院的LQTS随访患者.对先证者及其家族成员进行6导联或12导联心电图同步记录,对先证者的临床情况进行综合分析.对先证者及其家庭成员抽取外周血标本,用PCR-SSCP加测序验证或经心电图初步分型后再进行PCR-SSCP及测序的方法进行基因筛查.结果先证者平均发病年龄(17.3±14.2)岁,在20岁以前发病的占60%;女性居多,男性占24%,女性占76%.发病症状有晕厥(91.8%)、黑GB289(28.9%)、心悸(25.0%)、胸闷(34.2 %)及其它如抽搐、胸背痛、头晕(21.1%)等;诱发因素有情绪紧张或激动(51.3%),劳累、运动或体力劳动(51.3%),休息或睡眠(26.3%),突然惊吓/电话铃响(19.7%),经期或产褥期(15.8%),其它如寒冷或发烧(15.8%).病人的QTc值为(0.56±0.07)s.LQTS病人的心电图上T波多变,QT间期可出现暂时正常化.有猝死家族史的家系占31.6%.有LQTS家族史的占63%.在85个LQTS先证者中,同时伴聋哑1例,预激综合征(WPW) 1例,心肌炎2例,束支阻滞2例,一过性房室阻滞1例,高血压病2例.根据心电图特点预测LQTS病人的基因型,结果显示LQT1占29.4%,LQT2占57.6%,LQT3占3.5%,其余9.4%心电图特征不明显,无法预测.长QT综合征病人的治疗情况4例患者联合应用起搏器和β受体阻滞剂,1例联合应用植入型心律转复除颤器(ICD)和β受体阻滞剂,15例进行左心交感神经切除术(LCSD),其余多服用β受体阻滞剂类药物.发现了7个KCNQ1、5个KCNH2和1个KCNE1上的突变,有错义突变、缺失突变、无义突变、剪接突变.对HERG-R863X、KCNQ1-L191P和KCNE1-G52R进行功能表达研究发现,R863X突变使突变的通道蛋白不能转运到细胞膜的靶位置,从而引起IKr电流降低;L191P和G52R突变通过负显性机制造成IKs电流的降低.结论我国的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病人进行的基因分型预测结果显示,我国的LQTS病人可能以LQT2为主.β受体阻滞剂可使多数患者的症状得到控制;应用β受体阻滞剂疗效不好的患者,选择LCSD或联合应用起搏器或ICD可增加疗效.中国人LQTS患者的致病基因突变位点有其自身的特点,进一步的遗传学和功能学研究正在进行之中.     

《心脏离子通道病与心肌病基因检测专家共识》中的长QT综合征基因检测

2011年美国心律学会/欧洲心律学会发表了《心脏离子通道病与心肌病基因检测专家共识》,在有关长QT综合征(LQTS)的部分中推荐经心脏病专家诊断或高度怀疑的LQTS患者进行LQT1～3(KCNQ1、KCNH2、SCN5A)的基因检测;已在先证者发现LQTS致病基因突变者,推荐其直系亲属进行该特定突变的检测。如果基因检测、病史以及12导ECG均为阴性方可排除LQTS。通过对病人进行基因检测、综合评估及危险分层可帮助他们选择最适合的个体化治疗方案,并取得最佳的临床结果。     

心律失常的分子遗传学进展:从基因到疾病的诊断和治疗

心律失常是影响公众健康的一种重要病症，是常见的致死原因。分子遗传学在过去十年的重要进展，为我们理解心律失常的发病机理提供了很大帮助。50％～75％的长QT综合征(LQTS)和15％-35％Brugada综合征(BS)的致病基因已经被发现(LQTS：钾通道基因KCNQ1，KCNH2，KCNE1，KCNE2，KCNJ2；钠通道基因SCN5A；非离子通道基因ankyrin-B。BS：SCN5A)。遗传性LQTS致病基因的突变也与很多普通药物诱导的LQTS相关。基因特异性治疗和遗传诊断已经应用于LQTS和Brugada综合征。最近发现一种新的短QT综合征与KCNQ1和KCNH2突变有关。心脏钠离子通道基因SCN5A的突变也可导致心脏传导疾病和常染色体隐性病态窦房结综合征(SSS)。散发型SSS也与心脏起搏钾离子通道基因HCN4的突变有关。心脏ryanodine receptor 2基因(RYR2)和calsequestrin 2基因(CASQ2)的突变能导致儿茶酚胺多形室性心动过速。KCNQ1和KCNE2的突变可导致心房颤动。蛋白激酶基因PRKAG2是预激综合征(Wolff-Parkinson-White syndrome，WPWS)的致病基因。心律失常方面的已有研究成果与发现和将来的遗传学发现将会对疾病的治疗乃至现代医学产生革命性的影响。这些范例使现代医学向着个体针对性治疗发生转变，并首先在LQTS的治疗方面实现了，将来还会扩展到其它心律失常病的治疗。     

遗传性长QT间期综合征61个家系成员的心电图分析

目的　了解中国遗传性长QT间期综合征 (LQTS)心电图形态改变。方法　应用 12导联心电图对 6 1个遗传性LQTS家系共 32 2例成员观察了心电图ST T形态改变 ,并对其中 78例有症状患者加以分型。应用测序方法进行基因分型。结果　心电图类似LQT1型 32例 ,类似LQT2型 4 1例 ,类似LQT3型 2例。不典型的有 3例。患者不同时间T波形态发生变异者 4 8例。有症状患者QTc(0 5 4 7± 0 0 8)s,无症状患者QTc(0 5 2 6± 0 0 6 )s,显著长于正常成员。同一患者不同时间QTc的差值 (ΔQTc) :患者 (0 0 4 8± 0 0 5 7)s,正常成员 (0 0 2 3± 0 0 17)s,两组间差异有显著性 (P <0 0 0 1)。基因筛查证实LQT112例 ,LQT2 11例。结论　本组遗传性LQTS患者心电图表现不完全与欧美患者相同 ;T波形态变化较大 ,表现在同一类型间、同一家系中和同一患者的不同时间ECGST T均可出现较大的差异 ;同一患者不同时间QTc亦有较大变化。     

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)。     

先天性长QT综合征20个家系187例的调查与研究

目的调查与研究先天性长QT综合征(longQTsyndrome,LQTS)的遗传特点及家系图谱分析,LQTS的心电图分型、诊断以及治疗.方法应用惠普12导联心电图机对先证者及其家庭成员分别记录6导联及12导联常规体表心电图,对先证者行24h动态心电图检查,分别测量Ⅱ、V2导联的QT、QTc以及QTd.先证者及家族中有症状的患者给予普萘洛尔2～3mg/kg,每日3次治疗.结果187个家庭成员中有31例为LQTS患者,男性11例,女性20例.其中LQT118例,LQT212例,LQT31例.QT间期为(0.57±0.08)s,QTc为(0.58±0.08)s,QTd为(0.16±0.03)s.除1例应用阿托品治疗有效,6例猝死外,其余24例(77.4%)患者应用普萘洛尔治疗有效.无症状的QTc延长者56例,男性23例,女性33例,LQT122例,LQT234例.QT间期为(0.47±0.09)s,QTc为(0.52±0.07)s,QTd为(0.08±0.03)s,有症状组与无症状组相比有统计学意义.家系图谱分析符合常染色体显性遗传规律.结论12导联体表心电图是LQTS常用的最简单的检查方法,心电图对LQTS的临床分型基本准确可靠.普萘洛尔是预防LQTS患者猝死的有效药物.     

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。     

Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing.

OBJECTIVES: The purpose of this study was to determine the spectrum and prevalence of cardiac channel mutations among a large cohort of consecutive, unrelated patients referred for long QT syndrome (LQTS) genetic testing. BACKGROUND: Congenital LQTS is a primary cardiac channelopathy. More than 300 mutations have been identified in five genes encoding key ion channel subunits. Until the recent release of the commercial clinical genetic test, LQTS genetic testing had been performed in research laboratories during the past decade. METHODS: A cardiac channel gene screen for LQTS-causing mutations in KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 (LQT5), and KCNE2 (LQT6) was performed for 541 consecutive, unrelated patients (358 females, average age at diagnosis 24 +/- 16 years, average QTc 482 +/- 57 ms) referred to Mayo Clinic's Sudden Death Genomics Laboratory for LQTS genetic testing between August 1997 and July 2004. A comprehensive open reading frame and splice site analysis of the 60 protein-encoding exons was conducted using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing. RESULTS: Overall, 211 putative pathogenic mutations in KCNQ1 (88), KCNH2 (89), SCN5A (32), KCNE1 (1), and KCNE2 (1) were found in 272 unrelated patients (50%). Among the genotype positive patients (N = 272), 243 had single pathogenic mutations (LQT1: n = 120 patients; LQT2: n = 93; LQT3: n = 26; LQT5: n = 3; LQT6: n = 1), and 29 patients (10% of genotype-positive patients and 5% overall) had two LQTS-causing mutations. The majority of mutations were missense mutations (154/210 [73%]), singletons (identified in only a single unrelated patient: 165/210 [79%]), and novel (125/211 [59%]). None of the mutations identified were seen in more than 1,500 reference alleles. Those patients harboring multiple mutations were younger at diagnosis (15 +/- 11 years vs 24 +/- 16 years, P = .003). CONCLUSIONS: In this comprehensive cardiac channel gene screen of the largest cohort of consecutive, unrelated patients referred for LQTS genetic testing, half of the patients had an identifiable mutation. The majority of mutations continue to represent novel singletons that expand the published compendium of LQTS-causing mutations by 35%. These observations should facilitate diagnostic interpretation of the clinical genetic test for LQTS.     

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.     

N- and C-terminal KCNE1 mutations cause distinct phenotypes of long QT syndrome

BACKGROUND: Long QT syndromes (LQTS) are inherited diseases involving mutations to genes encoding a number of cardiac ion channels and a membrane adaptor protein. The MinK protein is a cardiac K-channel accessory subunit encoded by the KCNE1 gene, mutations of which are associated with the LQT5 form of LQTS. OBJECTIVE: The purpose of this study was to search for the KCNE1 mutations and clarify the function of those mutations. METHODS: We conducted a genetic screen of KCNE1 mutations in 151 Japanese LQTS patients using the denaturing high-performance liquid chromatography-WAVE system and direct sequencing. In two LQTS patients, we identified two KCNE1 missense mutations, located in the MinK N- and C-terminal domains. The functional effects of these mutations were examined by heterologous coexpression with KCNQ1 and KCNH2. RESULTS: One mutation, which was identified in a 67-year-old woman, A8V, was novel. Her electrocardiogram (ECG) revealed marked bradycardia and QT interval prolongation. Another mutation, R98W, was identified in a 19-year-old woman. She experienced syncope followed by palpitation in exercise. At rest, her ECG showed bradycardia with mild QT prolongation, which became more prominent during exercise. In electrophysiological analyses, R98W produced reduced I(Ks) currents with a positive shift in the half activation voltages. In addition, when the A8V mutation was coexpressed with KCNH2, this reduced current magnitude, which is suggestive of a modifier effect by the A8V KCNE1 mutation on I(Kr). CONCLUSION: KCNE1 mutations may be associated with mild LQTS phenotypes, and KCNE1 gene screening is of clinical importance for asymptomatic and mild LQTS patients.     

Allelic dropout in long QT syndrome genetic testing: A possible mechanism underlying false-negative results

BACKGROUND: Genetic testing for congenital long QT syndrome (LQTS) has been performed in research laboratories for the past decade. Approximately 75% of patients with high clinical probability for LQTS have a mutation in one of five LQTS-causing cardiac channel genes. Possible explanations for the remaining genotype-negative cases include LQTS mimickers, novel LQTS-causing genes, unexplored regions of the known genes, and genetic testing detection failures. OBJECTIVES: The purpose of this study was to explore the possibility of allelic dropout as a possible mechanism underlying false-negative test results. METHODS: The published primers currently used by many research laboratories to conduct a comprehensive analysis of the 60 translated exons in the KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 (LQT5), and KCNE2 (LQT6) genes were analyzed for the presence of common intronic single nucleotide polymorphisms (SNPs). Repeat mutational analysis, following primer/amplicon redesign using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing, was performed on a cohort of 541 consecutive, unrelated patients referred for LQTS genetic testing. RESULTS: Common (>1% minor allele frequency) intronic SNPs were discovered within the primer sequences of five of 60 translated exons. Following primer redesign to eliminate the possibility of allelic dropout, four previously genotype-negative index cases were found to possess LQTS-causing mutations: R591H-KCNQ1 and R594Q-KCNQ1 for exon 15 and E229X-KCNH2 in two unrelated cases. Repeat examination of these two amplicons in 400 reference alleles did not identify these or any additional amino acid variants. CONCLUSION: Allelic dropout secondary to intronic SNP-primer mismatch prevented the discovery of LQTS-causing mutations in four cases. Considering that many LQTS genetic testing research laboratories have used these primers, patients who reportedly are genotype negative may benefit from re-examination of those regions susceptible to allelic dropout due to primer-disrupting SNPs, particularly exon 15 in KCNQ1 and exon 4 in KCNH2.     

A novel mutation in KCNQ1 associated with a potent dominant negative effect as the basis for the LQT1 form of the long QT syndrome

Introduction: Long QT Syndrome (LQTS) is an inherited disorder characterized by prolonged QT intervals and life-threatening polymorphic ventricular tachyarrhythmias. LQT1 caused by KCNQ1 mutations is the most common form of LQTS.
Methods and Results: Patients diagnosed with LQTS were screened for disease-associated mutations in KCNQ1, KCNH2, KCNE1, KCNE2, KCNJ2, and SCN5A . A novel mutation was identified in KCNQ1 caused by a three-base deletion at the position 824–826, predicting a deletion of phenylalanine at codon 275 in segment 5 of KCNQ1 (ΔF275). Wild-type (WT) and ΔF275- KCNQ1 constructs were generated and transiently transfected together with a KCNE1 construct in CHO-K1 cells to characterize the properties of the slowly activating delayed rectifier current (IKs) using conventional whole-cell patch–clamp techniques. Cells transfected with WT- KCNQ1 and KCNE1 (1:1.3 molar ratio) produced slowly activating outward current with the characteristics of IKs. Tail current density measured at −40 mV following a two-second step to +60 mV was 381.3 ± 62.6 pA/pF (n = 11). Cells transfected with ΔF275- KCNQ1 and KCNE1 exhibited essentially no current. (Tail current density: 0.8 ± 2.1 pA/pF, n = 11, P = 0.00001 vs WT). Cotransfection of WT- and ΔF275- KCNQ1 (50/50), along with KCNE1, produced little to no current (tail current density: 10.3 ± 3.5 pA/pF, n = 11, P = 0.00001 vs WT alone), suggesting a potent dominant negative effect. Immunohistochemistry showed normal membrane trafficking of ΔF275- KCNQ1 .
Conclusion: Our data suggest that a ΔF275 mutation in KCNQ1 is associated with a very potent dominant negative effect leading to an almost complete loss of function of IKs and that this defect underlies a LQT1 form of LQTS.     

Characterization of a KCNQ1/KVLQT1 polymorphism in Asian families with LQT2: implications for genetic testing

Congenital long QT syndrome (LQTS) is a genetic disease that predisposes affected individuals to arrhythmias, syncope, and sudden death. Mutations in several ion channel genes have been discovered in different families with LQTS: KCNQ1 (KVLQT1, LQT1), KCNH2 (HERG, LQT2), SCN5A (LQT3), KCNE1 (minK, LQT5), and KCNE2 (MiRP1, LQT6). Previously, the P448R-KVLQT1 missense mutation has been reported as an LQT1-causing mutation. In this report, we demonstrate the presence of the P448R polymorphism in two, unrelated Chinese LQTS families. Although absent from 500 reference alleles derived from 150 white and 100 African-American subjects, P448R was present in 14% of healthy Chinese volunteers. Given the inconsistencies between the genotype (LQT1) and clinical phenotype (LQT2) in our two LQTS families, together with the finding that the P448R appears to be a common, ethnic-specific polymorphism, mutational analysis was extended to the other LQTS-causing genes resulting in the identification of distinct HERG missense mutations in each of these two families. Heterologous expression of P448R-KVLQT1 yielded normal, wild-type (WT) currents. In contrast, the two unique HERG mutations resulted in dominant-negative suppression of the WT HERG channel. Our study has profound implications for those engaged in genetic research. Importantly, one child of the original proband was initially diagnosed with LQT1 based upon the presence of P448R-KVLQT1 and was treated with beta-blockers. However, he did not possess the subsequently determined LQT2-causing mutation. On the other hand, his untreated P448R-negative brother harbored the true, disease-causing HERG mutation. These findings underscore the importance of distinguishing channel polymorphisms from mutations pathogenic for LQTS and emphasize the importance of using appropriate ethnically matched controls in the genotypic analysis of LQTS.     

Long QT and Brugada syndrome gene mutations in New Zealand.

BACKGROUND: Genetic testing in long QT syndrome (LQTS) is moving from research into clinical practice. We have recently piloted a molecular genetics program in a New Zealand research laboratory with a view to establishing a clinical diagnostic service. OBJECTIVE: This study sought to report the spectrum of LQTS and Brugada mutations identified by a pilot LQTS gene testing program in New Zealand. METHODS: Eighty-four consecutive index cases referred for LQT gene testing, from New Zealand and Australia, were evaluated. The coding sequence and splice sites of 5 LQTS genes (KCNQ1, HERG, SCN5A, KCNE1, and KCNE2) were screened for genomic variants by transgenomics denaturing high-performance liquid chromatography (dHPLC) system and automated DNA sequencing. RESULTS: Forty-five LQTS mutations were identified in 43 patients (52% of the cohort): 25 KCNQ1 mutations (9 novel), 13 HERG mutations (7 novel), and 7 SCN5A mutations (2 novel). Forty patients had LQTS, and 3 had Brugada syndrome. Mutations were identified in 14 patients with resuscitated sudden cardiac death: 4 KCNQ1, 5 HERG, 5 SCN5A. In 17 cases there was a family history of sudden cardiac death in a first-degree relative: 8 KCNQ1, 6 HERG, 2 SCN5A, and 1 case with mutations in both KCNQ1 and HERG. CONCLUSION: The spectrum of New Zealand LQTS and Brugada mutations is similar to previous studies. The high proportion of novel mutations (40%) dictates a need to confirm pathogenicity for locally prevalent mutations. Careful screening selection criteria, cellular functional analysis of novel mutations, and development of locally relevant control sample cohorts will all be essential to establishing regional diagnostic services.     

Value of genetic testing in the management of the congenital long QT syndrome

The congenital long QT syndrome (LQTS) is a variable clinical and genetic entity characterised by prolongation of the QT interval on the ECG associated with the risk of serious ventricular arrhythmias (torsades de pointe, ventricular fibrillation) which may cause syncope and sudden death in patients with otherwise normal hearts. To date, 6 loci have been identified with the genes responsible for the forms LQT1, LQT2, LQT5 and LQT6, coding for the potassium channels (KCNQ1, HERG, KCNE1 and KCNE2, respectively) which, in the heterozygote state, are responsible for the main forms of LQTS without deafness and, in the homozygote state (KCNQ1 and KCNE1) for the recessive forms of LQTS with or without deafness. The gene for the LQT3 form codes for the cardiac sodium channel (SCN5A). The genetic variability observed in the LQTS corresponds to the diversity of cardiac ionic channels implicated in the genesis of the action potential, so making the LQTS a disease of the ionic channels or a "channelopathy". The potential severity of the prognosis justifies testing of subjects with long QT intervals on the ECG and Holter recording. In order to identify subjects with the genetic abnormality who are asymptomatic, these investigations associated with genetic testing should be made in all close members of the family of an affected person. The major problem remains the evaluation of the risk of sudden death in asymptomatic subjects with a genetic abnormality. At present, in the absence of clearly proven prognostic factors and in the knowledge that effective treatment without major secondary effects is available, all patients should be given prophylactic betablocker therapy.     

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.     

Additional gene variants reduce effectiveness of beta-blockers in the LQT1 form of long QT syndrome

INTRODUCTION: Beta-blockers are widely used to prevent the lethal cardiac events associated with the long QT syndrome (LQTS), especially in KCNQ1-related LQTS (LQT1) patients. Some LQT1 patients, however, are refractory to this therapy. METHODS AND RESULTS: Eighteen symptomatic LQTS patients (12 families) were genetically diagnosed as having heterozygous KCNQ1 variants and received beta-blocker therapy. Cardiac events recurred in 4 members (3 families) despite continued therapy during mean follow-up of 70 months. Three of these patients (2 families) had the same mutation [A341V (KCNQ1)]; and the other had R243H (KCNQ1). The latter patient took aprindine, which seemed to be responsible for the event. By functional assay using a heterologous mammalian expression system, we found that A341V (KCNQ1) is a loss-of-function type mutation (not dominant negative). Further genetic screening revealed that one A341V (KCNQ1) family cosegregated with S706C (KCNH2) and another with G144S (KCNJ2). Functional assay of the S706C (KCNH2) mutation was found to reduce the current density of expressed heterozygous KCNH2 channels with a positive shift (+8 mV) of the activation curve. Action potential simulation study was conducted based on the KYOTO model to estimate the influence of additional gene modifiers. In both models mimicking LQT1 plus 2 and LQT1 plus 7, the incidence of early afterdepolarization was increased compared with the LQT1 model under the setting of beta-adrenergic stimulation. CONCLUSION: Multiple mutations in different LQTS-related genes may modify clinical characteristics. Expanded gene survey may be required in LQT1 patients who are resistant to beta-blocker therapy.