Prevalence and risk factors for acquired long QT syndrome in the emergency department:a retrospective observational study

BACKGROUND: Long QT syndrome(LQTS) is a heterogeneous syndrome that may be congenital or, more frequently, acquired. The real-world prevalence of acquired LQTS(aLQTS) in the emergency department(ED) remains to be determined. The aim of this study was to determine prevalence of aLQTS and its impact on symptoms on ED admissions.METHODS: Electrocardiograms(ECG) of 5,056 consecutively patients admitted in the ED of a tertiary hospital between January 28th and March 17th of 2020 were reviewed. All patients with aLQTS were included. Clinical data with a focus on QT prolonging drugs and clinical factors were recorded. Statistical comparison was made between the groups with and without corrected QT(QTc) interval greater than 500 ms(value that is considered severely increased).RESULTS: A total of 383 ECGs with prolonged QTc were recognized, corresponding to a prevalence of aLQTS at admission of 7.82%. Patients with aLQTS were more commonly men(53.3%) with an age of(73.49±14.79) years old and QTc interval of(505.3±32.4) ms. Only 20.4% of these patients with aLQTS were symptomatic. No ventricular arrhythmias were recorded. Patients with QT interval greater than 500 ms were more frequently female(59.5%;P<0.001) and were more frequently on QT prolonging drugs(77.3%;P=0.025). Main contributing factor was intake of antibiotics(odds ratio [OR] 4.680) followed by female gender(OR 2.473) and intake of antipsychotics(OR 1.925).CONCLUSION: aLQTS is particularly prevalent in the ED. Female patients on antibiotics and antipsychotics are at particularly high risk. Efforts must be made to avoid, detect and treat aLQTS as early as possible.

Comparison of QT Correction Methods in the Pediatric Population of a Community Hospital: A Retrospective Study

Objective:Accurate measurement of QT interval,the ventricular action potential from depolarization to repolarization,is important for the early detection of Long QT syndrome.The most effective QT correction(QTc)formula has yet to be determined in the pediatric population,although it has intrinsically greater extremes in heart rate(HR)and is more susceptible to errors in measurement.The authors of this study compare six dif-ferent QTc methods(Bazett,Fridericia,Framingham,Hodges,Rautaharju,and a computer algorithm utilizing the Bazett formula)for consistency against variations in HR and RR interval.Methods:Descriptive Retrospective Study.We included participants from a pediatric cardiology practice of a community hospital who had an ECG performed in 2017.All participants were healthy patients with no past medical history and no regular med-ications.Results:ECGs from 95 participants from one month to 21 years of age(mean 9.7 years)were included with a mean HR of 91 beats per minute(bpm).The two-sample paired t-test or Wilcoxon signed-rank test assessed for any difference between QTc methods.A statistically significant difference was observed between every combination of two QTc formulae.The Spearman’s rank correlation analysis explored the QTc/HR and QTc/RR relationships for each formula.Fridericia method was most independent of HR and RR with the lowest absolute value of correlation coefficients.Bazett and Computer had moderate correlations,while Framingham and Rautaharju exhibited strong correlations.Correlations were positive for Bazett and Computer,reflecting results from prior studies demonstrating an over-correction of Bazett at higher HRs.In the linear QTc/HR regression analysis,Bazett had the slope closest to zero,although Computer,Hodges,and Fridericia had comparable values.Alternatively,Fridericia had the linear QTc/RR regression coefficient closest to zero.The Bland-Altman method assessed for bias and the limits of agreement between correction formulae.Bazett and Computer exhibited good agreement with minimal bias along with Framingham and Rautaharju.To account for a possible skewed distri-bution of QT,all the above analyses were also performed excluding the top and bottom 2%of data as sorted by heart rate ranges(N=90).Results from this data set were consistent with those derived from all participants(N=95).Conclusions:Overall,the Fridericia correction method provided the best rate correction in our pedia-tric study cohort.

A novel splice mutation of HERG in a Chinese family with long QT syndrome

Congenital long QT syndrome (LQTS) is a genetically heterogeneous disease in which six ion-channel genes have been identified. The phenotype-genotype relationships of the HERG (human ether-a-go-go-related gene) mutations are not fully understood. The objective of this study is to identify the underlying genetic basis of a Chinese family with LQTS and to characterize the clinical manifestations properties of the mutation. Single strand conformation polymorphism (SSCP) analyses were conducted on DNA fragments amplified by polymerase chain reaction from five LQT-related genes. Aberrant conformers were analyzed by DNA sequencing. A novel splice mutation in C-terminus of HERG was identified in this Chinese LQTS family,leading to the deletion of 11-bp at the acceptor splice site of Exon9 [Exon9 IVS del (-12→-2)]. The mutation might affect,through deficient splicing, the putative cyclic nucleotide binding domain (CNBD) of the HERG K+ channel. This mutation resulted in a mildly affected phenotype. Only the proband had a history of syncopes, while the other three individuals with long QT interval had no symptoms. Two other mutation carriers displayed normal phenotype. No sudden death occurred in the family. The 4 affected individuals and the two silent mutation carriers were all heterozygous for the mutation. It is the first splice mutation of HERG reported in Chinese LQTS families. Clinical data suggest that the CNBD mutation may be less malignant than mutations occurring in the pore region and be partially dominant over wild-type function.

Genotypic diagnosis of long QT syndrome by analysis of candidate genes

Objective To diagnose 6 LQTS families by genetic analysis.Methods A total aof 6 LQTS pedigrees with 43 family members were brought together for genetic diagnosis by using short-sequence tandem-repeat(STR)markers or sequencing.Genomic DNA was extracted from blood samples by standard procedure.STR markers or KCNQ1,KCNH2 and SCN5A were amplified.The haplotype analysis for LQTS was performed.If the family got the negative haplotype analysis,the sequencing was performed.Results LQTS patients were always linkaged with the SCN5A gene in family 1.KCNH2 was linkaged with the disease in family 2 to 5.21 gene carriers were identified from these 5 families.A mutation(A561V-KCNH2)was only found in the proband of family 6 and an SNP(G1691A)was found in all the members of the family.Conclusion Genetic diagnosis can not only improve presymptomatic diagnosis,but also provide the basis for personal therapy and research on disease-causing mutations.

A novel mutation—L539fs/47 of hERG in a Chinese long QT syndrome family

Objective To identify the mutation of human ether-a-go-go-related gene(hERG)and analyze the clinical characteristics of a Chinese family with long ST syndrome(LQTS).Methods The electrocardiogram and DNA samples were obtained from a Chinese LQTS family of 26 members.Genotype was performed with polymorphic short tandem repeat(STR)markers at the known LQT1,LQT2,and LQT3 loci.SSCP analysis was used to find aberrant conformers.hERG mutation was confirmed by cloning and sequencing.Results Three gene carriers were linked to chromosome 7q35-36,where the potassium channel gene hERG was encoded.A 19-base pair deletion was identified.The mutation was located at nucleotide position 1 619-1 637 between transmembrane domains S4 and S5.Furthermore,A1692G polymorphism was found both in the normal control and patients.Conclusion A novel 19 bp deletion mutation of hERG is identified in a Chinese family.All gene carriers are demonstrated to be typical LQT2 ECG phenotype.

The Relationship between T-Wave Alternans and Adverse Cardiac Events in Patients with Congenital Long QT Syndrome:A Systematic Review and Meta-Analysis

Background:T-wave alternans(TWA)is a risk factor of ventricular arrhythmias or sudden cardiac death(SCD)in patients with ischemic cardiomyopathy.Nevertheless,the relationship between TWA and adverse cardiac events(ACE)in patients with congenital long QT syndrome(LQT)remains controversial.Methods:A systematic electronic search of PubMed,Embase and the Cochrane Library was conducted from database inception dates to 28 April 2021 and assessed the relationship between TWA and ACE in patients with LQTS.Sub-group analysis evaluated the association between microvolt TWA(MTWA)and ACE in different monitoring models and ECGlead numbers.Results:A pooled analysis of seven studies of 625 patients with LQTS showed that TWA was significantly associated with ACE(OR 3.16,95%CI 1.86–5.37,P<0.001).Advanced analysis showed that macroscopic TWA was significantly related to ACE(OR 6.01,95%CI 2.96–12.21,P<0.001),while MTWA did not(OR 0.92,95%CI 0.37–2.30,P=0.85).Sub-group analysis showed that MTWA recorded in 24 h continuous ECG(OR 6.79,95%CI 0.80–57.75,P=0.08)might have a stronger association with ACE than recorded in stress ECG(OR 0.28,95%CI 0.07–1.10,P=0.07).No difference was observed between MTWA measured in multi-lead ECG and limited ECG leads(P=0.15).Conclusions:Macroscopic TWA was significantly related to ACE in patients with LQTS.In terms of MTWA,MTWA recorded in 24 h continuous ECG might have a stronger association with ACE than stress ECG,but still deserves further evaluation.

Discovery of Digenic Mutation, KCNH2 c.1898A > C and JUP c.916dupA, in a Chinese Family with Long QT Syndrome via Whole-Exome Sequencing

Long QT syndrome(LQTS),which is caused by an ion channel–related gene mutation,is a malignant heart disease with a clinical course of a high incidence of ventricular fi brillation and sudden cardiac death in the young.Mutations in KCNH2(which encodes potassium voltage-gated channel subfamily H member 2)are responsible for LQTS in many patients.Here we report the novel mutation c.1898A>C in KCNH2 in a Chinese family with LQTS through whole-exome sequencing.The c.916dupA mutation in JUP(which encodes junction plakoglobin)is also discovered.Mutations in JUP were found to be associated with arrhythmogenic right ventricular cardiomyopathy.The double mutation in the proband may help explain his severe clinical manifestations,such as sudden cardiac death at an early age.Sequencing for the proband’s family members revealed that the KCNH2 mutation descends from his paternal line,while the mutation in JUP came from his maternal line.The data provided in this study may help expand the spectrum of LQTS-related KCNH2 mutations and add support to the genetic diagnosis and counseling of families affected by malignant arrhythmias.

Survey concerning internal medicine physicians and prolonged QT interval:Knowledge and treatment practices

Prolongation of the QT interval is associated with adverse cardiac events specifically Torsades de pointes(TdP).There are multiple mediations that have a known,possible,or conditional risk for prolonged QT interval,but general practitioners’knowledge of these medications is unknown.We conducted a survey to assess internal medicine(IM)providers’knowledge of risk factors and medications associated with prolonged QT as well as provider experience and comfort when treating patients with prolonged QT.A 17-question,anonymous survey was constructed in 2019 and distributed to IM providers and residents at a tertiary care center.Questions included demographic information,6 Likert-scale questions gauging provider experience with prolonged QT,and 10 multiple choice clinical vignettes to assess clinical knowledge.Data was analyzed descriptively.Knowledge was assessed via clinical vignettes and compared by level of training.Forty-one responses were received out of a total of 87 possible respondents(47.1%response rate).About 70%of respondents see patients with acquired prolonged QT once monthly or more.95%rarely see congenital prolonged QT.When presented with QTc drug issues,73%of providers seldom or sometimes consulted pharmacy,but about half used online resources.The average correct score on the clinical vignettes was 5.59/10,with the highest scores seen in attending physicians in their first five years of practice(6.96/10).Our survey suggests that IM providers commonly encounter QT prolonging drugs.Educational efforts to improve knowledge of drug and patient risk factors for TdP may be needed.

The Novel Long QT Syndrome Type 2-associated F129I Mutation in the KCNH2 Gene Significantly Affects IKr Through the hERG1 Homomeric and Heteromeric Potassium Channels

Objective:The long QT syndrome type 2 is caused by the loss-of-function mutations in the KCNH2 gene,which encodes hERG1,the voltage-gated potassium channel.The hERG1 channels conduct rapid delayed rectifier K^(+)currents(I_(Kr))in the human cardiac tissue.KCNH2 encodes 2 main isoforms-hERG1a and hERG1b,which assemble to form the homomeric or heteromeric hERG1 channels.However,the functional characteristics of the heteromeric hERG1 channels in long QT syndrome type 2 are not clear.In this study,a novel mutation in the N-terminus of hERG1a(F129l)was identified in a proband of long QT syndrome type 2.The purpose of this study was to identify the electrophysiological change of homomeric and heteromeric hERG1 channels with theF129l-hERG1a.Methods:Candidate genes were screened by direct sequencing.F129l-hERG1a was cloned in the pcDNA3.1 vector by site-directed mutagenesis.Then,the wild-type(WT)hERG1a and/or F129l-hERG1a were transiently expressed in the HEK293 cells with or without hERG1b co-expression.The expression levels of the transgenes,cellular distribution of hERG1a and hERG1b,and the electrophysiological features of the homomeric and the heteromeric hERG1 channels with the WT-hERG1a or F129l-hERG1a were analyzed using whole-cell patch-clamp electrophysiology,western blotting,and immunofluorescence techniques.Results:The proband was clinically diagnosed with long QT syndrome type 2 and carried a heterozygous mutation c.385T>A(F1291)in the KCNH2 gene.Electrophysiology study proved that the F129l substitution in hERG1a significantly decreased I_(Kr) in both the homomeric and heteromeric hERG1channels by 86%and 70%,respectively(WT-hERG1a(54.88±18.74)pA/pF vs.F129l-hERG1a(7.34±1.90)pA/pF,P<0.001;WT-hERG1a/hERG1b(89.92±24.51)pA/pF vs.F129l-hERG1a/hERG1b(26.54±9.83)pA/pF,P<0.001).The voltage dependence of I_(Kr) activation(V_(1/2) and k)was not affected by the mutation in both the homomeric and heteromeric hERG1 channels.The peak current densities and the kinetic characteristics of I_(Kr) were comparable for both WT/F129l-hERG1a and WT-hERG1a.The channel inactivation and deactivation analysis showed that F129l substitution did not affect deactivation of the homomeric hERG1a channel,but significantly accelerated the deactivation and recovery from inactivation of the heteromeric hERG1a/hERG1b channel based on the time constants of fast and slow recovery from deactivation F129l-hERG1a/hERG1b vs.WT-hERG1a/hERG1b(P<0.05).Western blotting and immunofluorescence labeling experiments showed that maturation and intracellular trafficking of the F129l-hERG1a protein was impaired and potentially increased the ratio of hERG1b to hERG1a in the F129l-hERG1a/hERG1b tetramer channel,thereby resulting in electrophysiological changes characteristic of the long QT syndrome type 2 pathology.Conclusions: I_(Kr) Was significantly reduced in the homomeric and heteromeric hERG1 channels with F129l-hERG1a.The F129l mutation significantly accelerated the deactivation and recovery from inactivation of the heteromeric F129l-hERG1a/hERG1b channel.F129l-hERG1a exhibited impaired maturation and intracellular trafficking,thereby potentially increasing the ratio of the hERG1b to hERG1a stoichiometry in the hERG1 tetrameric channel.These changes demonstrated the importance of the heteromeric hERG1 channel in long QT syndrome type 2 pathophysiology.

MODELING AND SIMULATION OF E1784K MUTATION AND SODIUM IONIC CHANNEL DISEASES

In the clinical reports, the E1784K mutation in SCN5A is recognized as a phenotypic overlap between the long QT syndrome （LQT3） and the Brugada syndrome （BrS） in the characteristics of electrocardiograms （ECGs） since the mutation can influence sodium channel functions. However it is still unclear if the E1784K mutation-induced sodium ionic channel alterations account for the overlap at tissue level. Thsu, a detailed computational model is developed to underpin the functional impacts of the E1784K mutation on the action potential （AP）, the effective refractory period （ERP） and the abnormal ECG. Simulation results stlggest＇that the E1784K mutation-induced sodium channel alterations are insufficient to produce the phenotypic overlap between LQT3 and BrS, and the overlap may arise from the complicated effects of the E1784K mutation-induced changes in sodium channel currents with an increase of the transient outward current ITo or a decrease of the L-type calcium current ICaL .

Clinical Characteristics of 5 Chinese LQTS Families and Phenotype-genotype Correlation

Summary: In order to assess the clinical manifestations and electrocardiogram (ECG) characteristics of Chinese long QT syndrome (LQTS) patients and describe the phenotype-genotype correlation, the subjects from 5 congenital LQTS families underwent clinical detailed examination including resting body surface ECG. QT interval and transmural dispersion of repolarization (TDR) were manually measured. Five families were genotyped by linkage analysis (polymerase chain reacting-short tandem repeat, PCR-STR). The phenotype-genotype correlation was analyzed. Four families were LQT2, 1 family was LQT3. Twenty-eight gene carriers were (14 males and 14 females) identified from 5 families. The mean QTc and TDRc were 0.56±0.04 s (range 0.42 to 0.63) and 0.16±0.04 s (range 0.09 to 0.24) respectively. 35.7 % (10/28) had normal to borderline QTc (≤ 0.460 s). There was significant difference in QTc and TDRc between the patients with symptomatic LQTS and those with asymptomatic LQTS, and there was significant difference in TDRc between the asymptomatic patients and normal people also. A history of cardiac events was present in 50 % (14/28), including 9 with syncope, 2 with sudden death (SD) and occurred in the absence of β-blocker. Three SDs occurred prior to the diagnosis of LQTS and had no ECG record. Two out of 5 SDs (40 %) occurred as the first symptom. Typical LQT2 T wave pattern were found in 40 % (6/15) of all affected members. The appearing-normal T wave was found in one LQT3 family. Low penetrance of QTc and symptoms resulted in diagnostic challenge. ECG patterns and repolarization parameters may be used to predict the genotype in most families. Genetic test is very important for identification of gene carriers.

Torsades de pointes episode in a woman with high-grade fever and inflammatory activation: A case report

BACKGROUND QT interval prolongation can induce torsades de pointes(TdP),a potentially fatal ventricular arrhythmia.Recently,an increasing number of non-cardiac drugs have been found to cause QT prolongation and/or TdP onset.Moreover,recent findings have demonstrated the key roles of systemic inflammatory activation and fever in promoting long-QT syndrome(LQTS)and TdP development.CASE SUMMARY A 30-year-old woman was admitted with a moderate to high-grade episodic fever for two weeks.The patient was administered with multiple antibiotics after hospitalization but still had repeating fever and markedly elevated C-reactive protein.Once after a high fever,the patient suddenly lost consciousness,and electrocardiogram(ECG)showed transient TdP onset after frequent premature ventricular contraction.The patient recovered sinus rhythm and consciousness spontaneously,and post-TdP ECG revealed a prolonged QTc interval of 560 ms.The patient’s clinical manifestations and unresponsiveness to the antibiotics led to the final diagnosis of adult-onset Still’s disease(AOSD).There was no evidence of cardiac involvement.After the AOSD diagnosis,discontinuation of antibiotics and immediate initiation of intravenous dexamethasone administration resulted in the normal temperature and QTc interval.The genetic analysis identified that the patient and her father had heterozygous mutations in KCNH2(c.1370C>T)and AKAP9(c.7725A>C).During the 2-year follow-up period,the patient had no recurrence of any arrhythmia and maintained normal QTc interval.CONCLUSION This case study highlights the risk of systemic inflammatory activation and antibiotic-induced TdP/LQTS onset.Genetic analysis should be considered to identify individuals at high risk of developing TdP.

Electrophysiological Study of V535M hERG Mutation of LQT2

This study examined the current changes of human ether-a-go-go-related gene （hERG） mutation derived from a LQT2 Chinese family with a highly penetrating phenotype. Mutation was identi-fied and site-directed mutagenesis was performed to induce the mutation in wild-type （WT） hERG. WT hERG and mutated V535M were cloned and transiently expressed in HEK293 cells. At the 48th and 72nd h after transfection, membrane currents were recorded using whole cell patch-clamp procedures. An A〉G transition at 1605 resulting in replacement of V535M was identified. Compared to WT, V535M mutation significantly decreased tail currents of hERG. At test potential of-40 mV after depolarizing at ＋50 mV, tail current densities were 83.354-7.06 pA/pF in WT and 50.38-4-7.74 pA/pF in V535M respectively （n=20, P〈0.01）. Gating kinetics of bERG revealed that Vl/2 of steady-state inactivation shifted to negative potential in the mutant （V1/2,v535M： -61.814-1.7 mV vs. V1/2, wx： -43.1q-0.71 mV）. The time constant of recovery from inactivation was markedly prolonged in the mutant compared to WT among test potentials. V535M hERG mutation demonstrated markedly decreased tail current densities, which suggests that V535M is a new loss-of-function mutation of hERG channel responsible for LQT2.

Slow and Steady: The Cautious Use of Neuroleptics in a Patient with Andersen-Tawil Syndrome

Long QT syndrome (LQT) is a disease of cardiac repolarization caused by alterations in the transmembrane potassium and sodium currents. This results in prolongation of the QT interval on electrocardiography (EKG) and can result in torsade de pointes and sudden cardiac death. We present a case of a patient who has Anderson Tawil syndrome;a congenital long QT syndrome, with a history of cardiac arrhythmias who developed acute paranoid schizophrenia that was refractory to treatment with non-QT-prolonging drugs and required institution of neuroleptics to control her psychiatric symptoms.

The Notched T Waves Associated With HERG Gene Ala561Val Mutation in Congenital LQT Syndrome

Objectives To study the phenotype of a China LQT family and investigate the relationship of phenotype and gene. Methods The clinical materials were analyzed and gene mutations were screened by sequencing. Results A distinctive biphasic T wave pattern was shown in the left precordial leads of all patients. The LQT2 related HERG gene Ala561Val mutation was found. Conclusions A prolonged QT interval accompanied biphasic T wave indicates HERG mutation.

Blocking effects of erythromycin on the rapid activating component(I_(kr)) of the delayed rectifier potassium current (I_k) in guinea pig ventricular myocytes ──Direct measurement of the fast inactivation current

Intravenous or oral administrations of erythromycin in humans have been reported to induce excessive prolongation of QT interval and even cause polymorphic ventricular tachycardia and torsade de points. Inthis study, we evaluated the effects of erythromycin on Ik, through direct measurement of the fast inactivationcurrent by using a two-pulses protocol. The results showed that erythrornycin 100 μmol/L restrained the fastinactivation current (P<0. 05), and its effects were both dose--dependent and voltage-dependent. As a result. the time course of erythromycin on the inactivation current was slow and washout was difficult. Our results expectedly may explain the reason why erythromycin slows the repolarization of action potential,lengthens QT interval, and causes torsade de points in humans.

QT hysteresis in long-QT syndrome children with exercise testing

Background Congenital long QT syndrome （LQTS） is an inherited ion channel disorder resulting in abnormal cardiac repolarization that can cause syncope and sudden death associated with a prolonged rate-corrected QT interval and polymorphic ventricular tachycardia. Several studies in adults showed that LQTS patients have altered QT adaptation to heart rate changes compared with normal subjects which forming a ＂hysteresis loop＂ in the QT-circle length plot. This study was to observe the QT interval changing during exercise testing in children long QT syndrome （LQTS） patients, explore the new diagnosis methods of LQTS. Methods The subjects were divided into 3 groups according to 1993 LQTS diagnostic criteria. Group 1： LQTS group （n=17） who scored 〉 or = 4 points indicating definite LQTS. Group 2： Middle group （n=16）, patients who have prolonged QT interval but scored 1.5 to 3.5. Group 3： Normal control group （n=18）. The average age of all study population is （12.3±5.8） years. No case had beta-adrenergic antagonists administration before exercise testing. All subjects were underwent tread mill exercise testing and electrocardiograph in whole exercise testing and recovery were recorded. QT and heart rate changing during whole exercise testing period were recorded. /kQT, the QT interval at 1, 2, 4, 6 minutes into recovery subtract from the QT interval at a similar heart rate during exercise, were calculated. Results In all three groups, QT intervals were shortening with the increasing of heart rate, but QTc had no significant change. ΔQT at 1 minute （（45±11） ms）, 2 minutes （（37±15） ms）, 4 minutes （（23±12） ms） into recovery in LQTS group were significantly greater than that of the other two groups （P〈0.05, P〈0.01, P〈0.01, respectively）. There was no ΔQT significant difference between middle group and normal control group at recovery time. During the recovery phase in LQTS group, the QT interval remained shortened despite a decelerating heart rate, forming a hysteresis ＂loop＂ in the curve relating the QT interval to the cycle length. Conclusions In children LQTS patients, there is significant QT hysteresis loop in the relation of QT interval with heart rate during recovery of exercise testing, which could be useful to the early diagnosis for LQTS.

Mutation analysis of potassium channel genes KCNQ1 and KCNH2 in patients with long QT syndrome

Objective To determine mutations of two common potassium channel subunit genes KCNQ1, KCNH2 causing long QT syndrome (LQTS) in the Chinese.Methods Thirty-one Chinese LQTS pedigrees were characterized for mutations in the two LQTS genes, KCNQ1 and KCNH2, by sequencing.Results Two novel KCNQ1 mutations, S277L in the S5 domain and G306V in the channel pore, and two novel KCNH2 mutations, L413P in the transmembrane domain S1 and L559H in the transmembrane domain S5 were identified. The triggering factors for cardiac events developed in these mutation carriers included physical exercise and excitation. Mutation L413P in KCNH2 was associated with the notched T wave on ECGs. Mutation L559H in KCNH2 was associated with the typical bifid T wave on ECGs. Mutation S277L in KCNQ1 was associated with a high-amplitude T wave and G306V was associated with a low-amplitude T wave. Two likely polymorphisms, IVS11 +18C >T in KCNQ1 and L520V in KCNH2 were also identified in two LQTS patients.Conclusions The mutation rates for both KCNQ1 (6.4%) and KCNH2 (6.4%) are lower in the Chinese population than those from North America or Europe.

A novel deletion-frameshift mutation in the S1 region of HERG gene in a Chinese family with long QT syndrome

Background The congenital Long QT syndrome （LQTS） is a hereditary cardiac channelopathy that is characterized by a prolonged QT interval,syncope,ventricular arrhythmias,and sudden death.The chromosome 7-linked type 2 congenital LQTS （LQT2） is caused by gene mutations in the human ether-a-go-go-related gene （HERG）.Methods A Chinese family diagnosed with LQTS were screened for KCNQ1,HERG and SCN5A,using polymerase chain reaction （PCR）,direct sequencing,and clong sequencing.We also investigated the mRNA expression of the HERG gene.Results We identified a novel i414fs＋98X mutation in the HERG gene.The deletion mutation of 14-bp in the first transmembrane segment （S1） introduced premature termination codons （PTCs） at the end of exon 6.This mutation would result in a serious phenotype if the truncated proteins co-assembled with normal subunit to form the defective channels.But only the proband was symptomatic.Conclusions We found that the mRNA level of the HERG gene was significantly lower in 1414fs＋98X carriers than in noncarriers.We found a novel 1414fs＋98X mutation.The mRNA level supports that NMD mechanism might regulate the novel mutation.

Mutation analysis of KCNQ1, KCNH2, SCN5A, KCNE1 and KCNE2 genes in Chinese patients with long QT syndrome

Long QT syndrome(LQTS)is the prototype of the cardiac ion channelopathies,which cause syncope and sudden death.Inherited LQTS is represented by the autosomal dominant Romano-ward syndrome(RWS),which is not accompanied by congenital deafness,and the autosomal recessive Jervell and Lange-Nielsen syndrome(JLNS),which is accompanied by congenital deafness.The LQTS-causing mutations have been reported in patients and families from Europe,North America and Japan.Few genetic studies have been carried out in families with JLNS from China.This study investigates the molecular pathology in four families with LQTS(including a family with JLNS)in the Chinese population.Polymerase chain reaction and DNA sequencing were used to screen for KCNQ1,KCNH2,KCNE1,KCNE2 and SCN5A mutation.A missense mutation G314S in an RWS family was identified,and a single nucleotide polymorphism(SNP)G643S was indentified in the KCNQ1 of the JLNS family.In this JLNS family,another heterozygous novel mutation in exon 2a was found in KCNQ1 of the patients.Our data provide useful information for the identification of polymorphisms and mutations related to LQTS and the Brugada Syndrome(BS)in Chinese populations.