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1.  KCNQ1 and KCNH2 Mutations Associated with Long QT Syndrome in a Chinese Population 
Human mutation  2002;20(6):475-476.
The long QT syndrome (LQTS) is a cardiac disorder characterized by prolongation of the QT interval on electrocardiograms (ECGs), syncope and sudden death caused by a specific ventricular tachyarrhythmia known as torsade de pointes. LQTS is caused by mutations in ion channel genes including the cardiac sodium channel gene SCN5A, and potassium channel subunit genes KCNQ1, KCNH2, KCNE1, and KCNE2. Little information is available about LQTS mutations in the Chinese population. In this study, we characterized 42 Chinese LQTS families for mutations in the two most common LQTS genes, KCNQ1 and KCNH2. We report here the identification of four novel KCNQ1 mutations and three novel KCNH2 mutations. The KCNQ1 mutations include L191P in the S2–S3 cytoplasmic loop, F275S and S277L in the S5 transmembrane domain, and G306V in the channel pore. The KCNH2 mutations include L413P in transmembrane domain S1, E444D in the extracellular loop between S1 and S2, and L559H in domain S5. The location and character of these mutations expand the spectrum of KCNQ1 and KCNH2 mutations causing LQTS. Excitement, exercises, and stress appear to be the triggers for developing cardiac events (syncope, sudden death) for LQTS patients with KCNQ1 mutations F275S, S277L, and G306V, and all three KCNH2 mutations L413P, E444D and L559H. In contrast, cardiac events for an LQTS patient with KCNQ1 mutation L191P occurred during sleep or awakening from sleep. KCNH2 mutations L413P and L559H are associated with the bifid T waves on ECGs. Inderal or propanolol (a beta blocker) appears to be effective in preventing arrhythmias and syncope for an LQTS patient with the KCNQ1 L191P mutation.
doi:10.1002/humu.9085
PMCID: PMC1679868  PMID: 12442276
Long QT Syndrome; LQTS; cardiac arrhythmia; KCNQ1; KVLQT1; KCNH2; HERG; potassium channel; mutation; torsade de pointes; sudden death; ion channel; IKs, IKr
2.  Protective effect of KCNH2 single nucleotide polymorphism K897T in LQTS families and identification of novel KCNQ1 and KCNH2 mutations 
BMC Medical Genetics  2008;9:87.
Background
KCNQ1 and KCNH2 are the two most common potassium channel genes causing long QT syndrome (LQTS), an inherited cardiac arrhythmia featured by QT prolongation and increased risks of developing torsade de pointes and sudden death. To investigate the disease expressivity, this study aimed to identify mutations and common variants that can modify LQTS phenotype.
Methods
In this study, a cohort of 112 LQTS families were investigated. Among them two large LQTS families linkage analysis with markers spanning known LQTS genes was carried out to identify the specific gene for mutational analysis. All exons and exon-intron boundaries of KCNH2 and KCNQ1 were sequenced for mutational analysis.
Results
LQTS-associated mutations were identified in eight of 112 families. Two novel mutations, L187P in KCNQ1 and 2020insAG in KCNH2, were identified. Furthermore, in another LQTS family we found that KCNH2 mutation A490T co-segregated with a common SNP K897T in KCNH2. KCNH2 SNP K897T was reported to exert a modifying effect on QTc, but it remains controversial whether it confers a risk or protective effect. Notably, we have found that SNP K897T interacts with mutation A490T in cis orientation. Seven carriers for A490T and the minor allele T of SNP K897T showed shorter QTc and fewer symptoms than carriers with A490T or A490P (P < 0.0001).
Conclusion
Our family-based approach provides support that KCNH2 SNP K897T confers a protective effect on LQTS patients. Our study is the first to investigate the effect of SNP K897T on another KCNH2 mutation located in cis orientation. Together, our results expand the mutational and clinical spectrum of LQTS and provide insights into the factors that determine QT prolongation associated with increased risk of ventricular tachycardia and sudden death.
doi:10.1186/1471-2350-9-87
PMCID: PMC2570672  PMID: 18808722
3.  Long QT syndrome in South Africa: the results of comprehensive genetic screening 
Cardiovascular Journal of Africa  2013;24(6):231-237.
Abstract
Congenital long QT syndrome (cLQTS) is a genetic disorder predisposing to ventricular arrhythmia, syncope and sudden death. Over 700 different cLQTS-causing mutations in 13 genes are known. The genetic spectrum of LQTS in 44 South African cLQTS patients (23 known to carry the South African founder mutation p.A341V in KCNQ1) was established by screening for mutations in the coding regions of KCNQ1, KCNH2, KCNE1, KCNE2 and SCN5A, the most frequently implicated cLQTS-causing genes (five-gene screening). Fourteen disease-causing mutations were identified, eight (including the founder mutation) in KCNQ1, five in KCNH2 and one in KCNE1. Two mutations were novel. Two double heterozygotes were found among the 23 families (8.5%) carrying the founder mutation. In conclusion, cLQTS in South Africa reflects both a strong founder effect and a genetic spectrum similar to that seen in other populations. Consequently, five-gene screening should be offered as a standard screening option, as is the case internationally. This will disclose compound and double heterozygotes. Fivegene screening will most likely be even more informative in other South African sub-populations with a greater genetic diversity.
doi:10.5830/CVJA-2013-032
PMCID: PMC3772322  PMID: 24217263
LQTS; mutation; ion-channels; sudden death; arrhythmia
4.  Identification of a novel KCNQ1 mutation associated with both Jervell and Lange-Nielsen and Romano-Ward forms of long QT syndrome in a Chinese family 
BMC Medical Genetics  2008;9:24.
Background
Long QT syndrome (LQTS) is a cardiac disorder characterized by prolonged QT intervals on electrocardiograms (ECG), ventricular arrhythmias, and sudden death. Clinically, two inherited forms of LQTS have been defined: autosomal dominant LQTS or Romano-Ward syndrome (RWS) not associated with deafness and autosomal recessive LQTS or Jervell and Lange-Nielsen syndrome (JLNS) associated with deafness.
Methods
A Chinese family with both RWS and JLNS was identified. Family members were diagnosed based on the presence of a prolonged QT interval as seen on a 12-lead ECG and a medical history of syncope, palpitation, and deafness. Mutational studies in the KCNQ1 potassium channel gene were performed using direct DNA sequence analysis and restriction length polymorphism analysis.
Results
The proband in the Chinese family and her brother had previously been diagnosed with JLNS, and two other members were affected with RWS. The proband was also affected with atrial fibrillation. A single nucleotide substitution of C to T at nucleotide 965 of KCNQ1 was identified, and the mutation resulted in the substitution of a threonine residue at codon 322 by a methionine residue (T322M). The novel heterozygous T322M mutation was identified in two patients with RWS, one member with borderline QTc, and two normal family members. The two JLNS patients in the family carried the homozygous T322M mutation. The T322M mutation was not found in 200 Chinese normal controls.
Conclusion
Our results suggest that T322M is a novel mutation that caused RWS with high intrafamilial variability in the heterozygous carriers and typical JLNS in the homozygous carriers within this Chinese family. The T322M mutation is the first mutation identified for JLNS in the Chinese population.
doi:10.1186/1471-2350-9-24
PMCID: PMC2322962  PMID: 18400097
5.  Overlapping LQT1 and LQT2 phenotype in a patient with long QT syndrome associated with loss-of-function variations in KCNQ1 and KCNH2 
Long QT syndrome (LQTS) is an inherited disorder characterized by prolonged QT intervals and potentially life-threatening arrhythmias. Mutations in 12 different genes have been associated with LQTS. Here we describe a patient with LQTS who has a mutation in KCNQ1 as well as a polymorphism in KCNH2. The proband (MMRL0362), a 32-year-old female, exhibited multiple ventricular extrasystoles and one syncope. Her ECG (QT interval corrected for heart rate (QTc) = 518ms) showed an LQT2 morphology in leads V4–V6 and LQT1 morphology in leads V1–V2. Genomic DNA was isolated from lymphocytes. All exons and intron borders of 7 LQTS susceptibility genes were amplified and sequenced. Variations were detected predicting a novel missense mutation (V110I) in KCNQ1, as well as a common polymorphism in KCNH2 (K897T). We expressed wild-type (WT) or V110I Kv7.1 channels in CHO-K1 cells cotransfected with KCNE1 and performed patch-clamp analysis. In addition, WT or K897T Kv11.1 were also studied by patch clamp. Current–voltage (I-V) relations for V110I showed a significant reduction in both developing and tail current densities compared to WT at potentials >+20 mV (p < 0.05; n = 8 cells, each group), suggesting a reduction in IKs currents. K897T- Kv11.1 channels displayed a significantly reduced tail current density compared with WT-Kv11.1 at potentials >+10 mV. Interestingly, channel availability assessed using a triple-pulse protocol was slightly greater for K897T compared with WT (V0.5 = −53.1 ± 1.13 mV and −60.7 ± 1.15 mV for K897T and WT, respectively; p < 0.05). Comparison of the fully activated I-V revealed no difference in the rectification properties between WT and K897T channels. We report a patient with a loss-of-function mutation in KCNQ1 and a loss-of-function polymorphism in KCNH2. Our results suggest that a reduction of both IKr and IKs underlies the combined LQT1 and LQT2 phenotype observed in this patient.
doi:10.1139/y10-094
PMCID: PMC3076201  PMID: 21164565
genetics; arrhythmias; electrophysiology; HERG
6.  Congenital long QT syndrome: A case report 
Journal of Thoracic Disease  2010;2(3):185-188.
The congenital long QT syndrome (LQTS) is characterized by abnormally prolonged ventricular repolarization due to inherited defects in cardiac sodium and potassium channels, which predispose the patients to syncope, seizure like activity, ventricular arrhythmias, and sudden cardiac death. Early diagnosis and preventive treatment are instrumental in preventing sudden cardiac deaths in patients with the congenital LQTS. The diagnostic criteria for congenital LQTS are based on certain electrocardiographic findings, clinical findings and findings of epinephrine stress test. Recently genotype specific electrocardiographic pattern in the congenital LQTS has also been described. Recent studies suggest feasibility of genotype specific treatment of LQTS and, in near future, mutation specific treatment will probably become a novel approach to this potentially fatal syndrome. We describe one case that fulfilled the electrocardiographic, historical diagnostic criteria and epinephrine stress test suggestive of LQT syndrome.
doi:10.3978/j.issn.2072-1439.2010.02.03.12
PMCID: PMC3256463  PMID: 22263042
congenital long QT syndrome; cardiac sodium; potassium channels
7.  Founder mutations characterise the mutation panorama in 200 Swedish index cases referred for Long QT syndrome genetic testing 
Background
Long QT syndrome (LQTS) is an inherited arrhythmic disorder characterised by prolongation of the QT interval on ECG, presence of syncope and sudden death. The symptoms in LQTS patients are highly variable, and genotype influences the clinical course. This study aims to report the spectrum of LQTS mutations in a Swedish cohort.
Methods
Between March 2006 and October 2009, two hundred, unrelated index cases were referred to the Department of Clinical Genetics, Umeå University Hospital, Sweden, for LQTS genetic testing. We scanned five of the LQTS-susceptibility genes (KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2) for mutations by DHPLC and/or sequencing. We applied MLPA to detect large deletions or duplications in the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes. Furthermore, the gene RYR2 was screened in 36 selected LQTS genotype-negative patients to detect cases with the clinically overlapping disease catecholaminergic polymorphic ventricular tachycardia (CPVT).
Results
In total, a disease-causing mutation was identified in 103 of the 200 (52%) index cases. Of these, altered exon copy numbers in the KCNH2 gene accounted for 2% of the mutations, whereas a RYR2 mutation accounted for 3% of the mutations. The genotype-positive cases stemmed from 64 distinct mutations, of which 28% were novel to this cohort. The majority of the distinct mutations were found in a single case (80%), whereas 20% of the mutations were observed more than once. Two founder mutations, KCNQ1 p.Y111C and KCNQ1 p.R518*, accounted for 25% of the genotype-positive index cases. Genetic cascade screening of 481 relatives to the 103 index cases with an identified mutation revealed 41% mutation carriers who were at risk of cardiac events such as syncope or sudden unexpected death.
Conclusion
In this cohort of Swedish index cases with suspected LQTS, a disease-causing mutation was identified in 52% of the referred patients. Copy number variations explained 2% of the mutations and 3 of 36 selected cases (8%) harboured a mutation in the RYR2 gene. The mutation panorama is characterised by founder mutations (25%), even so, this cohort increases the amount of known LQTS-associated mutations, as approximately one-third (28%) of the detected mutations were unique.
doi:10.1186/1471-2261-12-95
PMCID: PMC3520728  PMID: 23098067
Arrhythmia; Long QT syndrome; Ion-channel; Founder mutation; Variant of unknown significance
8.  KCNQ1 mutations in patients with a family history of lethal cardiac arrhythmias and sudden death 
Clinical genetics  2003;63(4):273-282.
Long QT syndrome (LQTS) is the prototype of the cardiac ion channelopathies which cause syncope and sudden death. LQT1, due to mutations of KCNQ1 (KVLQT1), is the most common form. This study describes the genotype–phenotype characteristics in 10 families with mutations of KCNQ1, including 5 novel mutations. One hundred and two families with a history of lethal cardiac events, 55 LQTS, 9 Brugada syndrome, 18 idiopathic ventricular fibrillation (IVF), and 20 acquired LQTS, were studied by single-strand conformational polymorphism (SSCP) and DNA sequence analyzes. Families found to have KCNQ1 mutations were phenotyped using ECG parameters and cardiac event history, and genotype–phenotype correlation was performed. No mutations were found in Brugada syndrome, IVF, or acquired LQTS families. Ten out of 55 LQTS families had KCNQ1 mutations and 62 carriers were identified. Mutations included G269S in domain S5; W305X, G314C, Y315C, and D317N in the pore region; A341E and Q357R in domain S6; and 1338insC, G568A and T587M mutations in the C-terminus. W305X, G314C, Q357R, 1338insC, and G568A, appeared to be novel mutations. Gene carriers were 26 ± 19 years (32 females). Baseline QTc was 0.47 ± 0.03 s (range 0.40–0.57 s) and 40% had normal to borderline QTc (≤0.46 s). Typical LQT1 T wave patterns were present in at least one affected member of each family, and in 73% of all affected members. A history of cardiac events was present in 19/62 (31%), 18 with syncope, 2 with aborted cardiac arrest (ACA) and six with sudden death (SD). Two out of 6 SDs (33%) occurred as the first symptom. No difference in phenotype was evident in pore vs. non-pore mutations. KCNQ1 mutations were limited to LQTS families. All five novel mutations produced a typical LQT1 phenotype. Findings emphasize (1) reduced penetrance of QTc and symptoms, resulting in diagnostic challenges, (2) the problem of sudden death as the first symptom (33% of those who died), and (3) genetic testing is important for identification of gene carriers with reduced penetrance, in order to provide treatment and to prevent lethal cardiac arrhythmias and sudden death.
PMCID: PMC1579805  PMID: 12702160
arrhythmias; ECG; KVLQT1/KCNQ1; long QT syndrome; mutations; sudden death
9.  Clinical Aspects of Type-1 Long-QT Syndrome by Location, Coding Type, and Biophysical Function of Mutations Involving the KCNQ1 Gene 
Circulation  2007;115(19):2481-2489.
Background
Type-1 long-QT syndrome (LQTS) is caused by loss-of-function mutations in the KCNQ1-encoded IKs cardiac potassium channel. We evaluated the effect of location, coding type, and biophysical function of KCNQ1 mutations on the clinical phenotype of this disorder.
Methods and Results
We investigated the clinical course in 600 patients with 77 different KCNQ1 mutations in 101 proband-identified families derived from the US portion of the International LQTS Registry (n=425), the Netherlands’ LQTS Registry (n=93), and the Japanese LQTS Registry (n=82). The Cox proportional hazards survivorship model was used to evaluate the independent contribution of clinical and genetic factors to the first occurrence of time-dependent cardiac events from birth through age 40 years. The clinical characteristics, distribution of mutations, and overall outcome event rates were similar in patients enrolled from the 3 geographic regions. Biophysical function of the mutations was categorized according to dominant-negative (>50%) or haploinsufficiency (≤50%) reduction in cardiac repolarizing IKs potassium channel current. Patients with transmembrane versus C-terminus mutations (hazard ratio, 2.06; P<0.001) and those with mutations having dominant-negative versus haploinsufficiency ion channel effects (hazard ratio, 2.26; P<0.001) were at increased risk for cardiac events, and these genetic risks were independent of traditional clinical risk factors.
Conclusions
This genotype–phenotype study indicates that in type-1 LQTS, mutations located in the transmembrane portion of the ion channel protein and the degree of ion channel dysfunction caused by the mutations are important independent risk factors influencing the clinical course of this disorder.
doi:10.1161/CIRCULATIONAHA.106.665406
PMCID: PMC3332528  PMID: 17470695
electrocardiography; genetics; long-QT syndrome
10.  LQTS Gene LOVD Database 
Human Mutation  2010;31(11):E1801-E1810.
The Long QT Syndrome (LQTS) is a group of genetically heterogeneous disorders that predisposes young individuals to ventricular arrhythmias and sudden death. LQTS is mainly caused by mutations in genes encoding subunits of cardiac ion channels (KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2). Many other genes involved in LQTS have been described recently (KCNJ2, AKAP9, ANK2, CACNA1C, SCNA4B, SNTA1, and CAV3). We created an online database (http://www.genomed.org/LOVD/introduction.html) that provides information on variants in LQTS-associated genes. As of February 2010, the database contains 1738 unique variants in 12 genes. A total of 950 variants are considered pathogenic, 265 are possible pathogenic, 131 are unknown/unclassified, and 292 have no known pathogenicity. In addition to these mutations collected from published literature, we also submitted information on gene variants, including one possible novel pathogenic mutation in the KCNH2 splice site found in ten Chinese families with documented arrhythmias. The remote user is able to search the data and is encouraged to submit new mutations into the database. The LQTS database will become a powerful tool for both researchers and clinicians. © 2010 Wiley-Liss, Inc.
doi:10.1002/humu.21341
PMCID: PMC3037562  PMID: 20809527
Long QT Syndrome; Arrhythmia; LOVD; Mutation database
11.  Atrial Fibrillation and Long QT Syndrome Presenting in a 12-Year-Old Girl 
Case Reports in Pediatrics  2012;2012:124838.
Atrial fibrillation (AF) is rare in the pediatric population; however, there is increasing recognition that AF can be inherited. Long QT syndrome (LQTS), likewise, can be both acquired and inherited with mutations leading to abnormalities in cardiac ion channel function. Mutations in KCNQ1 are the most common cause of LQTS. Although rare, mutations in KCNQ1 also can cause familial AF. This report describes a child with a KCNQ1 missense mutation who uniquely expresses concomitant AF and LQTS. Due to the potential for increased morbidity and mortality, young patients who present with AF and a family history suggestive of inherited arrhythmias should trigger further investigation for LQTS and subsequent familial genetic counseling.
doi:10.1155/2012/124838
PMCID: PMC3501806  PMID: 23193492
12.  Recent progress in congenital long QT syndrome 
Current Opinion in Cardiology  2010;25(3):216-221.
Purpose of review
As genetic testing for long QT syndrome (LQTS) has become readily available, important advances are being made in understanding the exact link between ion channel mutation and observed phenotype. This paper reviews recent findings in the literature.
Recent findings
Congenital LQTS is an important cause of sudden cardiac death. To date, 12 genes have been identified as the cause of congenital LQTS. With increasing availability of genetic testing, subtype-specific management of LQTS has become the standard of care. Detailed correlative studies between LQTS mutations and clinical phenotypes are leading the field towards ‘mutation-specific’ management within LQTS subtypes. A clear link between the distinct functional/biophysical defect in each LQT mutation and disease phenotype is complicated by the variable penetrance and pleiotropic expression of clinical phenotype. This is especially evident with the overlap syndrome now documented for several sodium channel (SCN5A) mutations.
Summary
The management of LQTS has become subtype-specific due to the availability of genotype information. Review of recent literature suggests that ‘mutation-specific’ management is possible based upon distinct functional/biophysical characteristics of mutations within each LQT gene. Further research is required to clearly delineate the molecular and cellular mechanisms underlying variable penetrance, and pleiotropic expression of LQTS mutations.
doi:10.1097/HCO.0b013e32833846b3
PMCID: PMC3151313  PMID: 20224391
genetics; ion channels; long QT syndrome; mutation-specific management; sudden cardiac death
13.  Genotype-phenotype analysis of three Chinese families with Jervell and Lange-Nielsen syndrome 
Background:
Long QT syndrome (LQTS) is characterized by QT prolongation, syncope and sudden death. This study aims to explore the causes, clinical manifestations and therapeutic outcomes of Jervell and Lange-Nielsen syndrome (JLNS), a rare form of LQTS with congenital sensorineural deafness, in Chinese individuals.
Materials and Methods:
Three JLNS kindreds from the Chinese National LQTS Registry were investigated. Mutational screening of KCNQ1 and KCNE1 genes was performed by polymerase chain reaction and direct DNA sequence analysis. LQTS phenotype and therapeutic outcomes were evaluated for all probands and family members.
Results:
We identified 7 KCNQ1 mutations. c.1032_1117dup (p.Ser373TrpfsX10) and c.1319delT (p.Val440AlafsX26) were novel, causing JLNS in a 16-year-old boy with a QTc (QT interval corrected for heart rate) of 620 ms and recurrent syncope. c.605-2A>G and c.815G>A (p.Gly272Asp) caused JLNS in a 12-year-old girl and her 5-year-old brother, showing QTc of 590 to 600 ms and recurrent syncope. The fourth JLNS case, a 46-year-old man carrying c.1032G>A (p.Ala344Alasp) and c.569G>A (p.Arg190Gln) and with QTc of 460 ms, has been syncope-free since age 30. His 16-year-old daughter carries novel missense mutation c.574C>T (p.Arg192Cys) and c.1032G>A(p.Ala344Alasp) and displayed a severe phenotype of Romano-Ward syndrome (RWS) characterized by a QTc of 530 ms and recurrent syncope with normal hearing. Both the father and daughter also carried c.253G>A (p.Asp85Asn; rs1805128), a rare single nucleotide polymorphism (SNP) on KCNE1. Bizarre T waves were seen in 3/4 JLNS patients. Symptoms were improved and T wave abnormalities became less abnormal after appropriate treatment.
Conclusion:
This study broadens the mutation and phenotype spectrums of JLNS. Compound heterozygous KCNQ1 mutations can result in both JLNS and severe forms of RWS in Chinese individuals.
doi:10.4103/0975-3583.95357
PMCID: PMC3354473  PMID: 22629021
Compound heterozygous mutation; frameshift mutation; Jervell and Lange-Nielsen syndrome; KCNQ1; KCNE1; long QT syndrome; Romano-Ward syndrome; single nucleotide polymorphism
14.  Congenital long QT syndrome 
Congenital long QT syndrome (LQTS) is a hereditary cardiac disease characterized by a prolongation of the QT interval at basal ECG and by a high risk of life-threatening arrhythmias. Disease prevalence is estimated at close to 1 in 2,500 live births.
The two cardinal manifestations of LQTS are syncopal episodes, that may lead to cardiac arrest and sudden cardiac death, and electrocardiographic abnormalities, including prolongation of the QT interval and T wave abnormalities. The genetic basis of the disease was identified in the mid-nineties and all the LQTS genes identified so far encode cardiac ion channel subunits or proteins involved in modulating ionic currents. Mutations in these genes (KCNQ1, KCNH2, KCNE1, KCNE2, CACNA1c, CAV3, SCN5A, SCN4B) cause the disease by prolonging the duration of the action potential. The most prevalent LQTS variant (LQT1) is caused by mutations in the KCNQ1 gene, with approximately half of the genotyped patients carrying KCNQ1 mutations.
Given the characteristic features of LQTS, the typical cases present no diagnostic difficulties for physicians aware of the disease. However, borderline cases are more complex and require the evaluation of various electrocardiographic, clinical, and familial findings, as proposed in specific diagnostic criteria. Additionally, molecular screening is now part of the diagnostic process.
Treatment should always begin with β-blockers, unless there are valid contraindications. If the patient has one more syncope despite a full dose β-blockade, left cardiac sympathetic denervation (LCSD) should be performed without hesitation and implantable cardioverter defibrillator (ICD) therapy should be considered with the final decision being based on the individual patient characteristics (age, sex, clinical history, genetic subgroup including mutation-specific features in some cases, presence of ECG signs – including 24-hour Holter recordings – indicating high electrical instability).
The prognosis of the disease is usually good in patients that are correctly diagnosed and treated. However, there are a few exceptions: patients with Timothy syndrome, patients with Jervell Lange-Nielsen syndrome carrying KCNQ1 mutations and LQT3 patients with 2:1 atrio-ventricular block and very early occurrence of cardiac arrhythmias.
doi:10.1186/1750-1172-3-18
PMCID: PMC2474834  PMID: 18606002
15.  Model for long QT syndrome type 2 using human iPS cells demonstrates arrhythmogenic characteristics in cell culture 
Disease Models & Mechanisms  2011;5(2):220-230.
SUMMARY
Long QT syndrome (LQTS) is caused by functional alterations in cardiac ion channels and is associated with prolonged cardiac repolarization time and increased risk of ventricular arrhythmias. Inherited type 2 LQTS (LQT2) and drug-induced LQTS both result from altered function of the hERG channel. We investigated whether the electrophysiological characteristics of LQT2 can be recapitulated in vitro using induced pluripotent stem cell (iPSC) technology. Spontaneously beating cardiomyocytes were differentiated from two iPSC lines derived from an individual with LQT2 carrying the R176W mutation in the KCNH2 (HERG) gene. The individual had been asymptomatic except for occasional palpitations, but his sister and father had died suddenly at an early age. Electrophysiological properties of LQT2-specific cardiomyocytes were studied using microelectrode array and patch-clamp, and were compared with those of cardiomyocytes derived from control cells. The action potential duration of LQT2-specific cardiomyocytes was significantly longer than that of control cardiomyocytes, and the rapid delayed potassium channel (IKr) density of the LQT2 cardiomyocytes was significantly reduced. Additionally, LQT2-derived cardiac cells were more sensitive than controls to potentially arrhythmogenic drugs, including sotalol, and demonstrated arrhythmogenic electrical activity. Consistent with clinical observations, the LQT2 cardiomyocytes demonstrated a more pronounced inverse correlation between the beating rate and repolarization time compared with control cells. Prolonged action potential is present in LQT2-specific cardiomyocytes derived from a mutation carrier and arrhythmias can be triggered by a commonly used drug. Thus, the iPSC-derived, disease-specific cardiomyocytes could serve as an important platform to study pathophysiological mechanisms and drug sensitivity in LQT2.
doi:10.1242/dmm.008409
PMCID: PMC3291643  PMID: 22052944
16.  Fever-induced QTc prolongation and ventricular arrhythmias in individuals with type 2 congenital long QT syndrome 
The Journal of Clinical Investigation  2008;118(7):2552-2561.
Type 2 congenital long QT syndrome (LQT-2) is linked to mutations in the human ether a-go-go–related gene (HERG) and is characterized by rate-corrected QT interval (QTc) prolongation, ventricular arrhythmias, syncope, and sudden death. Recognized triggers of these cardiac events include emotional and acoustic stimuli. Here we investigated the repeated occurrence of fever-induced polymorphic ventricular tachycardia and ventricular fibrillation in 2 LQT-2 patients with A558P missense mutation in HERG. ECG analysis showed increased QTc with fever in both patients. WT, A558P, and WT+A558P HERG were expressed heterologously in HEK293 cells and were studied using biochemical and electrophysiological techniques. A558P proteins showed a trafficking-deficient phenotype. WT+A558P coexpression caused a dominant-negative effect, selectively accelerated the rate of channel inactivation, and reduced the temperature-dependent increase in the WT current. Thus, the WT+A558P current did not increase to the same extent as the WT current, leading to larger current density differences at higher temperatures. A similar temperature-dependent phenotype was seen for coexpression of the trafficking-deficient LQT-2 F640V mutation. We postulate that the weak increase in the HERG current density in WT-mutant coassembled channels contributes to the development of QTc prolongation and arrhythmias at febrile temperatures and suggest that fever is a potential trigger of life-threatening arrhythmias in LQT-2 patients.
doi:10.1172/JCI35337
PMCID: PMC2423868  PMID: 18551196
17.  Long QT Syndrome: a Korean Single Center Study 
Journal of Korean Medical Science  2013;28(10):1454-1460.
The long QT syndrome (LQTS) is a rare hereditary disorder in which affected individuals have a possibility of ventricular tachyarrhythmia and sudden cardiac death. We investigated 62 LQTS (QTc ≥ 0.47 sec) and 19 family members whose genetic study revealed mutation of LQT gene. In the proband group, the modes of presentation were ECG abnormality (38.7%), aborted cardiac arrest (24.2%), and syncope or seizure (19.4%). Median age of initial symptom development was 10.5 yr. Genetic studies were performed in 61; and mutations were found in 40 cases (KCNQ1 in 19, KCNH2 in 10, SCN5A in 7, KCNJ2 in 3, and CACNA1C in 1). In the family group, the penetrance of LQT gene mutation was 57.9%. QTc was longer as patients had the history of syncope (P = 0.001), ventricular tachycardia (P = 0.017) and aborted arrest (P = 0.010). QTc longer than 0.508 sec could be a cut-off value for major cardiac events (sensitivity 0.806, specificity 0.600). Beta-blocker was frequently applied for treatment and had significant effects on reducing QTc (P = 0.007). Implantable cardioverter defibrillators were applied in 6 patients. Congenital LQTS is a potentially lethal disease. It shows various genetic mutations with low penetrance in Korean patients.
doi:10.3346/jkms.2013.28.10.1454
PMCID: PMC3792599  PMID: 24133349
Long QT Syndrome; Tachycardia; Heart Ventricles; Mutation
18.  Identification of a possible pathogenic link between congenital long QT syndrome and epilepsy 
Neurology  2009;72(3):224-231.
Background:
Long QT syndrome (LQTS) typically presents with syncope, seizures, or sudden death. Patients with LQTS have been misdiagnosed with a seizure disorder or epilepsy and treated with antiepileptic drug (AED) medication. The gene, KCNH2, responsible for type 2 LQTS (LQT2), was cloned originally from the hippocampus and encodes a potassium channel active in hippocampal astrocytes. We sought to test the hypothesis that a “seizure phenotype” was ascribed more commonly to patients with LQT2.
Methods:
Charts were reviewed for 343 consecutive, unrelated patients (232 females, average age at diagnosis 27 ± 18 years, QTc 471 ± 57 msec) clinically evaluated and genetically tested for LQTS from 1998 to 2006 at two large LQTS referral centers. A positive seizure phenotype was defined as the presence of either a personal or family history of seizures or history of AED therapy.
Results:
A seizure phenotype was recorded in 98/343 (29%) probands. A seizure phenotype was more common in LQT2 (36/77, 47%) than LQT1 (16/72, 22%, p < 0.002) and LQT3 (7/28, 25%, p < 0.05, NS). LQT1 and LQT3 combined cohorts did not differ significantly from expected, background rates of a seizure phenotype. A personal history of seizures was more common in LQT2 (30/77, 39%) than all other subtypes of LQTS (11/106, 10%, p < 0.001).
Conclusions:
A diagnostic consideration of epilepsy and treatment with antiepileptic drug medications was more common in patients with LQT2. Like noncardiac organ phenotypes observed in other LQTS-susceptibility genes such as KCNQ1/deafness and SCN5A/gastrointestinal symptoms, this novel LQT2-epilepsy association raises the possibility that LQT2-causing perturbations in the KCNH2-encoded potassium channel may confer susceptibility for recurrent seizure activity.
GLOSSARY
= antiepileptic drug;
= type 1 LQTS;
= type 2 LQTS;
= long QT syndrome;
= torsades de pointes.
doi:10.1212/01.wnl.0000335760.02995.ca
PMCID: PMC2677528  PMID: 19038855
19.  Novel characteristics of a trafficking-defective G572R-hERG channel linked to hereditary long QT syndrome 
BACKGROUND:
The congenital long QT syndrome is a heterogeneous genetic disease associated with delayed cardiac repolarization, prolonged QT intervals, the development of ventricular arrhythmias and sudden death. Type 2 congenital long QT syndrome (LQT2) results from KCNH2 or hERG gene mutations. hERG encodes the Kv11.1 alpha subunit of the rapidly activating delayed rectifier K+ current in the heart. Studies of mutant hERG channels indicate that most LQT2 missense mutations generate trafficking-deficient Kv11.1 channels.
OBJECTIVE:
To identify the mechanism underlying G572R-hERG by using molecular and electrophysiological analyses.
METHODS AND RESULTS:
To elucidate the electrophysiological properties of the G572R-hERG mutant channels, mutant hERG subunits were heterologously expressed in HEK293 cells alone or in combination with wild-type (WT)-hERG subunits. Patch-clamp techniques were used to record currents, and double immunofluorescence protein tagging and Western blotting were performed to examine the cellular trafficking of mutant subunits. When expressed alone, G572R-hERG subunits were not present in the cell membrane and did not produce detectable currents. When coexpressed with WT-hERG subunits, G572R-hERG decreased current density and altered gating properties of the WT-hERG channel.
CONCLUSION:
The hERG-associated missense mutation G572R, like most LQT2 missense mutations, generates a trafficking-deficient phenotype. Furthermore, G572R-hERG causes a loss of function in hERG by a strong dominant negative effect on the WT-hERG channel.
PMCID: PMC2954534  PMID: 20931094
hERG; Long QT syndrome; Mutation; Potassium channel; Protein trafficking
20.  KCNE1 D85N polymorphism — a sex-specific modifier in type 1 long QT syndrome? 
BMC Medical Genetics  2011;12:11.
Background
Long QT syndrome (LQTS) is an inherited ion channel disorder manifesting with prolongation of the cardiac repolarization phase and severe ventricular arrhythmias. The common KCNE1 D85N potassium channel variant prolongs QT interval by inhibiting IKs (KCNQ1) and IKr (KCNH2) currents and is therefore a suitable candidate for a modifier gene in LQTS.
Methods
We studied the effect of D85N on age-, sex-, and heart rate-adjusted QT-interval duration by linear regression in LQTS patients carrying the Finnish founder mutations KCNQ1 G589D (n = 492), KCNQ1 IVS7-2A>G (n = 66), KCNH2 L552S (n = 73), and KCNH2 R176W (n = 88). We also investigated the association between D85N and clinical variables reflecting the severity of the disease.
Results
D85N was associated with a QT prolongation by 26 ms (SE 8.6, p = 0.003) in males with KCNQ1 G589D (n = 213), but not in females with G589D (n = 279). In linear regression, the interaction between D85N genotype and sex was significant (p = 0.028). Within the KCNQ1 G589D mutation group, KCNE1 D85N carriers were more often probands of the family (p = 0.042) and were more likely to use beta blocker medication (p = 0.010) than non-carriers. The number of D85N carriers in other founder mutation groups was too small to assess its effects.
Conclusions
We propose that KCNE1 D85N is a sex-specific QT-interval modifier in type 1 LQTS and may also associate with increased severity of disease. Our data warrant additional studies on the role of KCNE1 D85N in other genetically homogeneous groups of LQTS patients.
doi:10.1186/1471-2350-12-11
PMCID: PMC3032654  PMID: 21244686
21.  Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION® long QT syndrome genetic test 
BACKGROUND
Long QT syndrome (LQTS) is a potentially lethal, highly treatable cardiac channelopathy for which genetic testing has matured from discovery to translation and now clinical implementation.
OBJECTIVES
Here we examine the spectrum and prevalence of mutations found in the first 2,500 unrelated cases referred for the FAMILION® LQTS clinical genetic test.
METHODS
Retrospective analysis of the first 2,500 cases (1,515 female patients, average age at testing 23 ± 17 years, range 0 to 90 years) scanned for mutations in 5 of the LQTS-susceptibility genes: KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 (LQT5), and KCNE2 (LQT6).
RESULTS
Overall, 903 referral cases (36%) hosted a possible LQTS-causing mutation that was absent in >2,600 reference alleles; 821 (91%) of the mutation-positive cases had single genotypes, whereas the remaining 82 patients (9%) had >1 mutation in ≥1 gene, including 52 cases that were compound heterozygous with mutations in >1 gene. Of the 562 distinct mutations, 394 (70%) were missense, 428 (76%) were seen once, and 336 (60%) are novel, including 92 of 199 in KCNQ1, 159 of 226 in KCNH2, and 70 of 110 in SCN5A.
CONCLUSION
This cohort increases the publicly available compendium of putative LQTS-associated mutations by >50%, and approximately one-third of the most recently detected mutations continue to be novel. Although control population data suggest that the great majority of these mutations are pathogenic, expert interpretation of genetic test results will remain critical for effective clinical use of LQTS genetic test results.
doi:10.1016/j.hrthm.2009.05.021
PMCID: PMC3049907  PMID: 19716085
Long QT syndrome; Genetic testing; Potassium channels; Sodium channels
22.  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 3 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 −40mV following a 2 sec step to +60mV 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). Co-transfection 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.
doi:10.1111/j.1540-8167.2007.00889.x
PMCID: PMC2085492  PMID: 17655673
Ion channel; Mutation; Inherited syndrome; Electrophysiology; Torsade de Pointes
23.  Sodium overload due to a persistent current that attenuates the arrhythmogenic potential of a novel LQT3 mutation 
Long QT syndrome (LQTS) is a congenital abnormality of cardiac repolarization that manifests as a prolonged QT interval on 12-lead electrocardiograms (ECGs). The syndrome may lead to syncope and sudden death from ventricular tachyarrhythmias known as torsades de pointes. An increased persistent Na+ current is known to cause a Ca2+ overload in case of ischemia for example. Such increased Na+ persistent current is also usually associated to the LQT3 syndrome. The purpose of this study was to investigate the pathological consequences of a novel mutation in a family affected by LQTS. The impact of biophysical defects on cellular homeostasis are also investigated. Genomic DNA was extracted from blood samples, and a combination of PCR and DNA sequencing of several LQTS-linked genes was used to identify mutations. The mutation was reproduced in vitro and was characterized using the patch clamp technique and in silico quantitative analysis. A novel mutation (Q1476R) was identified on the SCN5A gene encoding the cardiac Na+ channel. Cells expressing the Q1476R mutation exhibited biophysical alterations, including a shift of SS inactivation and a significant increase in the persistent Na+ current. The in silico analysis confirmed the arrhythmogenic character of the Q1476R mutation. It further revealed that the increase in persistent Na+ current causes a frequency-dependent Na+ overload in cardiomyocytes co-expressing WT and mutant Nav1.5 channels that, in turn, exerts a moderating effect on the lengthening of the action potential (AP) duration caused by the mutation. The Q1476R mutation in SCN5A results in a three-fold increase in the window current and a persistent inward Na+ current. These biophysical defects may expose the carrier of the mutation to arrhythmias that occur preferentially in the patient at rest or during tachycardia. However, the Na+ overload counterbalances the gain-of-function of the mutation and is beneficial in that it prevents severe arrhythmias at intermediate heart rates.
doi:10.3389/fphar.2013.00126
PMCID: PMC3787509  PMID: 24098284
cardiac arrhythmia; electrophysiology; Nav1.5; long QT syndrome; LQT3; sodium overload; heart
24.  Functional Interactions between KCNE1 C-Terminus and the KCNQ1 Channel 
PLoS ONE  2009;4(4):e5143.
The KCNE1 gene product (minK protein) associates with the cardiac KvLQT1 potassium channel (encoded by KCNQ1) to create the cardiac slowly activating delayed rectifier, IKs. Mutations throughout both genes are linked to the hereditary cardiac arrhythmias in the Long QT Syndrome (LQTS). KCNE1 exerts its specific regulation of KCNQ1 activation via interactions between membrane-spanning segments of the two proteins. Less detailed attention has been focused on the role of the KCNE1 C-terminus in regulating channel behavior. We analyzed the effects of an LQT5 point mutation (D76N) and the truncation of the entire C-terminus (Δ70) on channel regulation, assembly and interaction. Both mutations significantly shifted voltage dependence of activation in the depolarizing direction and decreased IKs current density. They also accelerated rates of channel deactivation but notably, did not affect activation kinetics. Truncation of the C-terminus reduced the apparent affinity of KCNE1 for KCNQ1, resulting in impaired channel formation and presentation of KCNQ1/KCNE1 complexes to the surface. Complete saturation of KCNQ1 channels with KCNE1-Δ70 could be achieved by relative over-expression of the KCNE subunit. Rate-dependent facilitation of K+ conductance, a key property of IKs that enables action potential shortening at higher heart rates, was defective for both KCNE1 C-terminal mutations, and may contribute to the clinical phenotype of arrhythmias triggered by heart rate elevations during exercise in LQTS mutations. These results support several roles for KCNE1 C-terminus interaction with KCNQ1: regulation of channel assembly, open-state destabilization, and kinetics of channel deactivation.
doi:10.1371/journal.pone.0005143
PMCID: PMC2659744  PMID: 19340287
25.  Characterization of novel KCNH2 mutations in type 2 long QT syndrome manifesting as seizures 
BACKGROUND
Long QT syndrome (LQTS) is characterized by corrected QT interval prolongation leading to torsades de pointes and sudden cardiac death. LQTS type 2 (LQTS2) is caused by mutations in the KCNH2 gene, leading to a reduction of the rapidly activating delayed rectifier K+ current and loss of human ether-à-go-go-related gene (hERG) channel function by different mechanisms. Triggers for life-threatening arrhythmias in LQTS2 are often auditory stimuli.
OBJECTIVES
To screen KCNH2 for mutations in patients with LQTS2 on an electrocardiogram and auditory-induced syncope interpreted as seizures and sudden cardiac death, and to analyze their impact on the channel function in vitro.
METHODS
The KCNH2 gene was screened for mutations in the index patients of three families. The novel mutations were reproduced in vitro using site-directed mutagenesis and characterized using the Xenopus oocyte expression system in voltage clamp mode.
RESULTS
Novel KCNH2 mutations (Y493F, A429P and del234–241) were identified in the index patients with mostly typical LQTS2 features on their electrocardiograms. The biochemical data revealed a trafficking defect. The biophysical data revealed a loss of function when mutated hERG channels were coexpressed with the wild type.
CONCLUSIONS
In all families, at least one patient carrying the mutation had a history of seizures after auditory stimuli, which is a major trigger for arrhythmic events in LQTS2. Seizures are likely due to cardiac syncope as a consequence of mutation-induced loss of function of the rapidly activating delayed rectifier K+ current.
PMCID: PMC2732373  PMID: 19668779
KCNH2; Long QT syndrome type 2; Loss of IKr channel function; Potassium channel; Seizure; Sudden cardiac death

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