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1.  Genetic Testing for Long QT Syndrome - Distinguishing Pathogenic Mutations from Benign Variants 
Circulation  2009;120(18):1752-1760.
Genetic testing for long QT syndrome (LQTS) has diagnostic, prognostic, and therapeutic implications. Hundreds of causative mutations in 12 known LQTS-susceptibility genes have been identified. Genetic testing that includes the 3 most commonly mutated genes is available clinically. Distinguishing pathogenic mutations from innocuous rare variants is critical to the interpretation of test results. We sought to quantify the value of mutation type and gene/protein region in determining the probability of pathogenicity for mutations.
Methods and Results
Type, frequency, and location of mutations across KCNQ1 (LQT1), KCNH2 (LQT2) and SCN5A (LQT3) were compared between 388 unrelated “definite” (clinical diagnostic score > 4 and/or QTc > 480 ms) cases of LQTS and over 1300 healthy controls for each gene. From these data, estimated predictive values (EPV, meaning the percent of mutations found in definite cases that would be LQTS-causing) were determined according to mutation type and location. Mutations were 10× more common in cases than controls (0.58/case vs 0.06/control). Missense mutations were the most common, accounting for 78%, 67%, and 89% of mutations in KCNQ1, KCNH2, and SCN5A in cases and >95% in controls. Non-missense mutations have an EPV >99% regardless of location. In contrast, location appears to be critical for characterizing missense mutations. Relative frequency of missense mutations between cases and controls ranged from ~1:1 in the SCN5A interdomain linker (IDL) to infinity in KCNH2’s pore (P), transmembrane (TM), and linker (L). These correspond to EPVs ranging from 0% in the IDL of SCN5A to 100% in the TM/L/P regions of KCNH2. EPV is also high in KCNQ1’s L, P, TM, and C-terminus and the TM/L of SCN5A.
Distinguishing pathogenic mutations from rare variants is of critical importance in the interpretation of genetic testing in LQTS. Mutation type, mutation location, and ethnic specific background rates are critical factors in predicting pathogenicity of novel mutations. Novel mutations in low-EPV regions, such as the IDL of SCN5A, should be viewed as variants of uncertain significance (VUS) and prompt further investigation to clarify the likelihood of disease causation. However, mutations in regions such as the TM, L, and P of KCNQ1 and KCNH2 may be defined confidently as high probability LQTS-causing mutations. These findings will have implications for other genetic disorders involving mutational analysis.
PMCID: PMC3025752  PMID: 19841300
Genetics; Long-QT Syndrome; Ion Channels
2.  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.
PMCID: PMC2474834  PMID: 18606002
3.  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
4.  Long QT Syndrome–Associated Mutations in Intrauterine Fetal Death 
JAMA : the journal of the American Medical Association  2013;309(14):10.1001/jama.2013.3219.
Intrauterine fetal death or stillbirth occurs in approximately 1 out of every 160 pregnancies and accounts for 50% of all perinatal deaths. Postmortem evaluation fails to elucidate an underlying cause in many cases. Long QT syndrome (LQTS) may contribute to this problem.
To determine the spectrum and prevalence of mutations in the 3 most common LQTS susceptible genes (KCNQ1, KCNH2, and SCN5A) for a cohort of unexplained cases.
Design, Setting, and Patients
In this case series, retrospective postmortem genetic testing was conducted on a convenience sample of 91 unexplained intrauterine fetal deaths (mean [SD] estimated gestational age at fetal death, 26.3 [8.7] weeks) that were collected from 2006-2012 by the Mayo Clinic, Rochester, Minnesota, or the Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. More than 1300 ostensibly healthy individuals served as controls. In addition, publicly available exome databases were assessed for the general population frequency of identified genetic variants.
Main Outcomes and Measures
Comprehensive mutational analyses of KCNQ1 (KV7.1, LQTS type 1), KCNH2 (HERG/KV11.1, LQTS type 2), and SCN5A (NaV1.5, LQTS type 3) were performed using denaturing high-performance liquid chromatography and direct DNA sequencing on genomic DNA extracted from decedent tissue. Functional analyses of novel mutations were performed using heterologous expression and patch-clamp recording.
The 3 putative LQTS susceptibility missense mutations (KCNQ1, p.A283T; KCNQ1, p.R397W; and KCNH2[1b], p.R25W), with a heterozygous frequency of less than 0.05% in more than 10000 publicly available exomes and absent in more than 1000 ethnically similar control patients, were discovered in 3 intrauterine fetal deaths (3.3% [95% CI, 0.68%-9.3%]). Both KV7.1-A283T (16-week male) and KV7.1-R397W (16-week female) mutations were associated with marked KV7.1 loss-of-function consistent with in utero LQTS type 1, whereas the HERG1b-R25W mutation (33.2-week male) exhibited a loss of function consistent with in utero LQTS type 2. In addition, 5 intrauterine fetal deaths hosted SCN5A rare nonsynonymous genetic variants (p.T220I, p.R1193Q, involving 2 cases, and p.P2006A, involving 2 cases) that conferred in vitro electrophysiological characteristics consistent with potentially proarrhythmic phenotypes.
Conclusions and Relevance
In this molecular genetic evaluation of 91 cases of intrauterine fetal death, missense mutations associated with LQTS susceptibility were discovered in 3 cases (3.3%) and overall, genetic variants leading to dysfunctional LQTS-associated ion channels in vitro were discovered in 8 cases (8.8%). These preliminary findings may provide insights into mechanisms of some cases of stillbirth.
PMCID: PMC3852902  PMID: 23571586
5.  α-1-Syntrophin Mutation and the Long-QT Syndrome: A Disease of Sodium Channel Disruption 
Long-QT syndrome (LQTS) is an inherited disorder associated with sudden cardiac death. The cytoskeletal protein syntrophin-α1 (SNTA1) is known to interact with the cardiac sodium channel (hNav1.5), and we hypothesized that SNTA1 mutations might cause phenotypic LQTS in patients with genotypically normal hNav1.5 by secondarily disturbing sodium channel function.
Methods and Results
Mutational analysis of SNTA1 was performed on 39 LQTS patients (QTc≥480 ms) with previously negative genetic screening for the known LQTS-causing genes. We identified a novel A257G-SNTA1 missense mutation, which affects a highly conserved residue, in 3 unrelated LQTS probands but not in 400 ethnic-matched control alleles. Only 1 of these probands had a preexisting family history of LQTS and sudden death with an additional intronic variant in KCNQ1. Electrophysiological analysis was performed using HEK-293 cells stably expressing hNav1.5 and transiently transfected with either wild-type or mutant SNTA1 and, in neonatal rat cardiomyocytes, transiently transfected with either wild-type or mutant SNTA1. In both HEK-293 cells and neonatal rat cardiomyocytes, increased peak sodium currents were noted along with a 10-mV negative shift of the onset and peak of currents of the current-voltage relationships. In addition, A257G-SNTA1 shifted the steady-state activation (Vh) leftward by 9.4 mV, whereas the voltage-dependent inactivation kinetics and the late sodium currents were similar to wild-type SNTA1.
SNTA1 is a new susceptibility gene for LQTS. A257G-SNTA1 can cause gain-of-function of Nav1.5 similar to the LQT3.
PMCID: PMC2726717  PMID: 19684871
arrhythmia; death; sudden (if surviving; use heart arrest); ion channels; long-QT syndrome
6.  Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION® long QT syndrome genetic test 
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.
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.
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).
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.
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.
PMCID: PMC3049907  PMID: 19716085
Long QT syndrome; Genetic testing; Potassium channels; Sodium channels
7.  R231C mutation in KCNQ1 causes long QT syndrome type 1 and familial atrial fibrillation 
Loss-of-function mutations in the gene KCNQ1 encoding the Kv7.1 K+ channel cause long QT syndrome type 1 (LQT1), whereas gain-of-function mutations are associated with short QT syndrome as well as familial atrial fibrillation (FAF). However, KCNQ1 mutation pleiotropy, which is capable of expressing both LQT1 and FAF, has not been demonstrated for a discrete KCNQ1 mutation. The genotype–phenotype relationship for a family with FAF suggests a possible association with the LQT1 p.Arg231Cys-KCNQ1 (R231C-Q1) mutation.
The purpose of this study was to determine whether R231C-Q1 also can be linked to FAF.
The R231C-Q1 proband with AF underwent genetic testing for possible mutations in 10 other AF-linked genes plus KCNH2 and SCN5A. Sixteen members from five other R231C-positive LQT1 families were genetically tested for 21 single nucleotide polymorphisms (SNPs) to determine if the FAF family had discriminatory SNPs associated with AF. R231C-Q1 was expressed with KCNE1 (E1) in HEK293 cells, and Q1E1 currents (IQ1E1) were analyzed using the whole-cell patch-clamp technique.
Genetic analyses revealed no additional mutations or discriminatory SNPs. Cells expressing WT-Q1 and R231C-Q1 exhibited some constitutively active IQ1E1 and smaller maximal IQ1E1 compared to cells expressing WT-Q1.
Constitutively active IQ1E1 and a smaller peak IQ1E1 are common features of FAF-associated and LQT1-associated mutations, respectively. These data suggest that the mixed functional properties of R231C-Q1 may predispose some families to LQT1 or FAF. We conclude that R231C is a pleiotropic missense mutation capable of LQT1 expression, AF expression, or both.
PMCID: PMC3706092  PMID: 20850564
Atrial fibrillation; Familial atrial fibrillation; Genetics; Ion channel; KCNQ1; Long QT syndrome; Long QT syndrome type 1
8.  Identification of a possible pathogenic link between congenital long QT syndrome and epilepsy 
Neurology  2009;72(3):224-231.
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.
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.
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).
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.
= antiepileptic drug;
= type 1 LQTS;
= type 2 LQTS;
= long QT syndrome;
= torsades de pointes.
PMCID: PMC2677528  PMID: 19038855
9.  Founder mutations characterise the mutation panorama in 200 Swedish index cases referred for Long QT syndrome genetic testing 
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.
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).
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.
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.
PMCID: PMC3520728  PMID: 23098067
Arrhythmia; Long QT syndrome; Ion-channel; Founder mutation; Variant of unknown significance
10.  Mutations in Danish patients with long QT syndrome and the identification of a large founder family with p.F29L in KCNH2 
BMC Medical Genetics  2014;15:31.
Long QT syndrome (LQTS) is a cardiac ion channelopathy which presents clinically with palpitations, syncope or sudden death. More than 700 LQTS-causing mutations have been identified in 13 genes, all of which encode proteins involved in the execution of the cardiac action potential. The most frequently affected genes, covering > 90% of cases, are KCNQ1, KCNH2 and SCN5A.
We describe 64 different mutations in 70 unrelated Danish families using a routine five-gene screen, comprising KCNQ1, KCNH2 and SCN5A as well as KCNE1 and KCNE2.
Twenty-two mutations were found in KCNQ1, 28 in KCNH2, 9 in SCN5A, 3 in KCNE1 and 2 in KCNE2. Twenty-six of these have only been described in the Danish population and 18 are novel. One double heterozygote (1.4% of families) was found. A founder mutation, p.F29L in KCNH2, was identified in 5 “unrelated” families. Disease association, in 31.2% of cases, was based on the type of mutation identified (nonsense, insertion/deletion, frameshift or splice-site). Functional data was available for 22.7% of the missense mutations. None of the mutations were found in 364 Danish alleles and only three, all functionally characterised, were recorded in the Exome Variation Server, albeit at a frequency of < 1:1000.
The genetic etiology of LQTS in Denmark is similar to that found in other populations. A large founder family with p.F29L in KCNH2 was identified. In 48.4% of the mutations disease causation was based on mutation type or functional analysis.
PMCID: PMC4007532  PMID: 24606995
11.  Long QT syndrome in South Africa: the results of comprehensive genetic screening 
Cardiovascular Journal of Africa  2013;24(6):231-237.
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.
PMCID: PMC3772322  PMID: 24217263
LQTS; mutation; ion-channels; sudden death; arrhythmia
12.  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.
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.
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.
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).
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.
PMCID: PMC2570672  PMID: 18808722
13.  Prevalence and Spectrum of Large Deletions or Duplications in the Major Long QT Syndrome-Susceptibility Genes and Implications for Long QT Syndrome Genetic Testing 
The American journal of cardiology  2010;106(8):1124-1128.
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 three cardiac ion channel alpha-subunits (LQT1-3). However, traditional mutational analyses have limited detection capabilities for atypical mutations such as large gene rearrangements. Here, we set out to determine the prevalence and spectrum of large deletions/duplications in the major LQTS-susceptibility genes among unrelated patients who were mutation-negative following point mutation analysis of LQT1-12-susceptibility genes. Forty-two unrelated clinically strong LQTS patients were analyzed using multiplex ligation-dependent probe amplification (MLPA), a quantitative fluorescent technique for detecting multiple exon deletions and duplications. The SALSA-MLPA LQTS Kit from MRC-Holland was used to analyze the three major LQTS-associated genes: KCNQ1, KCNH2, and SCN5A and the two minor genes: KCNE1 and KCNE2. Overall, 2 gene rearrangements were found in 2/42 (4.8%, CI, 1.7–11%) unrelated patients. A deletion of KCNQ1 exon 3 was identified in a 10 year-old Caucasian boy with a QTc of 660 milliseconds (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 QTc of 480 ms, a personal history of exercise-induced syncope, and a family history of sudden cardiac death. In conclusion, since 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.
PMCID: PMC2950837  PMID: 20920651
Long QT syndrome; Genetic Testing; Sudden Cardiac Death; Gene Rearrangements
14.  Genotype-phenotype analysis of three Chinese families with Jervell and Lange-Nielsen syndrome 
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.
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.
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.
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
15.  Exome Sequencing and Systems Biology Converge to Identify Novel Mutations in the L-Type Calcium Channel, CACNA1C, Linked to Autosomal Dominant Long QT Syndrome 
Long QT syndrome (LQTS) is the most common cardiac channelopathy with 15 elucidated LQTS-susceptibility genes. Approximately 20% of LQTS cases remain genetically elusive.
Methods and Results
We combined whole exome sequencing (WES) and bioinformatic/systems biology to identify the pathogenic substrate responsible for non-syndromic, genotype-negative, autosomal dominant LQTS in a multigenerational pedigree and established the spectrum and prevalence of variants in the elucidated gene among a cohort of 102 unrelated patients with “genotype-negative/phenotype-positive” LQTS. WES was utilized on three members within a genotype-negative/phenotype-positive family. Genomic triangulation combined with bioinformatic tools and ranking algorithms led to the identification of a CACNA1C mutation. This mutation, Pro857Arg-CACNA1C, co-segregated with the disease within the pedigree, was ranked by three disease-network algorithms as the most probable LQTS-susceptibility gene, and involves a conserved residue localizing to the PEST domain in the II–III linker. Functional studies reveal that Pro857Arg-CACNA1C leads to a gain-of-function with increased ICa,L and increased surface membrane expression of the channel compared to wildtype. Subsequent mutational analysis identified 3 additional variants within CACNA1C in our cohort of 102 unrelated cases of genotype-negative/phenotype-positive LQTS. Two of these variants also involve conserved residues within Cav1.2’s PEST domain.
This study provides evidence that coupling WES and bioinformatic/systems biology is an effective strategy for the identification of potential disease causing genes/mutations. The identification of a functional CACNA1C mutation co-segregating with disease in a single pedigree suggests that CACNA1C perturbations may underlie autosomal dominant LQTS in the absence of Timothy syndrome.
PMCID: PMC3760222  PMID: 23677916
arrhythmia; calcium; genetics; ion channel; long QT syndrome
16.  Novel Chemical Suppressors of Long QT Syndrome Identified by an in vivo Functional Screen 
Circulation  2010;123(1):23-30.
Genetic long QT (LQT) syndrome is a life-threatening disorder caused by mutations that result in prolongation of cardiac repolarization. Recent work has demonstrated that a zebrafish model of LQT syndrome faithfully recapitulates several features of human disease including prolongation of ventricular action potential duration (APD), spontaneous early after-depolarizations, and 2:1 atrioventricular (AV) block in early stages of development. Due to their transparency, small size, and absorption of small molecules from their environment, zebrafish are amenable to high throughput chemical screens. We describe a small molecule screen using the zebrafish KCNH2 mutant breakdance to identify compounds that can rescue the LQT type 2 phenotype.
Methods and Results
Zebrafish breakdance embryos were exposed to test compounds at 48 hours of development and scored for rescue of 2:1 AV block at 72 hours in a 96-well format. Only compounds that suppressed the LQT phenotype in three of three fish were considered hits. Screen compounds were obtained from commercially available small molecule libraries (Prestwick and Chembridge). Initial hits were confirmed with dose response testing and time course studies. Optical mapping using the voltage sensitive dye di-4 ANEPPS was performed to measure compound effects on cardiac APDs. Screening of 1200 small molecules resulted in the identification of flurandrenolide and 2-methoxy-N-(4-methylphenyl) benzamide (2-MMB) as compounds that reproducibly suppressed the LQT phenotype. Optical mapping confirmed that treatment with each compound caused shortening of ventricular APDs. Structure activity studies and steroid receptor knockdown suggest that flurandrenolide functions via the glucocorticoid signaling pathway.
Using a zebrafish model of LQT type 2 syndrome in a high throughput chemical screen, we have identified two compounds, flurandrenolide and the novel compound, 2-MMB, as small molecules that rescue the zebrafish LQTS 2 by shortening the ventricular action potential duration. We provide evidence that flurandrenolide functions via the glucocorticoid receptor mediated pathway. These two molecules, and future discoveries from this screen, should yield novel tools for the study of cardiac electrophysiology and may lead to novel therapeutics for human LQT patients.
PMCID: PMC3015011  PMID: 21098441
long QT syndrome; animal models of human disease; ion channels; chemical screening
17.  Modeling Tissue- and Mutation- Specific Electrophysiological Effects in the Long QT Syndrome: Role of the Purkinje Fiber 
PLoS ONE  2014;9(6):e97720.
Congenital long QT syndrome is a heritable family of arrhythmias caused by mutations in 13 genes encoding ion channel complex proteins. Mounting evidence has implicated the Purkinje fiber network in the genesis of ventricular arrhythmias. In this study, we explore the hypothesis that long QT mutations can demonstrate different phenotypes depending on the tissue type of expression. Using computational models of the human ventricular myocyte and the Purkinje fiber cell, the biophysical alteration in channel function in LQT1, LQT2, LQT3, and LQT7 are modeled. We identified that the plateau potential was important in LQT1 and LQT2, in which mutation led to minimal action potential prolongation in Purkinje fiber cells. The phenotype of LQT3 mutation was dependent on the biophysical alteration induced as well as tissue type. The canonical ΔKPQ mutation causes severe action potential prolongation in both tissue types. For LQT3 mutation F1473C, characterized by shifted channel availability, a more severe phenotype was seen in Purkinje fiber cells with action potential prolongation and early afterdepolarizations. The LQT3 mutation S1904L demonstrated striking effects on action potential duration restitution and more severe action potential prolongation in Purkinje fiber cells at higher heart rates. Voltage clamp simulations highlight the mechanism of effect of these mutations in different tissue types, and impact of drug therapy is explored. We conclude that arrhythmia formation in long QT syndrome may depend not only on the basis of mutation and biophysical alteration, but also upon tissue of expression. The Purkinje fiber network may represent an important therapeutic target in the management of patients with heritable channelopathies.
PMCID: PMC4043730  PMID: 24892747
18.  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.
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
19.  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.
PMCID: PMC3076201  PMID: 21164565
genetics; arrhythmias; electrophysiology; HERG
20.  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.
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.
PMCID: PMC3151313  PMID: 20224391
genetics; ion channels; long QT syndrome; mutation-specific management; sudden cardiac death
21.  A Novel Mutation in KCNQ1 Associated with a Potent Dominant Negative Effect as the Basis for the LQT1 Form of the Long QT Syndrome 
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.
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.
PMCID: PMC2085492  PMID: 17655673
Ion channel; Mutation; Inherited syndrome; Electrophysiology; Torsade de Pointes
22.  In Utero Diagnosis of Long QT Syndrome by Magnetocardiography 
Circulation  2013;128(20):10.1161/CIRCULATIONAHA.113.004840.
The electrophysiology of long QT syndrome (LQTS) in utero is virtually unstudied. Our goal here was to evaluate the efficacy of fetal magnetocardiography (fMCG) for diagnosis and prognosis of fetuses at risk of LQTS.
Methods and Results
We reviewed the pre/postnatal medical records of 30 fetuses referred for fMCG due to a family history of LQTS (n=17); neonatal/childhood sudden cardiac death (n=3) and/or presentation of prenatal LQTS rhythms (n=12): 2° AVB, ventricular tachycardia, heart rate < 3rd percentile. We evaluated heart rate and reactivity, cardiac time intervals, T-wave characteristics, and initiation/termination of Torsade de Pointes (TdP), and compared these with neonatal ECG findings. After birth, subjects were tested for LQTS mutations.
Based on accepted clinical criteria, 21 subjects (70%; 9 KCNQ1, 5 KCNH2, 2 SCN5A, 2 other, 3 untested) had LQTS. Using a threshold of QTc= 490 ms, fMCG accurately identified LQTS fetuses with 89% (24/27) sensitivity and 89% (8/9) specificity in 36 sessions. Four fetuses (2 KCNH2 and 2 SCN5A), all with QTc ≥ 620 ms, had frequent episodes of TdP, which were present 22–79% of the time. While some episodes initiated with a long-short sequence, most initiations showed QRS aberrancy and a notable lack of pause dependency. T-wave alternans was strongly associated with severe LQTS phenotype.
QTc prolongation (≥490 ms) assessed by fMCG accurately identified LQTS in utero; extreme QTc prolongation (≥620 ms) predicted TdP. FMCG can play a critical role in the diagnosis and management of fetuses at risk of LQTS.
PMCID: PMC3831174  PMID: 24218437
arrhythmia; long QT syndrome; torsades de pointes; alternans; magnetocardiography; fetus
23.  Prevalence and Potential Genetic Determinants of Sensorineural Deafness in KCNQ1 Homozygosity and Compound Heterozygosity 
Homozygous or compound heterozygous mutations in KCNQ1 cause Jervell and Lange-Nielsen syndrome (JLNS), a rare, autosomal recessive form of long QT syndrome (LQTS) characterized by deafness, marked QT prolongation, and a high risk of sudden death. However, it is not understood why some individuals with mutations on both KCNQ1 alleles present without deafness. Here, we sought to determine the prevalence and genetic determinants of this phenomenon in a large referral population of LQTS patients.
Methods and Results
Retrospective analysis of all LQTS patients evaluated from July 1998 to April 2012 was used to identify those with ≥1 KCNQ1 mutation. Of the 249 KCNQ1-positive patients identified, 15 patients (6.0%) harbored a rare putative pathogenic mutation on both KCNQ1 alleles. Surprisingly, 11 (73%) of these patients presented without the sensorineural deafness associated with JLNS. The degree of QT interval prolongation and number of breakthrough cardiac events were similar between cases with and without deafness. Interestingly, truncating mutations were more prevalent in JLNS (79%) than non-deaf cases (36%, p<0.001) derived from this study and those in the literature.
Here, we provide evidence that the “recessive” inheritance of a severe LQT1 phenotype in the absence of an auditory phenotype may represent a more common pattern of LQTS inheritance than previously anticipated and that these cases should be treated as a higher-risk LQTS subset similar to their JLNS counterparts. Furthermore, mutation type may serve as a genetic determinant of deafness, but not cardiac expressivity, in individuals harboring ≥1 KCNQ1 mutation on each allele.
PMCID: PMC3683572  PMID: 23392653
long QT syndrome; genetics; ion channels; pediatrics; sudden cardiac death
24.  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.
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.
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.
PMCID: PMC3332528  PMID: 17470695
electrocardiography; genetics; long-QT syndrome
25.  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 ( 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.
PMCID: PMC3037562  PMID: 20809527
Long QT Syndrome; Arrhythmia; LOVD; Mutation database

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