LQT1/2, DIGENIC, INCLUDED
VENTRICULAR FIBRILLATION WITH PROLONGED QT INTERVAL LONG QT SYNDROME 1/2, DIGENIC, INCLUDED
LONG QT SYNDROME 1, ACQUIRED, SUSCEPTIBILITY TO, INCLUDED
WARD-ROMANO SYNDROME
ROMANO-WARD SYNDROME
LQT1
WRS
RWS
LQT1
LQT1 is a sub-type of Romano-Ward syndrome, a variant of the familial long QT syndrome. It is characterized by mutations in the KCNQ1 gene. A specific trigger for arrhythmic events in LQT1 subtype is physical exertion, especially swimming, or emotional stress. Typically, ECG shows a broad T wave. (PMID:25274057; 26370830)
Congenital long QT syndrome is electrocardiographically characterized by a prolonged QT interval and polymorphic ventricular arrhythmias (torsade de pointes). These cardiac arrhythmias may result in recurrent syncopes, seizure, or sudden death (Jongbloed et al., 1999).
A ... Congenital long QT syndrome is electrocardiographically characterized by a prolonged QT interval and polymorphic ventricular arrhythmias (torsade de pointes). These cardiac arrhythmias may result in recurrent syncopes, seizure, or sudden death (Jongbloed et al., 1999). A form of torsade de pointes in which the first beat has a short coupling interval has been described (613600). - Genetic Heterogeneity of Long QT Syndrome There are other forms of LQT syndrome (LQTS) associated with mutations in various genes encoding ion channel subunits: LQT2 (613688) is caused by mutation in the KCNH2 gene (152427), LQT3 (603830) is caused by mutation in the SCN5A gene (600163), LQT4 (see 600919) is caused by mutation in the ANK2 gene (106410), LQT5 is caused by mutation in the KCNE1 gene (176261), LQT6 (613693) is caused by mutation in the KCNE2 gene (603796), LQT7 (Andersen cardiodysrhythmic periodic paralysis, 170390) is caused by mutation in the KCNJ2 gene (600681), LQT8 (Timothy syndrome; 601005) is caused by mutation in the CACNA1C gene (114205), LQT9 (611818) is caused by mutation in the CAV3 gene (601253), LQT10 (611819) is caused by mutation in the SCN4B gene (608256), LQT11 (611820) is caused by mutation in the AKAP9 gene (604001), LQT12 (612955) is caused by mutation in the SNTA1 gene (601017), and LQT13 (613485) is caused by mutation in the KCNJ5 gene (600734). Approximately 10% of LQTS patients in whom a mutation is identified in one ion channel gene carry a second mutation in the same gene or in another ion channel gene (Tester et al., 2005).
Ward (1964) observed syncope due to ventricular fibrillation in a brother and sister whose resting electrocardiogram showed abnormal prolongation of the QT interval. The mother, although asymptomatic, had a prolonged QT interval also. Her sister had attacks of ... Ward (1964) observed syncope due to ventricular fibrillation in a brother and sister whose resting electrocardiogram showed abnormal prolongation of the QT interval. The mother, although asymptomatic, had a prolonged QT interval also. Her sister had attacks of syncope and died in one of these at the age of 30 years. Deafness was not a feature, making this disorder distinct from the recessively inherited syndrome described by Jervell and Lange-Nielsen (JLNS; see 220400). Similar families with involvement of multiple generations were reported by Romano et al. (1963), Romano (1965), Barlow et al. (1964), and Garza et al. (1970). Hashiba (1978) concluded that in Japan women are more severely affected than men. (As indicated later, Moss et al. (1991) found that the proband was female in 69% of multiplex families and on the average was younger than other affected members.) Gamstorp et al. (1964) reported a family with prolonged QT interval and cardiac arrhythmias without deafness; affected members were hypokalemic and benefited from administration of potassium. Vincent (1986) found that the resting heart rate was significantly slower in newborns and children under age 3 with WRS but not in older children and adults. He interpreted the data as consistent with right-sided sympathetic deficiency manifested by a slower heart rate in early life, when sympathetic tone is high and contributes to resting heart rate, but not in older persons in whom resting heart rate is predominantly under parasympathetic control. Bonduelle (1993) suggested that death in utero is an expression of the Ward-Romano syndrome in some families. Moss et al. (1991) prospectively investigated the clinical characteristics and long-term course of 3,343 individuals from 328 families in which one or more members were identified as affected with LQT. The 328 probands were younger at first contact (age 21 +/- 15 years) and more likely to be female (69%), and had a higher frequency of preenrollment syncope or cardiac arrest with resuscitation (80%), congenital deafness (7%), a resting heart rate less than 60 beats/min (31%), and a history of ventricular tachyarrhythmia (47%) than other affected and unaffected family members. Arrhythmogenic syncope often occurred in association with acute physical, emotional, or auditory arousal. The syncopal episodes were frequently misinterpreted as a seizure disorder. By age 12 years, 50% of the probands had experienced at least one syncopal episode or death. Gohl et al. (1991) tested the hypothesis of sympathetic imbalance by a scintigraphic display of efferent cardiac sympathetic innervation using I-123-MIBG, an analog of norepinephrine and guanethidine. Single photon emission computed tomography (SPECT) was the method of scanning. All scans of the healthy volunteers showed a uniform tracer uptake with sometimes slightly decreased activity in the apex. All 5 patients with prolonged QT and all who had suffered from at least one episode of torsade de pointes, ventricular fibrillation, or syncope had reduced or abolished MIBG uptakes in the inferior and inferior septal parts of the left ventricle. They referred to this as congenital myocardial sympathetic dysinnervation (CMSD). One woman without symptoms or QT prolongation showed an abnormal MIBG SPECT similar to that of her daughter, who did have LQT with symptoms. One male without LQT who had suffered from ventricular fibrillation showed CMSD similar to that of his father, who had LQT but no symptoms. All members of the families with normal MIBG SPECTs had neither LQT nor symptoms. Pacia et al. (1994) reported 2 cases of LQT presenting as epilepsy and found 8 other cases in the literature. Vincent et al. (1992) obtained medical histories and electrocardiograms from 199 members of families with LQT. Carriers of the LQT gene (83 subjects) and noncarriers (116 subjects) were distinguished by genetic linkage analysis. A history of syncope was obtained in 52 of the carriers of the long QT gene (63%), and 4 (5%) had a history of aborted sudden death. The QT intervals corrected for heart rate in gene carriers ranged from 0.41 to 0.59 seconds (mean, 0.49). The values for noncarriers ranged from 0.38 to 0.47 seconds (mean, 0.42). Although the QT intervals were, on the average, longer in carriers, there was substantial overlap in the 2 groups. The use of a directed QT interval above 0.44 seconds as a diagnostic criterion resulted in 22 misclassifications among the 199 family members (11%). A corrected QT interval of 0.47 seconds or longer in males and 0.48 seconds or longer in females was completely predictive but resulted in false-negative diagnoses in 40% of the males and 20% of the females. Vincent et al. (1992) concluded that the QT interval cannot be used as the basis of accurate diagnosis and that, whenever possible, DNA markers should be used to obtain a reliable diagnosis. Ohkuchi et al. (1999) described a fetus who exhibited transient (at most 30 seconds long), repeated episodes of tachyarrhythmia (240 beats per minute). The infant was born at 36 weeks' gestation and showed a markedly prolonged QT interval and transient, repeated episodes of polymorphic ventricular tachycardia. Retrospective analysis of the videotape showing fetal cardiac movement showed that atrioventricular dissociation was present prenatally and thus, that fetal tachyarrhythmia was due to ventricular tachycardia. An excess of females with long QT syndrome is well recognized. The QT interval is longer in females, even in LQTS, which may bias the diagnostic rate in this group. To investigate the possible age- and sex-related differences in phenotype in carriers of mutations in LQTS genes (KVLQT1 (KCNQ1, 607542); HERG (KCNH2, 152427), and SCN5A, 600163), Locati et al. (1998) analyzed data from 479 probands (335 females and 144 males) referred to the International LQTS Registry. The first cardiac event (defined as syncope, nonfatal cardiac arrest, or sudden unexplained death before the age of 40) occurred significantly earlier in males. In 69 KVLQT1 mutation carriers this effect was more marked, with all first cardiac events occurring before puberty in males. A persisting cumulative risk was demonstrated beyond puberty in females. Locati et al. (1998) suggested that this apparent age- and sex-related phenomenon placed young male gene carriers in a high-risk category and that all female gene carriers should be considered for long-term prophylactic therapy. Imboden et al. (2006) investigated the distribution of mutant alleles for the long-QT syndrome in 484 nuclear families with type I disease (LQT1 due to mutation in the KCNQ1 gene) and 269 nuclear families with type II disease (LQT2 (613688) due to mutation in the KCNH2 gene; 152427). In offspring of the female carriers of LQT1 or male and female carriers of LQT2, classic mendelian inheritance ratios were not observed. Among the 1,534 descendants, the proportion of genetically affected offspring was significantly greater than that expected according to mendelian inheritance: 870 were carriers of a mutation (57%), and 664 were noncarriers (43%) (P less than 0.001). Among the 870 carriers, the allele for the long-QT syndrome was transmitted more often to female offspring (476; 55%) than to male offspring (394; 45%) (P = 0.005). Increased maternal transmission of the long QT syndrome to daughters was also observed, possibly contributing to the excess of female patients with autosomal dominant long QT syndrome. Priori et al. (1999) identified 9 families, each with a 'sporadic' case of LQTS, i.e., only the proband was diagnosed clinically as being affected by LQTS. Six probands were symptomatic for syncope, 2 were asymptomatic with QT prolongation found on routine examination, and 1 was asymptomatic but showed QT prolongation when examined following her brother's sudden death while swimming. Five had mutations in HERG (4 missense, 1 nonsense) and 4 had missense mutations in KCNQ1. Four of the mutations were de novo; in the remaining families at least 1 silent gene carrier was found, allowing estimation of penetrance at 25%. This contrasted greatly with the prevailing view that LQTS gene mutations may have penetrances of 90% or more. This study highlighted the importance of detecting such silent gene carriers since they are at risk of developing torsade de pointes if exposed to drugs that block potassium channels. Further, the authors stated, carrier status cannot be reliably excluded on clinical grounds alone. In 108 first-degree relatives of 26 patients with the sudden infant death syndrome (SIDS), Kukolich et al. (1977) found normal QT intervals in all. Thus, they were unable to confirm the notion that the Ward-Romano syndrome is the basis for a large proportion of cases of SIDS. On the other hand, Schwartz et al. (1998) maintained that a relationship exists between prolongation of the QT interval and the sudden infant death syndrome. The conclusions of this study and the recommendations based thereon were the target of multiple criticisms, as reviewed elsewhere (272120).
In a large collaborative study, Zareba et al. (1998) demonstrated that the genotype of the long QT syndrome influences the clinical course. The risk of cardiac events (syncope, aborted cardiac arrest, or sudden death) was significantly higher among ... In a large collaborative study, Zareba et al. (1998) demonstrated that the genotype of the long QT syndrome influences the clinical course. The risk of cardiac events (syncope, aborted cardiac arrest, or sudden death) was significantly higher among subjects with mutations at the LQT1 or LQT2 locus than among those with mutations at the LQT3 locus. Although the cumulative mortality was similar regardless of the genotype, the percentage of cardiac events that were lethal was significantly higher in families with mutations at the LQT3 locus. In this large study, 112 patients had mutations at the LQT1 locus, 72 at the LQT2 locus, and 62 at the LQT3 locus. Thus, paradoxically, cardiac events were less frequent in LQT3 but more likely to be lethal; the likelihood of dying during a cardiac event was 20% in families with an LQT3 mutation and 4% with either an LQT1 or an LQT2 mutation. Priori et al. (2003) stratified risk according to genotype, in conjunction with other clinical variables such as sex and QT interval length, in 647 patients from 193 consecutively genotyped families with LQTS, of whom 386 carried a mutation at the LQT1 locus, 206 a mutation at the LQT2 locus, and 55 a mutation at the LQT3 locus. The cumulative probability of a first cardiac event, defined as the occurrence of syncope, cardiac arrest, or sudden death before the age of 40 years and before the initiation of therapy, was determined according to genotype, sex, and the QT interval corrected for heart rate (QTc). Within each genotype, Priori et al. (2003) also assessed risk in the 4 categories derived from the combination of sex and QTc (less than 500 ms and 500 ms or more). They found that the incidence of a first cardiac event before the age of 40 years and before the initiation of therapy was lower among patients with a mutation at the LQT1 locus (30%) than among those with a mutation at the LQT2 or LQT3 loci (46% and 42%, respectively). Multivariate analysis showed that the genetic locus and the QTc, but not sex, were independent predictors of risk. The QTc was an independent predictor of risk among patients with a mutation at either the LQT1 or the LQT2 locus but not among those with a mutation at the LQT3 locus. Among patients with a mutation at the LQT3 locus, sex was an independent predictor of events, i.e., male patients became symptomatic much earlier than female patients even when their QTc was below 500 ms; the authors noted, however, that caution was required in drawing conclusions from this group because of its relatively small size. Vincent (2003) noted that even with the important work of Priori et al. (2003), risk prediction remained difficult, which he illustrated with several cases. A 13-year-old boy with the LQT1 genotype died suddenly while running, with no prior symptoms. His electrocardiogram, obtained 2 weeks earlier as part of family screening, was normal, with a QTc of 450 ms. A 20-year-old woman with the LQT2 genotype died in her sleep; her electrocardiogram has been found to be normal, with a QTc of 460 ms. Westenskow et al. (2004) analyzed the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes in 252 probands with long QT syndrome and identified 19 with biallelic mutations in LQTS genes, of whom 18 were either compound heterozygous (monogenic) or double heterozygous (digenic) and 1 was homozygous. They also identified 1 patient who had triallelic digenic mutations (see 152427.0021). Compared with probands who had 1 or no identified mutation, probands with 2 mutations had longer QTc intervals (p less than 0.001) and were 3.5-fold more likely to undergo cardiac arrest (p less than 0.01). All 20 probands with 2 mutations had experienced cardiac events. Westenskow et al. (2004) concluded that biallelic mono- or digenic mutations (which the authors termed 'compound mutations') cause a severe phenotype and are relatively common in long QT syndrome. The authors noted that these findings support the concept of arrhythmia risk as a multi-hit process and suggested that genotype can be used to predict risk.
In affected members of 16 families with long QT syndrome, Wang et al. (1996) identified several mutations in the KVLQT1 gene (e.g., 607542.0001).
Russell et al. (1996) used SSCP analysis to screen 2 large and 9 ... In affected members of 16 families with long QT syndrome, Wang et al. (1996) identified several mutations in the KVLQT1 gene (e.g., 607542.0001). Russell et al. (1996) used SSCP analysis to screen 2 large and 9 small LQT families for mutations of the KVLQT1 potassium channel gene. They identified a mutation (607542.0012) in the KVLQT1 gene in 2 unrelated families and, in a third family, another mutation (607542.0010) that resulted in the spontaneous occurrence of LQT in monozygotic twin offspring of unaffected parents. A comprehensive review of the genetic and molecular basis of long QT syndromes was given by Priori et al. (1999, 1999). Splawski et al. (2000) screened 262 unrelated individuals with LQT syndrome for mutations in the 5 defined genes (KCNQ1; KCNH2; SCN5A; KCNE1, 176261; KCNE2, 603796) and identified mutations in 177 individuals (68%). KCNQ1 and KCNH2 accounted for 87% of mutations (42% and 45%, respectively), and SCN5A, KCNE1, and KCNE2 for the remaining 13% (8%, 3%, and 2%, respectively). From a cohort of 2,008 healthy individuals, Gouas et al. (2005) analyzed a group of 200 individuals with the shortest QTc intervals and a group of 198 with the longest QTc intervals, comparing the allele, genotype, and haplotype frequencies of polymorphisms in cardiac ion channel genes (10 SNPs in KCNQ1, 2 in KCNE1, 4 in SCN5A, and 1 in KCNH2) between the 2 groups. Based on observed differences, Gouas et al. (2005) suggested that genetic determinants located in these genes influence QTc length in healthy individuals and may represent risk factors for arrhythmias or cardiac sudden death in patients with cardiovascular disease. Arbour et al. (2008) identified a missense mutation (607542.0040) causing long QT syndrome-1 among a First Nations community of northern British Columbia. - Acquired Long QT Syndrome In a patient who developed QT prolongation and torsade de pointes while taking the drug dofetilide, Yang et al. (2002) identified heterozygosity for a missense mutation in the KCNQ1 gene (R583C; 607542.0031). In vitro expression studies of the mutant protein confirmed a significant reduction in potassium currents, suggesting that the R583C mutation was responsible for the patient's response to dofetilide. - Digenic Inheritance Berthet et al. (1999) studied a large Belgian family with LQTS in which both parents of 3 affected sisters had long QT intervals and family histories of sudden death. Haplotype analysis using microsatellite markers revealed linkage to LQT1 in the father and 2 severely affected daughters and linkage to LQT2 in the mother, the same 2 daughters, another more mildly affected daughter, and a grandson. In the 2 most severely affected sisters, who required multiple medications, cardiac sympathectomy, and pacemaker implantation for control of symptoms, Berthet et al. (1999) identified biallelic digenic mutations: a missense mutation in the KCNQ1 gene (A341E; 607542.0009) and a splice site mutation in the KCNH2 gene (2592+1G-A; 152427.0019). The father, 2 of his brothers, and a niece were all heterozygous for the A341E mutation in KCNQ1; the mother, the more mildly affected sister, and the grandson were heterozygous for the splice site mutation in KCNH2. Neither mutation was found in 2 unaffected sibs or in other unaffected members of the family. Berthet et al. (1999) stated that this was the first description of double heterozygosity in long QT syndrome. Tester et al. (2005) analyzed 5 LQTS-associated cardiac channel genes in 541 consecutive unrelated patients with LQT syndrome (average QTc, 482 ms). In 272 (50%) patients, they identified 211 different pathogenic mutations, including 88 in KCNQ1, 89 in KCNH2, 32 in SCN5A, and 1 each in KCNE1 and KCNE2. Mutations considered pathogenic were absent in more than 1,400 reference alleles. Among the mutation-positive patients, 29 (11%) had 2 LQTS-causing mutations, of which 16 (8%) were in 2 different LQTS genes (biallelic digenic). Tester et al. (2005) noted that patients with multiple mutations were younger at diagnosis, but they did not discern any genotype/phenotype correlations associated with location or type of mutation. In 44 unrelated patients with LQT syndrome, Millat et al. (2006) used DHLP chromatography to analyze the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes for mutations and SNPs. Most of the patients (84%) showed a complex molecular pattern, with an identified mutation associated with 1 or more SNPs located in several LQTS genes; 4 of the patients also had a second mutation in a different LQTS gene (biallelic digenic inheritance; see 607542.0038, 607542.0039, 152427.0023, and 600163.0007). Millat et al. (2006) suggested that because double heterozygosity appears to be more common than expected, molecular diagnosis should be performed on all LQTS-related genes, even after a single mutation has been identified.
The diagnosis of Romano-Ward syndrome (RWS) is made on the basis of ECG characteristics, clinical presentation, and family history. Schwartz et al [1993] proposed a score system to diagnose RWS, which has recently been updated [Schwartz & Crotti 2011]. Points are assigned to various criteria (see Table 1). ...
DiagnosisClinical DiagnosisThe diagnosis of Romano-Ward syndrome (RWS) is made on the basis of ECG characteristics, clinical presentation, and family history. Schwartz et al [1993] proposed a score system to diagnose RWS, which has recently been updated [Schwartz & Crotti 2011]. Points are assigned to various criteria (see Table 1). Table 1. Scoring System for Diagnosis of Romano-Ward SyndromeView in own windowFindingsPointsECG 1QTc 2 ≥480 ms3=460-479 ms2=450-459 ms1≥480 ms during 4th minute of recovery from exercise stress test1Torsade de pointes 32T wave alternans1Notched T wave in 3 leads1Low heart rate for age 40.5Clinical historySyncope 3 With stress2Without stress1Family members with definite LQTS 51Family historyUnexplained sudden cardiac death before age 30 years among immediate family members 50.5Total scoreAdapted from Schwartz & Crotti [2011]Scoring:≤1.0 point = low probability of LQTS1.5-3.0 points = intermediate probability of LQTS≥3.5 points = high probability of LQTS1. In the absence of medications or disorders known to affect these electrocardiographic features2. QTc (corrected QT) calculated by Bazett’s formula where QTc = QT/√RR3. Mutually exclusive4. Resting heart rate <2nd percentile for age5. The same family member cannot be counted for both criteria.QTc values on resting ECG. The QTc on resting ECG is neither completely sensitive nor specific for the diagnosis of RWS. Table 2 shows the diagnostic criteria for the resting ECG QTc value in the absence of the following, all of which can lengthen the QTc interval and cause a form of acquired long QT syndrome (LQTS) [Vincent et al 1992, Vincent 2000]:QT-prolonging drugsHypokalemiaCertain neurologic conditions including subarachnoid bleedStructural heart diseaseTable 2. Utility of the Resting QTc or Exercise ECG Maximum QTc Interval in Diagnosis of RWSView in own windowCertainty of RWS Diagnosis% of Affected IndividualsQTcMalesFemalesPositive68%>470 msec>480 msecUncertain20%450-460 msec 1 460-470 msec 111%400-450 msec400-450 msecNegative2 21. In a member of a family with documented RWS, the diagnosis of RWS is suspected in males with a QTc >450 msec and in females with a QTc >460 msec. These criteria are not applicable to the general population, which includes many more normal than abnormal individuals with these values.2. QT measurement varies by observer; therefore, some differences in reporting are found. However, only a few instances of an individual with a disease-causing mutation and QTc <400 msec have been reported.QTc on exercise and ambulatory ECG and during pharmacologic provocation testing. The following tests are particularly helpful for further evaluation of individuals with "uncertain" QTc values on resting ECG:Exercise ECG commonly shows failure of the QTc to shorten normally [Jervell & Lange-Nielsen 1957, Vincent et al 1991, Swan et al 1998] and prolongation of the QTc to values in Table 2. Many individuals develop characteristic T-wave abnormalities [Zhang et al 2000].Ambulatory ECG may demonstrate similar findings [Viitasalo et al 2002] but less frequently than the exercise ECG. QTc as high as 500 msec may be seen on ambulatory ECG in normal individuals, and thus a higher value is required for suspicion of RWS.Intravenous pharmacologic provocation testing, such as with epinephrine, may be helpful by demonstrating inappropriate prolongation of the QTc interval [Ackerman et al 2002]. The sensitivity and specificity have not been evaluated in a large sample of individuals with LQTS and normals. With the small risk of induction of arrhythmia, such provocative testing is best performed in laboratories experienced in arrhythmia induction and control.Other ECG changes. T-wave patterns characteristic of each phenotype may assist in diagnosis [Zhang et al 2000]. The heart rate may be lower than normal. The presence of the ventricular arrhythmia torsade de pointes is characteristic of QT prolongation syndromes but not specific for RWS.History. A family history or personal history of syncope, aborted cardiac arrest, or sudden death in a child or young adult may lead to suspicion of RWS. The syncope is typically precipitous and without warning, thus differing from the common vasovagal and orthostatic forms of syncope in which presyncope and other warning symptoms occur. Absence of aura, incontinence, and postictal findings help differentiate RWS from seizures.Family history. A family history consistent with autosomal dominant inheritance supports the diagnosis.TestingNo other routine clinical tests are helpful in the diagnosis of RWS.Molecular Genetic TestingGenes. Ten genes (KCNQ1, KCNE1, KCNH2, KCNE2, SCN5A, CAV3, SCN4B, AKAP9, SNTA1, and KCNJ5) are known to be associated with RWS [Splawski et al 2000, Vatta et al 2006, Chen et al 2007, Medeiros-Domingo et al 2007, Ueda et al 2008, Yang et al 2010].Other genes. RWS is defined as a purely cardiac electrophysiologic disorder. Prolonged QT interval can also be associated with other cardiac and non-cardiac abnormalities. ANK2 has been proposed as LQT4. ANK2 mutations can cause a broad spectrum of clinical cardiac phenotypes, such as catecholaminergic polymorphic ventricular arrhythmias, sinus node dysfunction, atrial fibrillation, and prolonged QT syndrome. Based on this wide variety of symptoms the term “ankyrin B syndrome” has been proposed [Mohler et al 2003, Mohler et al 2007].KCNJ2 has been proposed as LQT7. Mutations in KCNJ2 also cause Andersen Tawil syndrome (ATS) (see Differential Diagnosis). CACNA1C has been proposed as LQT8. Mutations in CACNA1C cause Timothy syndrome (see Differential Diagnosis). Approximately 25% of families with a clinically firm diagnosis of RWS do not have a detectable mutation in one of the ten genes (KCNQ1, KCNE1, KCNH2, KCNE2, SCN5A, CAV3, SCN4B, AKAP9, SNTA1, and KCNJ5) known to be associated with RWS, suggesting that mutations in other genes can also cause RWS and/or that current test methods do not detect all mutations in the known genes.Clinical testingTable 3. Summary of Molecular Genetic Testing Used in RWSView in own windowGene SymbolProportion of RWS Attributed to Mutations in This Gene 1Test MethodMutations DetectedTest AvailabilityKCNQ146%Sequence analysis / mutation scanning 2 Sequence variants 3ClinicalDeletion / duplication analysis 4Exonic or whole-gene deletions KCNH238%Sequence analysis / mutation scanning 2Sequence variants 3ClinicalDeletion / duplication analysis 4 Exonic or whole-gene deletions / duplicationsSCN5A13%Sequence analysis / mutation scanning 2Sequence variants 3ClinicalDeletion / duplication analysis 4None reported 5,6KCNE12%Sequence analysis / mutation scanning 2Sequence variants 3ClinicalDeletion / duplication analysis 4None reported 5KCNE21%Sequence analysis / mutation scanning 2Sequence variants 3ClinicalDeletion / duplication analysis 4None reported 5CAV3RareSequence analysis 2Sequence variants 3ClinicalDeletion / duplication analysis 4None reported 5 SCN4BRare (1 case)Sequence analysis 2Sequence variants 3ClinicalDeletion / duplication analysis 4None reported 5AKAP9Rare (1 case)Sequence analysis 2Sequence variants 3ClinicalDeletion / duplication analysis 4None reported 5SNTA1Rare (2 cases)Sequence analysis 2Sequence variants 3ClinicalDeletion / duplication analysis 4None reported 5KCNJ5Rare (1 case)Sequence analysis 2Sequence variants 3Clinical1. Proportion of RWS caused by a mutation in each gene is based on Splawski et al [2000], Napolitano et al [2005], Tester et al [2005], Kapa et al [2009], Kapplinger et al [2009].2. Sequence analysis and mutation scanning of the entire gene can have similar mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably between laboratories depending on the specific protocol used.3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.5. Deletions or duplications involving KCNQ1 or KCNH2 have been shown to be causal for Romano-Ward syndrome in ~3% of cases [Barc et al 2011]. Deletions or duplications in the other genes have not been reported. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)6. The mutations in SCN5A that cause RWS are gain of function mutations (loss of function mutations in SCN5A cause Brugada syndrome). Therefore, it is highly unlikely that deletions or duplications in SCN5A will be identified as a cause of RWS.Multi-gene panels. Multi-gene panels can be used for the simultaneous analysis of some or all of the genes known to cause RWS. The panels vary by methods used and genes included; thus, the ability of a panel to detect a causative mutation(s) in any given individual with prolonged QT phenotype also varies. Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis in a probandIdentification of prolonged QTc on exercise or ambulatory ECG, or during pharmacologic provocation testingIdentification of a disease-causing mutation in one of the ten genes known to be associated with RWS: KCNQ1, KCNE1, KCNH2, KCNE2, SCN5A, CAV3, SCN4B, AKAP9, SNTA1 and KCNJ5. Analysis of the genes may be done either simultaneously or sequentially. Because the clinical phenotype has been shown to predict the genotype [Zhang et al 2000, van Langen et al 2003], the gene(s) associated with the individual’s clinical phenotype could be analyzed first (see Table 4). Alternatively, the strategy could be based on the proportion of RWS cases caused by mutations in each gene. Analysis of KCNQ1 and KCNH2 can be considered first followed by analysis of SCN5A. If neither a KCNQ1, KCNH2, or SCN5A mutation is identified, analysis of the remaining genes can be considered. Alternatively, a panel in which some or all of the genes known to cause RWS are evaluated simultaneously could be pursued. This panel may consist of either the more commonly mutated genes (KCNQ, KCNH2, SCN5A, KCNE1, and KCNE2) or may also include the remaining, rarely mutated genes.Deletion/duplication analysis of KCNQ1 and KCNH2 is included in the standard test in some laboratories and needs to be requested as a separate test in other laboratories. Note: If a sequential screening strategy has been chosen and a variant of unknown clinical significance has been identified, continued screening of the remaining genes is recommended. Another mutation may be present. Predictive testing for at-risk asymptomatic family members can be performed by one or both of the following:QTc analysis on resting and exercise ECGs Note: The diagnostic accuracy by QTc analysis is considerably improved by evaluation of the exercise ECG QTc intervals, in addition to the resting ECG, using the QTc values listed in Table 1.Specific mutation testing when the disease-causing mutation in the family is knownPrenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersJervell and Lange-Nielsen syndrome (JLNS) is characterized by congenital profound bilateral sensorineural hearing loss and long QTc interval usually greater than 500 msec. Prolongation of the QTc interval is associated with tachyarrhythmias, including: ventricular tachycardia; episodes of torsade de pointes ventricular tachycardia; and ventricular fibrillation, which may culminate in syncope or sudden death. More than half of untreated individuals with JLNS die before age 15 years. JLNS, inherited in an autosomal recessive manner, is caused by homozygous or compound heterozygous disease-causing mutations in either KCNQ1 (locus name LQT1) or KCNE1 (locus name LQT5).Brugada syndrome. Loss-of-function mutations in SCN5A are associated with cardiac conduction defects, such as rapid polymorphic ventricular tachycardia/ventricular fibrillation, and sudden death.Caveolinopathies. Mutations in CAV3, the gene encoding caveolin-3, have been associated with sudden infant death syndrome (SIDS) and LQT syndrome (LQT9) [Vatta et al 2006, Arnestad et al 2007, Cronk et al 2007]. CAV3 mutations cause an increase in late sodium current similar to that seen in the LQT3 phenotype. CAV3 mutations are also associated with a range of muscular disease. Acquired, drug-induced long QT syndrome (LQTS). Some individuals with drug-induced LQTS have a genetic predisposition to LQTS caused by a mutation of one of the genes associated with RWS [Napolitano et al 2000].
Romano-Ward syndrome (RWS) is characterized by QT prolongation and T-wave abnormalities on ECG that are associated with tachyarrhythmias, typically the ventricular tachycardia torsade de pointes (TdP). TdP is usually self-terminating, thus causing syncope, the most common symptom in individuals with RWS. Syncope is typically precipitous and without warning. In some instances, TdP degenerates to ventricular fibrillation and aborted cardiac arrest (if the individual is defibrillated) or sudden death....
Natural HistoryRomano-Ward syndrome (RWS) is characterized by QT prolongation and T-wave abnormalities on ECG that are associated with tachyarrhythmias, typically the ventricular tachycardia torsade de pointes (TdP). TdP is usually self-terminating, thus causing syncope, the most common symptom in individuals with RWS. Syncope is typically precipitous and without warning. In some instances, TdP degenerates to ventricular fibrillation and aborted cardiac arrest (if the individual is defibrillated) or sudden death.Mutations in KCNQ1, KCNH2 and SCN5A account for the vast majority of cases (46%, 38%, and 13% respectively) and distinct genotype-phenotype correlations have been reported (see Table 4). Three clinical phenotypes are recognized in individuals with RWS:LQT1, caused by mutations in KCNQ1 and leading to abnormal IKs potassium channel functionLQT2, caused by mutations in KCNH2 leading to IKr potassium channel dysfunctionLQT3, caused by mutations in SCN5A, the cardiac sodium channel gene, and leading to abnormal INa channel functionApproximately 50% or fewer of individuals with a disease-causing mutation in one of the genes associated with RWS have symptoms and 50% or more never show symptoms [Vincent et al 1992, Zareba et al 1998]. The number of syncopal events in symptomatic individuals ranges from one to hundreds, averaging just a few.The primary triggers for cardiac events in RWS [Schwartz et al 2001]:LQT1. Exercise and sudden emotionLQT2. Exercise, emotion, and sleepLQT3. SleepCardiac events may occur from infancy through middle age but are most common from the pre-teen years through the 20s, with the risk generally diminishing throughout that time period. The usual age range of events differs somewhat for each genotype. Cardiac events are uncommon after age 40 years; when present, they are often triggered by administration of a QT-prolonging drug or hypokalemia or are associated with the LQT3 phenotype.Of individuals who die of complications of RWS, death is the first sign of the disorder in an estimated 10%-15%. The risk for sudden death from birth to age 40 years has been reported at approximately 4% in each of the phenotypes [Zareba et al 1998]. Although syncopal events are most common in LQT1 (63%), followed by LQT2 (46%) and LQT3 (18%), the incidence of death is similar in all three. Table 4. Romano-Ward PhenotypesView in own windowPercent of Individuals with RWSPhenotypeGene SymbolAverage QTcST-T-Wave MorphologyIncidence of Cardiac EventsCardiac Event TriggerSudden Death Risk>60%LQT1KCNQ1480 msecBroad-base T-wave63%Exercise, emotion4%~35%LQT2KCNH2Bifid T-waves46%Exercise, emotion, sleep4% 1LQT3SCN5A~490 msecLong ST, small T18%Sleep4%1. Sudden death risk may be higher in individuals with specific KCNH2 mutations.QTc range is similar across phenotypes (~400-600+ msec). The average QTc values are similar for the LQT1 and LQT2 phenotypes and somewhat longer for the LQT3 phenotype. T-wave patterns characteristic for the LQT1, 2, and 3 phenotypes have been reported and can assist in directing molecular genetic testing strategies to identify the gene involved [Zhang et al 2000]. The predominant triggering stimuli for cardiac events vary by phenotype. In general, the phenotype does not vary much by mutation type; however, a recent study indicated that individuals with the LQT2 phenotype and mutations in the pore region of KCNH2 had a higher risk for sudden death than those individuals with mutations in other regions of KCNH2. In those individuals with KCNQ1 mutations, the risk is the same in pore as in other region mutations.
LQTS with syndactyly (Timothy syndromeor syndactyly-related LQTS) is characterized by cardiac (LQTS and/or congenital heart defects), hand (variable unilateral or bilateral cutaneous syndactyly of fingers or toes), facial, and neurodevelopmental features. LQTS typically manifests with a rate-corrected QT interval between 480 ms and 700 ms. Facial anomalies include: flat nasal bridge, low-set ears, thin upper lip, and round face. Neurologic symptoms include: autism, seizures, intellectual disability, and hypotonia. Ventricular tachyarrhythmia is the leading cause of death; average age of death is 2.5 years. Timothy syndrome is diagnosed by clinical features and by the presence of the de novo p.Gly406Arg mutation in the CaV1.2 calcium channel gene, CACNA1C, the only gene known to be associated with Timothy syndrome [Splawski et al 2004]....
Differential DiagnosisLQTS with syndactyly (Timothy syndrome or syndactyly-related LQTS) is characterized by cardiac (LQTS and/or congenital heart defects), hand (variable unilateral or bilateral cutaneous syndactyly of fingers or toes), facial, and neurodevelopmental features. LQTS typically manifests with a rate-corrected QT interval between 480 ms and 700 ms. Facial anomalies include: flat nasal bridge, low-set ears, thin upper lip, and round face. Neurologic symptoms include: autism, seizures, intellectual disability, and hypotonia. Ventricular tachyarrhythmia is the leading cause of death; average age of death is 2.5 years. Timothy syndrome is diagnosed by clinical features and by the presence of the de novo p.Gly406Arg mutation in the CaV1.2 calcium channel gene, CACNA1C, the only gene known to be associated with Timothy syndrome [Splawski et al 2004].This disorder is designated LQT8 and best fits as one of the “atypical” or “complex” forms of LQTS (see Nomenclature).Jervell and Lange-Nielsen syndrome. See Genetically Related Disorders.Brugada syndrome. See Genetically Related Disorders.Andersen-Tawil syndrome (ATS) is characterized by a triad of episodic flaccid muscle weakness (i.e., periodic paralysis), ventricular arrhythmias and prolonged QT interval, and anomalies including low-set ears, ocular hypertelorism, small mandible, fifth-digit clinodactyly, syndactyly, short stature, and scoliosis. KCNJ2 is the only gene known to be associated with ATS [Plaster et al 2001, Ai et al 2002, Tristani-Firouzi et al 2002, Zhang et al 2005]. Approximately 70% of individuals with ATS have a detectable mutation in KCNJ2.Other causes of syncope or sudden death to be considered in children and young adults:Sudden infant death syndrome (SIDS) is commonly defined as unexpected sudden death within the first year of life. Death during the first year of life in families with RWS appears to be rare, yet a percent of infants dying of SIDS have been shown to have mutations in one of the LQTS-related genes [Ackerman et al 2001, Schwartz et al 2001, Arnestad et al 2007]. While it seems probable that these mutations were the cause of the SIDS, the association is uncertain, and the frequency of pathogenic mutations in SIDS cases has been questioned [Wedekind et al 2006].Vasovagal (neurally mediated) syncope, orthostatic hypotensionSeizuresFamilial ventricular fibrillationSubtle hypertrophic cardiomyopathyArrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C)Catecholaminergic polymorphic ventricular tachycardiaAnomalous coronary arteryDrug-induced long QT syndrome (see drugs at www.qtdrugs.org)Note to clinicians: For a patient-specific ‘simultaneous consult’ related to Romano-Ward syndrome, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the diagnosis in an individual suspected of having Romano-Ward syndrome (RWS), determine whether symptoms are attributable to LQTS or to some other disorder. For example, dizziness, pre-syncope, palpitations, vasovagal syncope, and orthostatic syncope are common in the general population and rarely caused by LQTS. Treatment decisions should be based on LQTS-related events, not on unrelated disorders....
ManagementEvaluations to Establish the DiagnosisTo establish the diagnosis in an individual suspected of having Romano-Ward syndrome (RWS), determine whether symptoms are attributable to LQTS or to some other disorder. For example, dizziness, pre-syncope, palpitations, vasovagal syncope, and orthostatic syncope are common in the general population and rarely caused by LQTS. Treatment decisions should be based on LQTS-related events, not on unrelated disorders.Treatment of ManifestationsAll symptomatic persons should be treated. Complete cessation of symptoms is the goal. Management is focused on the prevention of syncope, cardiac arrest, and sudden death through use of the following:Beta blockers. Beta blockers are the mainstay of therapy for the LQT1 phenotype (see Table 4) and the LQT2 phenotype; however, their use in the management of the LQT3 phenotype is controversial. Some individuals have symptoms despite the use of beta blockers [Moss et al 2000]. It has recently been demonstrated that the very large majority of cardiac events that occur in individuals with LQT1 “on beta-blockers” are not caused by failure of the medication, but in fact by failure to take the medication (non-compliance) and/or the administration of QT prolonging drugs [Vincent et al 2009]. It is suspected that the same holds true for individuals with LQT2, but that has not been systematically studied. In some individuals, recurrence of events while on medication is the result of inadequate dosing; thus, the dose must be adjusted regularly in growing children, and the efficacy must be evaluated by assessment of the exercise ECG or ambulatory ECG.Many events “on beta blockers” appear to be caused by non-compliance (failure to take the medication). It is important to emphasize that beta blockers must be taken daily and to have strategies in place in case of missed doses.Many events “on beta blockers” appear to be caused by the administration of QT-prolonging drugs (see Agents/Circumstances to Avoid). QT-prolonging drugs should not be administered to persons with LQTS without careful consideration of risk versus benefit by patient(s) and physician(s).Pacemakers. Pacemakers may be necessary for those individuals with symptomatic bradycardia associated with beta-blocker therapy [Viskin 2000].External defibrillators. Having automatic external defibrillators readily available at home, at school, and in play areas may be appropriate in some cases.Implantable cardioverter-defibrillators (ICDs). ICDs may be necessary for those individuals with beta-blocker-resistant symptoms, inability to take beta blockers (significant asthma, severe fatigue), history of cardiac arrest, and LQTS associated with syndactyly (Timothy syndrome). ICD therapy may be best for symptomatic individuals with the LQT3 phenotype [Wilde 2002]. Note: Implantable cardioverter-defibrillators have largely replaced left thoracic sympathectomy as the preferred treatment in individuals for whom beta blockers are ineffective.Prevention of Primary ManifestationsAlthough the percent of affected individuals who experience cardiac arrest or sudden death is small, all affected but asymptomatic persons younger than age 40 years should be treated prophylactically (usually with beta blockers) because it is not possible to identify those individuals who are at greatest risk for these events.Because symptoms occur primarily in the pre-teen years to early 20s, prophylactic treatment may not be necessary for those affected individuals who (1) are older than age 40 years at diagnosis and (2) either are life-long asymptomatic or have a very remote history of LQTS-type syncope.As emphasized in Treatment of Manifestations, QT-prolonging drugs should not be used unless the benefit of taking the QT-prolonging drug clearly outweighs the risk of torsade de pointes.Prevention of Secondary ComplicationsExamine the past medical history for asthma, orthostatic hypotension, depression, and diabetes mellitus because these disorders may be exacerbated by treatment with beta blockers.Although the incidence of arrhythmias during elective interventions such as surgery, endoscopies, childbirth, or dental work is low, it is prudent to monitor the ECG during such interventions and to alert the appropriate medical personnel in case intervention is needed.SurveillanceBeta-blocker dose should be regularly assessed for efficacy and adverse effects; doses should be altered as needed. Because dose adjustment is especially important in growing children, evaluation is appropriate every three to six months during rapid growth phases.Affected individuals should have regular, periodic evaluations of ICDs for inappropriate shocks and pocket or lead complications.Agents/Circumstances to AvoidDrugs that cause further prolongation of the QT interval or provoke torsade de pointes should be avoided. See www.qtdrugs.org [Woosley 2001] for a complete and updated list.Epinephrine given as part of local anesthetics can trigger arrhythmias and is best avoided.Individuals with the LQT1 or LQT2 phenotype should be advised to avoid competitive sports and activities likely to be associated with intense physical activity and/or emotional stress (e.g., amusement park rides, scary movies, jumping into cold water).Evaluation of Relatives at RiskPresymptomatic diagnosis of at-risk relatives by ECG and/or molecular genetic testing (if the disease-causing mutation in the family is known) followed by treatment is necessary to prevent syncope and sudden death in those individuals who have inherited the disease-causing mutation and/or have ECG findings consistent with RWS. At-risk family members should be alerted to their risk and the need to be evaluated.Note: Relatives at high potential risk who require further testing include members of a family:That has documented LQTS;In which evaluation for LQTS has not been performed.Relatives at low potential risk who do not require further testing include members of a family in which the symptomatic ancestor: Had a low probability of LQTS based on QTc interval (see Table 1) and no relative who experienced LQTS-type events;Had no evidence of a mutation in one of the genes known to cause RWS (or the family-specific mutation, if known) and normal QTc interval.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy Management The postpartum period is associated with increased risk for a cardiac event, especially in individuals with the LQT2 phenotype. Beta blocker treatment was associated with a reduction of events in this nine-month time period after delivery [Seth et al 2007]. Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.OtherMost affected individuals live normal lifestyles. Education of adult individuals and the parents of affected children is an important aspect of management.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Romano-Ward Syndrome: Genes and DatabasesView in own windowLocus NameGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDLQT1KCNQ111p15.5-p15.4Potassium voltage-gated channel subfamily KQT member 1Deafness Gene Mutation Database Gene Connection for the Heart - KCNQ1 (KVLQT1) KCNQ1 @ LOVD KCNQ1 @ ZAC-GGMKCNQ1LQT2KCNH27q36.1Potassium voltage-gated channel subfamily H member 2Gene Connection for the Heart - KCNH2(HERG) KCNH2 @ ZAC-GGM KCNH2 homepage - Mendelian genesKCNH2LQT3SCN5A3p22.2Sodium channel protein type 5 subunit alphaGene Connection for the Heart - SCN5A (LQT3) SCN5A @ LOVD SCN5A @ ZAC-GGMSCN5ALQT5KCNE121q22.12Potassium voltage-gated channel subfamily E member 1Deafness Gene Mutation Database Gene Connection for the Heart - Long QT syndrome type 5 mutation database CCHMC - Human Genetics Mutation Database KCNE1 @ LOVD KCNE1 @ ZAC-GGMKCNE1LQT6KCNE221q22.11Potassium voltage-gated channel subfamily E member 2Gene Connection for the Heart - Long QT syndrome type 6 mutation database KCNE2 @ ZAC-GGM KCNE2 homepage - Mendelian genesKCNE2LQT9CAV33p25.3Caveolin-3Gene Connection for the Heart - Long QT syndrome type 9 mutation database CAV3 @ ZAC-GGM CAV3 homepage - Leiden Muscular Dystrophy pagesCAV3LQT10SCN4B11q23.3Sodium channel subunit beta-4SCN4B @ ZAC-GGM SCN4B homepage - Mendelian genesSCN4BLQT11AKAP97q21.2A-kinase anchor protein 9AKAP9 @ ZAC-GGM AKAP9 homepage - Mendelian genesAKAP9LQT12SNTA120q11.21Alpha-1-syntrophinSNTA1 @ ZAC-GGM SNTA1 homepage - Mendelian genesSNTA1LQT13KCNJ511q24.3G protein-activated inward rectifier potassium channel 4KCNJ5 homepage - Mendelian genesKCNJ5Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Romano-Ward Syndrome (View All in OMIM) View in own window 152427POTASSIUM CHANNEL, VOLTAGE-GATED, SUBFAMILY H, MEMBER 2; KCNH2 176261POTASSIUM CHANNEL, VOLTAGE-GATED, ISK-RELATED SUBFAMILY, MEMBER 1; KCNE1 192500LONG QT SYNDROME 1; LQT1 600163SODIUM CHANNEL, VOLTAGE-GATED, TYPE V, ALPHA SUBUNIT; SCN5A 600734POTASSIUM CHANNEL, INWARDLY RECTIFYING, SUBFAMILY J, MEMBER 5; KCNJ5 601017SYNTROPHIN, ALPHA-1; SNTA1 601253CAVEOLIN 3; CAV3 603796POTASSIUM CHANNEL, VOLTAGE-GATED, ISK-RELATED SUBFAMILY, MEMBER 2; KCNE2 603830LONG QT SYNDROME 3; LQT3 604001A-KINASE ANCHOR PROTEIN 9; AKAP9 607542POTASSIUM CHANNEL, VOLTAGE-GATED, KQT-LIKE SUBFAMILY, MEMBER 1; KCNQ1 608256SODIUM CHANNEL, VOLTAGE-GATED, TYPE IV, BETA SUBUNIT; SCN4B 611818LONG QT SYNDROME 9; LQT9 611819LONG QT SYNDROME 10; LQT10 611820LONG QT SYNDROME 11; LQT11 612955LONG QT SYNDROME 12; LQT12 613485LONG QT SYNDROME 13; LQT13 613688LONG QT SYNDROME 2; LQT2 613693LONG QT SYNDROME 6; LQT6 613695LONG QT SYNDROME 5; LQT5Molecular Genetic PathogenesisThe genes associated with RWS encode for potassium or sodium cardiac ion channels or interacting proteins. Mutations in these genes cause abnormal ion channel function: a loss of function in the potassium channels and a gain of function in the sodium channel. This abnormal ion function results in prolongation of the cardiac action potential and susceptibility of the cardiac myocytes to early after depolarizations (EADs), which initiate the ventricular arrhythmia, torsade de pointes (TdP).KCNQ1Normal allelic variants. KCNQ1 is located at chromosome 11p15 and spans approximately 400 kb. The predominant isoform (isoform 1, refseq NM_000218.2) consists of 16 exons and produces a protein of 676 amino acids. Other isoforms, encoding a protein with an alternative N terminal domain (isoform 2) or non-coding transcripts exist. Pathologic allelic variants. More than 400 mutations of KCNQ1 have been reported, including missense, nonsense, splice site, and frameshift mutations as well as large multiexonic deletions (see Note).Normal gene product. The potassium voltage-gated channel subfamily KQT member 1 is the alpha subunit forming the slowly activating potassium delayed rectifier IKs [Keating & Sanguinetti 2001].Abnormal gene product. IKs channel with reduced functionKCNE1Normal allelic variants. KCNE1 is located at chromosome 21q22.12, consists of three exons spanning approximately 40 kb, and encodes a protein of 129 amino acids (NM_000219.3). Pathologic allelic variants. At least 36 mutations have been described, including missense, nonsense, and frameshift mutations (see Note).Normal gene product. The potassium voltage-gated channel subfamily E member 1 is the beta subunit forming the slowly activating potassium delayed rectifier IKs. The two subunits encoded by KCNE1 and KCNQ1 coassemble to form the IKs channel.Abnormal gene product. IKs channel with reduced functionKCNH2Normal allelic variants. KCNH2 is located at chromosome 21q22.12, spanning approximately 19 kb. The longest isoform consists of 16 exons and produces a protein of 1159 amino acids (NM_000238.3). Two shorter isoforms of KCNH2 exist.Pathologic allelic variants. More than 500 mutations have been reported, including missense, nonsense, splice site and frameshift mutations as well as large multiexonic deletions (see Note). Normal gene product. The potassium voltage-gated channel subfamily H member 2 is the alpha subunit forming the rapidly activating potassium delayed rectifier Ikr.Abnormal gene product. IKr channel with reduced functionKCNE2Normal allelic variants. KCNE2 is located at chromosome 21q22.12, consists of three exons spanning approximately 40 kb, and encodes a protein of 123 amino acids (NM_172201.1). Pathologic allelic variants. At least 12 mutations have been reported; they include missense and frameshift mutations (see Molecular Genetic Pathogenesis).Normal gene product. The potassium voltage-gated channel subfamily E member 2 is the beta subunit forming the rapidly activating potassium delayed rectifier IKr. The two subunits encoded by KCNH2 and KCNE2 coassemble to form the IKr channel.Abnormal gene product. IKr channel with reduced functionSCN5ANormal allelic variants. SCN5A is located at chromosome 3p21, consists of 28 exons, spans approximately 80 kb, and encodes a protein of 2016 amino acids (NM_198056.2). An isoform lacking amino acid Gln1077 exists. Pathologic allelic variants. More than 100 mutations are known; they include missense mutations and in-frame deletions or insertions.Normal gene product. The sodium channel protein type V alpha subunit is the alpha subunit forming the cardiac sodium channel.Abnormal gene product. Gain-of-function mutation resulting in a cardiac sodium channel with increased persistent inward currentCAV3Normal allelic variants. CAV3 is located at chromosome 3p25, consists of two exons spanning approximately 12 kb, and encodes a protein of 151 amino acids (NM_033337.2). Pathologic allelic variants. Two probable LQT causing missense mutations in CAV3 have been described.Normal gene product. The caveolin-3 protein is the major scaffolding protein present in caveolae in the heart.Abnormal gene product. Persistent late sodium currentSCN4BNormal allelic variants. SCN4B is located at chromosome 11q23.3; it consists of five exons spanning approximately 20 kb and encodes a protein of 228 amino acids (NM_174934). A shorter isoform exists.Pathologic allelic variants. One missense mutation in SCN4B has been described.Normal gene product. The sodium channel protein type IV beta subunit is a beta subunit forming the cardiac sodium channel.Abnormal gene product. Loss-of-function mutation resulting in a cardiac sodium channel with increased persistent inward currentAKAP9Normal allelic variants. AKAP9 is located at chromosome 7q21-q22, consists of 50 exons and encodes a protein of 3907 amino acids (NM_005751.4). A shorter isoform exists.Pathologic allelic variants. One missense mutation in AKAP9 has been described.Normal gene product. The A kinase (prka) anchor protein (yotiao) 9 is involved in macromolecular complexes controlling phosphorylation of a number of proteins, including the Iks channel. Abnormal gene product. Loss-of-function mutation resulting in an IKs channel with reduced functionSNTA1Normal allelic variants. SNTA1 is located at chromosome 20q11.1, consists of eight exons spanning approximately 35 kb, and encodes a protein of 505 amino acids (NM_003098.2). Pathologic allelic variants. Two missense mutations in SNTA1 have been described.Normal gene product. The alpha-1 syntrophin is a scaffolding protein involved in macromolecular complexes controlling the function of, among others, the cardiac sodium channel.Abnormal gene product. Loss-of-function mutation resulting in a cardiac sodium channel with increased persistent inward currentKCNJ5Normal allelic variants. KCNJ5 is located at chromosome 11q24, consists of three exons spanning approximately 30 kb and encodes a protein of 419 amino acids (NM_000890.3). Pathologic allelic variants. One missense mutation in KCNJ5 has been described.Normal gene product. The potassium inwardly-rectifying channel, subfamily J, member 5 is a subunit of the cardiac inwardly rectifying potassium channel IKACh.Abnormal gene product. Loss of function mutation resulting in an IKACh channel with reduced functionNoteMore than 900 mutations in the ten LQTS-related genes have been reported and are listed in the various databases found in Table A. In general, approximately 70% are missense mutations, 15% are frameshift mutations, and in-frame deletions, nonsense mutations, and splice site mutations make up 3%-6% each. However, this distribution varies by gene. Radical mutations such as frameshift, nonsense, and splice site mutations are relatively more frequent in KCNQ1 and KCNH2 and are not present in SCN5A in individuals with LQT (such mutations in SCN5A cause Brugada syndrome rather than LQTS).