Long QT Syndrome

Clinical characteristics.

Long QT syndrome (LQTS) is a cardiac electrophysiologic disorder, characterized by QT prolongation and T-wave abnormalities on the EKG that are associated with tachyarrhythmias, typically the ventricular tachycardia torsade de pointes (TdP). TdP is usually self-terminating, thus causing a syncopal event, the most common symptom in individuals with LQTS. Such cardiac events typically occur during exercise and emotional stress, less frequently during sleep, and usually without warning. In some instances, TdP degenerates to ventricular fibrillation and causes aborted cardiac arrest (if the individual is defibrillated) or sudden death. Approximately 50% of untreated individuals with a pathogenic variant in one of the genes associated with LQTS have symptoms, usually one to a few syncopal events. While cardiac events may occur from infancy through middle age, they are most common from the preteen years through the 20s. Some types of LQTS are associated with a phenotype extending beyond cardiac arrhythmia. In addition to the prolonged QT interval, associations include muscle weakness and facial dysmorphism in Andersen-Tawil syndrome (LQTS type 7); hand/foot, facial, and neurodevelopmental features in Timothy syndrome (LQTS type 8); and profound sensorineural hearing loss in Jervell and Lange-Nielson syndrome.

Diagnosis/testing.

Diagnosis of LQTS is established by prolongation of the QTc interval in the absence of specific conditions known to lengthen it (for example, QT-prolonging drugs) and/or by molecular genetic testing that identifies a diagnostic change (or changes) in one or more of the 15 genes known to be associated with LQTS – of which KCNH2 (LQT2), KCNQ1 (locus name LQT1), and SCN5A (LQT3) are the most common. Approximately 20% of families meeting clinical diagnostic criteria for LQTS do not have detectable pathogenic variants in a known gene. LQTS associated with biallelic pathogenic variants or heterozygosity for pathogenic variants in two different genes (i.e., digenic pathogenic variants) is generally associated with a more severe phenotype with longer QTc interval.

Management.

Treatment of manifestations: Beta blocker medication is the primary treatment for LQTS; possible implantable cardioverter-defibrillators (ICD) and/or left cardiac sympathetic denervation (LCSD) for those with beta-blocker-resistant symptoms, inability to take beta blockers, and/or history of cardiac arrest. Sodium channel blockers can be useful as additional pharmacologic therapy for patients with a QTc interval >500 ms.

Prevention of primary manifestations: Beta blockers are clinically indicated in all asymptomatic individuals meeting diagnostic criteria, including those who have a pathogenic variant on molecular testing and a normal QTc interval. In general, ICD implantation is not indicated for individuals with LQTS who are asymptomatic and who have not been tried on beta blocker therapy. Prophylactic ICD therapy can be considered for individuals with LQTS who are asymptomatic but suspected to be at very high risk (e.g., those with ≥2 pathogenic variants on molecular testing).

Surveillance: Regular assessment of beta blocker dose for efficacy and adverse effects in all individuals with LQTS, especially children during rapid growth; regular periodic evaluations of ICDs for inappropriate shocks and pocket or lead complications.

Agents/circumstances to avoid: Drugs that cause further prolongation of the QT interval or provoke torsade de pointes; competitive sports / activities associated with intense physical activity and/or emotional stress for most individuals.

Evaluation of relatives at risk: Presymptomatic diagnosis and treatment is warranted in relatives at risk to prevent syncope and sudden death.

Other: For some individuals, availability of automatic external defibrillators at home, at school, and in play areas.

Genetic counseling.

LQTS is typically inherited in an autosomal dominant manner. An exception is LQTS associated with sensorineural deafness (known as Jervell and Lange-Nielsen syndrome), which is inherited in an autosomal recessive manner. Most individuals diagnosed with LQTS have an affected parent. The proportion of LQTS caused by a de novo pathogenic variant is small. Each child of an individual with autosomal dominant LQTS has a 50% risk of inheriting the pathogenic variant. Penetrance of the disorder may vary. Prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible once the pathogenic variant(s) have been identified in the family.

Suggestive Findings

Long QT syndrome (LQTS) should be suspected in individuals on the basis of EKG characteristics, clinical presentation, and family history.

Establishing the Diagnosis

Schwartz et al [1993] proposed a scoring system to diagnose LQTS on a clinical basis; it was updated by Schwartz & Crotti [2011]. Points are assigned to various criteria (see Table 1).

Table 1.

Scoring System for Clinical Diagnosis of Long QT Syndrome

The diagnosis of LQTS is established in a proband with one or more of the following [Priori et al 2013]:

• A risk score of ≥3.5 (see Table 1) in the absence of a secondary cause for QT prolongation
• The presence of a corrected QT interval ≥500 ms in repeated EKGs in the absence of a secondary cause for QT prolongation
• The identification of a pathogenic variant in one of the genes known to be associated with LQTS (see Tables 2a and 2b)

Molecular genetic testing approaches can include use of a multigene panel, single-gene testing, and more comprehensive genomic testing:

• A multigene panel that includes the genes listed in Tables 2a and 2b and other genes of interest (see Differential Diagnosis) is recommended for molecular diagnosis. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Single-gene testing. Molecular genetic testing based on the individual's phenotype (T-wave pattern and triggers of syncope), which has been shown to predict the genotype [Zhang et al 2000, Van Langen et al 2003] (see Table 3) can be performed. Sequence analysis is performed first; it may be followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
• More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 2a.

Molecular Genetics of Long QT Syndrome (LQTS): Most Common Genetic Causes

Table 2b.

Molecular Genetics of LQTS: Less Common Genetic Causes

Note: Approximately 20% of families with a clinically firm diagnosis of LQTS do not have a detectable pathogenic variant in one of the 15 genes (AKAP9, ANK2, CACNA1C, CALM1, CALM2, CAV3, KCNE1, KCNE2, KCNH2, KCNJ2, KCNJ5, KCNQ1, SCN4B, SCN5A, and SNTA1) known to be associated with LQTS, suggesting that pathogenic variants in other genes can also cause LQTS and/or that current test methods do not detect all pathogenic variants in the known genes [Schwartz et al 2012, Giudicessi & Ackerman 2013].

Clinical Description

Long QT syndrome (LQTS) is characterized by QT prolongation and T-wave abnormalities on EKG 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 LQTS. 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.

Approximately 50% or fewer of untreated individuals with a pathogenic variant in one of the 15 genes (see Table 2a, Table 2b) associated with LQTS have 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.

Most Common Phenotypes

Pathogenic variants in KCNH2, KCNQ1, and SCN5A account for the vast majority of cases of LQTS and distinct genotype-phenotype correlations have been reported (see Table 3). Three clinical phenotypes (LQTS types 1, 2, and 3) are recognized in individuals with pathogenic variants in these genes.

• QTc range is similar across phenotypes (~400-600+ msec). The average QTc values are similar for the LQTS type 1 and LQTS type 2 phenotypes and somewhat longer for the LQTS type 3 phenotype.
• T-wave patterns characteristic for the LQTS type 1, 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].
• Cardiac events often have genotype-specific triggers [Schwartz et al 2001]. In the LQTS type 1 phenotype symptoms are mostly triggered by exercise while in the LQTS type 2 phenotype events are mostly triggered by auditory stimuli and emotional stress. In the LQTS type 3 phenotype symptoms mostly occur during sleep.

Table 3.

Phenotype Correlations by Gene

Genotype-Phenotype Correlations

Long QT syndrome (LQTS) associated with biallelic pathogenic variants or heterozygosity for pathogenic variants in two different genes (i.e., digenic pathogenic variants) is generally associated with a more severe phenotype with longer QTc interval and a higher incidence of cardiac events [Schwartz et al 2003, Westenskow et al 2004, Tester et al 2005, Itoh et al 2010].

There are no specific genotype-phenotype correlations known other than as noted in Clinical Description.

Penetrance

LQTS exhibits reduced penetrance of the EKG changes and symptoms. Overall, approximately 25% of individuals with a pathogenic variant have a normal QTc (defined as <440 msec) on baseline EKG. The percentage of genetically affected individuals with a normal QTc was higher in the LQTS type 1 group (36%) than in the LQTS type 2 group (19%) or type 3 group (10%) [Priori et al 2003, Goldenberg et al 2011].

As noted in Table 3, penetrance for symptoms is also reduced. At least 37% of individuals with the LQTS type 1 phenotype, 54% with the type 2 phenotype, and 82% with the type 3 phenotype remain asymptomatic.

Nomenclature

The term "Romano-Ward syndrome" refers to forms of long QT syndrome with a purely cardiac phenotype, inherited in an autosomal dominant manner (LQTS types 1-3, type 5, type 6, and types 9-15).

Prevalence

The prevalence of LQTS has been estimated at 1:2,500 [Schwartz et al 2009, Giudicessi & Ackerman 2013, Lieve & Wilde 2015].

LQTS has been identified in all ethnic groups.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with LQTS, the main focus in the management of individuals with LQTS is to identify the subset of individuals at high risk for cardiac events. For this risk stratification the following evaluations are recommended if they have not already been completed:

• EKG evaluation. Individuals with a QTc interval >500 ms are at higher risk for an event; individuals with QTc interval >600 ms are at extremely high risk [Priori et al 2003, Goldenberg et al 2008]. Overt T-wave alternans, especially when present despite proper beta blocker therapy, is also associated with a higher risk for cardiac events [Priori et al 2013]. Individuals with a pathogenic variant who have a normal QTc interval are at low risk [Priori et al 2013].
• Medical history. Individuals with syncope or cardiac arrest in the first year of life [Schwartz et al 2009, Spazzolini et al 2009] or younger than age seven years [Priori et al 2004] are at higher risk. These individuals may not be fully protected by pharmacologic treatment. Individuals with arrhythmic events while on proper pharmacologic treatment are also at higher risk [Priori et al 2013]. Asymptomatic individuals with pathogenic variants or individuals with prolonged QT intervals who have been asymptomatic at a young age (age <40 years) are at low risk for events later in life, although females remain at risk after age 40 years [Locati et al 1998].
• Other. Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

All symptomatic persons should be treated (see Priori et al [2013]). 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 are the mainstay of therapy for LQTS, including asymptomatic individuals with prolonged QT intervals and individuals who have a pathogenic variant on molecular testing with a normal QTc interval [Priori et al 2004, Schwartz et al 2009]. Some individuals have symptoms despite the use of beta blockers [Moss et al 2000]. However, a majority of cardiac events that occur in individuals with LQTS type 1 phenotype "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 LQTS type 2, but that has not been systematically studied. It is therefore important to:
  • Avoid inadequate beta blocker dosing by regular adjustments in growing children, with evaluation of the efficacy of dose by assessment of the exercise EKG or ambulatory EKG;
  • Administer beta blockers daily, and have strategies are in place in case of missed doses;
  • Use long-acting agents (e.g., nadolol) preferentially to increase compliance and avoid use of short-acting metoprolol [Chockalingam et al 2012];
  • Administer QT-prolonging drugs (see Agents/Circumstances to Avoid) to individuals with LQTS ONLY after careful consideration of risk versus benefit by the individual(s) and physician(s).
• Implantable cardioverter-defibrillators (ICDs) are recommended in individuals with LQTS resuscitated from a cardiac arrest, although children with a LQTS type 1 phenotype with an arrest while not receiving beta blockers can be treated with beta blockers or with left cardiac sympathetic denervation [Alexander et al 2004, Vincent et al 2009, Jons et al 2010]. ICDs can be useful for those individuals with beta-blocker-resistant symptoms or a contraindication for beta blocker therapy (severe asthma) [Zareba et al 2003, Priori et al 2013].
• Left cardiac sympathetic denervation (LCSD) is recommended for high-risk patients with LQTS in whom ICD therapy is refused or contraindicated and/or in whom beta blockers are either not effective, not tolerated, not accepted, or contraindicated [Schwartz et al 2004, Priori et al 2013]. LCSD can be useful in individuals who experience events while on therapy with beta blockers or ICD [Priori et al 2013].
• Sodium channel blockers can be useful as additional pharmacologic therapy for individuals with a LQTS type 3 phenotype with a QTc interval >500 ms in whom this additional compound is shown to shorten the QTc interval by >40 ms [Priori et al 2013].

Note: Most affected individuals live normal lives. Education of adult individuals and the parents of affected children, especially about beta blocker compliance, is an important aspect of management.

Prevention of Primary Manifestations

Beta blockers. Beta blockers are clinically indicated in all asymptomatic individuals, including those who have a pathogenic variant on molecular testing with a normal QTc interval [Priori et al 2004, Schwartz et al 2009]. Males who have a pathogenic variant and who have been asymptomatic before age 40 years are at low risk for cardiac events. In these individuals the necessity of beta blockers can be discussed [Locati et al 1998].

ICD. In general, ICD implantation is not indicated for asymptomatic individuals with LQTS who have not been tried on beta blocker therapy. Prophylactic ICD therapy can be considered for asymptomatic individuals suspected to be at very high risk, such as asymptomatic individuals with two or more pathogenic variants on molecular testing [Priori et al 2013]. LQTS-related sudden death in a close relative is not an indication for an ICD in surviving relatives [Kaufman et al 2008].

Prevention of Secondary Complications

Examine 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 EKG during such interventions and to alert the appropriate medical personnel in case intervention is needed.

Surveillance

Beta blocker dose should be regularly assessed for efficacy and adverse effects; doses should be altered as needed. Dose adjustment including efficacy testing is especially important in growing children.

Individuals with an ICD implanted should have regular, periodic evaluations of ICDs for inappropriate shocks and pocket or lead complications.

Agents/Circumstances to Avoid

Drugs that cause further prolongation of the QT interval or provoke torsade de pointes should be avoided for all individuals with LQTS. See CredibleMeds^® (free registration required) for a complete and updated list. Epinephrine given as part of local anesthetics can trigger arrhythmias and is best avoided.

Since electrolyte imbalances may also lengthen the QTc interval, identification and correction of electrolyte abnormalities is important. These imbalances can occur as a result of diarrhea, vomiting, metabolic conditions, and unbalanced diets for weight loss.

Lifestyle modifications are advised based on genotype. For individuals with LQTS type 1 phenotype, avoidance of strenuous exercise – especially swimming without supervision – is advised. In individuals with LQTS type 2 phenotype, reduction in exposure to loud noises such as alarm clocks and phone ringing is advised. Individuals at high risk for cardiac events or with exercise-induced symptoms should avoid competitive sports [Priori et al 2013]. For some individuals participation in competitive sports may be safe. It is therefore recommended that all individuals with LQTS who wish to engage in competitive sports have their risk evaluated by a clinical expert [Johnson & Ackerman 2012, Priori et al 2013].

Evaluation of Relatives at Risk

Presymptomatic diagnosis of at-risk relatives followed by treatment is necessary to prevent syncope and sudden death in those individuals who have inherited the pathogenic variant and/or have EKG findings consistent with LQTS. At-risk family members should be alerted to their risk and the need to be evaluated.

Relatives at high potential risk for LQTS who require further testing include members of a family:

• That has documented LQTS;
• In which evaluation for LQTS has not been performed.

Presymptomatic diagnosis for at-risk asymptomatic family members can be performed by one or both of the following:

• Molecular genetic testing if the pathogenic variant in the family is known
• If the pathogenic variant is not known or if genetic testing is not possible, QTc analysis on resting and in case of normal QTc also QTc analysis on exercise EKGs
  Note: The diagnostic accuracy by QTc analysis is considerably improved by evaluation of the exercise EKG QTc intervals, in addition to the resting EKG, using the QTc values listed in Table 1.

Relatives at low potential risk who do not require further testing include members of a family sharing a common relative with the proband where the common relative:

• Has a low probability of LQTS based on QTc interval (see Table 1) and has not experienced LQTS-type events; or
• Has a normal QTc interval and no evidence of a pathogenic variant in one of the genes known to cause LQTS; or
• Does not have the family-specific pathogenic variant, if known.

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 LQTS type 2 phenotype. Beta blocker treatment was associated with a reduction of events in this nine-month time period after delivery [Seth et al 2007].

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

A current study is evaluating the drug ranolazine in individuals with LQTS who have a pathogenic variant in SCN5A.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Long QT syndrome (LQTS) is typically inherited in an autosomal dominant manner.

LQTS with extracardiac signs can be inherited in an autosomal dominant or autosomal recessive manner. Timothy syndrome and Andersen-Tawil syndrome are inherited in an autosomal dominant manner. Jervell and Lange-Nielsen syndrome is inherited in an autosomal recessive manner (see Jervell and Lange-Nielsen Syndrome, Genetic Counseling for discussion of autosomal recessive inheritance and genetic counseling for this disorder).

Risk to Family Members (Autosomal Dominant Inheritance)

Parents of a proband

• The majority of individuals diagnosed with LQTS have inherited a pathogenic variant from a parent.
• A proband with LQTS may have the disorder as the result of a de novo pathogenic variant. The proportion of cases caused by de novo pathogenic variants is small.
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
• If the pathogenic variant identified in the proband cannot be detected in the DNA of either parent, possible explanations include a de novo pathogenic variant in the proband and germline mosaicism in a parent (the incidence of germline mosaicism is very low: 0.17%, see Priest et al [2016]).
• The family history of some individuals diagnosed with LQTS may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband (see Management, Evaluation of Relatives at Risk).

Note: Biallelic and digenic pathogenic variants have been described (see Genotype-Phenotype Correlations). If an individual with LQTS has biallelic or digenic pathogenic variants, the possibility that both parents have pathogenic variants should be considered.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is heterozygous for the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Because LQTS exhibits reduced penetrance, sibs who inherit a pathogenic variant may or may not have symptomatic LQTS. Considerable phenotypic variability within families has also been reported [Giudicessi & Ackerman 2013].
• If the proband has a known LQTS-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent; the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [Priest et al 2016].
• If the parents are clinically unaffected but have not been tested for the pathogenic variant, recurrence risk in sibs is estimated to be 50% because a heterozygous parent may be clinically unaffected due to reduced penetrance of LQTS-related EKG changes and symptoms.

Offspring of a proband. Each child of an individual with LQTS has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent is clinically affected or has a pathogenic variant, his or her family members are at risk.

Specific risk issues. With the reduced penetrance of symptoms in individuals with LQTS, careful EKG evaluation including exercise EKG is often necessary to identify affected family members accurately. The absence of a family history of sudden death is common and does not negate the diagnosis or preclude the possibility of sudden death in relatives.

Related Genetic Counseling Issues

Testing of at-risk asymptomatic adults and children. Testing of at-risk asymptomatic adults for LQTS is possible using the techniques described in Diagnosis, Establishing the Diagnosis. Such testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. To facilitate the use of morbidity- and mortality-reducing interventions, presymptomatic testing of all at-risk family members (especially of individuals age <18 years, as the risk for cardiac events is greatest in childhood) should be considered (see Management, Evaluation of Relatives at Risk). When testing at-risk individuals for LQTS, an affected family member should be tested first to identify the pathogenic variant in the family. If no pathogenic variant is identified in an affected family member (the case in ~20% of families with LQTS) [Ackerman et al 2011], at-risk relatives should undergo careful clinical examination.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband, it is likely that the proband has a de novo pathogenic variant. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

The genes associated with LQTS encode for potassium or sodium cardiac ion channels or interacting proteins. Pathogenic variants 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).

More than 1,400 pathogenic variants in the 15 LQTS-related genes have been reported and are listed in the various databases found in Table A. In general, approximately 70% of pathogenic variants reported are missense, 15% are frameshift, and in-frame deletions and nonsense and splice site variants make up 3%-6% each. However, this distribution varies by gene. Radical pathogenic variants such as frameshift, nonsense, and splice site types are relatively more frequent in KCNQ1 and KCNH2 and are not present in SCN5A in individuals with LQTS (such pathogenic variants in SCN5A cause Brugada syndrome rather than LQTS).

For a detailed summary of gene and protein information for the genes listed below, see Table A, Gene.

Published Guidelines / Consensus Statements

• American College of Cardiology/American Heart Association Task Force, and the European Society of Cardiology/Committee for Practice Guidelines. Guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Available online. 2006. Accessed 2-24-22.

• Vincent GM. Role of DNA testing for diagnosis, management, and genetic screening in long QT syndrome, hypertrophic cardiomyopathy, and Marfan syndrome. Available online. 2001. Accessed 2-24-22. [PMC free article: PMC1729812] [PubMed: 11410552]

Literature Cited

• Ackerman MJ, Khositseth A, Tester DJ, Hejlik JB, Shen WK, Porter CB. Epinephrine-induced QT interval prolongation: a gene-specific paradoxical response in congenital long QT syndrome. Mayo Clin Proc. 2002;77:413–21. [PubMed: 12004990]

• Ackerman MJ, Priori SG, Willems S, Berul C, Brugada R, Calkins H, Camm AJ, Ellinor PT, Gollob M, Hamilton R, Hershberger RE, Judge DP, Le Marec H, McKenna WJ, Schulze-Bahr E, Semsarian C, Towbin JA, Watkins H, Wilde A, Wolpert C, Zipes DP. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Heart Rhythm. 2011;8:1308–39. [PubMed: 21787999]

• Ackerman MJ, Siu BL, Sturner WQ, Tester DJ, Valdivia CR, Makielski JC, Towbin JA. Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome. JAMA. 2001;286:2264–9. [PubMed: 11710892]

• Alexander ME, Cecchin F, Walsh EP, Triedman JK, Bevilacqua LM, Berul CI. Implications of implantable cardioverter defibrillator therapy in congenital heart disease and pediatrics. J Cardiovasc Electrophysiol. 2004;2004;15:72–6. [PubMed: 15028076]

• Arnestad M, Crotti L, Rognum TO, Insolia R, Pedrazzini M, Ferrandi C, Vege A, Wang DW, Rhodes TE, George AL Jr, Schwartz PJ. Prevalence of long-QT syndrome gene variants in sudden infant death syndrome. Circulation. 2007;115:361–7. [PubMed: 17210839]

• Barc J, Briec F, Schmitt S, Kyndt F, Le Cunff M, Baron E, Vieyres C, Sacher F, Redon R, Le Caignec C, Le Marec H, Probst V, Schott JJ. Screening for copy number variation in genes associated with the long QT syndrome: clinical relevance. J Am Coll Cardiol. 2011;57:40–7. [PubMed: 21185499]

• Chen L, Marquardt ML, Tester DJ, Sampson KJ, Ackerman MJ, Kass RS. Mutation of an A-kinase-anchoring protein causes long-QT syndrome. Proc Natl Acad Sci U S A. 2007;104:20990–5. [PMC free article: PMC2409254] [PubMed: 18093912]

• Chockalingam P, Crotti L, Girardengo G, Johnson JN, Harris KM, van der Heijden JF, Hauer RN, Beckmann BM, Spazzolini C, Rordorf R, Rydberg A, Clur SA, Fischer M, van den Heuvel F, Kääb S, Blom NA, Ackerman MJ, Schwartz PJ, Wilde AA. Not all beta-blockers are equal in the management of long QT syndrome types 1 and 2: higher recurrence of events under metoprolol. J Am Coll Cardiol. 2012;60:2092–9. [PMC free article: PMC3515779] [PubMed: 23083782]

• Cronk LB, Ye B, Kaku T, Tester DJ, Vatta M, Makielski JC, Ackerman MJ. Novel mechanism for sudden infant death syndrome: persistent late sodium current secondary to mutations in caveolin-3. Heart Rhythm. 2007;4:161–6. [PMC free article: PMC2836535] [PubMed: 17275750]

• Crotti L, Johnson CN, Graf E, De Ferrari GM, Cuneo BF, Ovadia M, Papagiannis J, Feldkamp MD, Rathi SG, Kunic JD, Pedrazzini M, Wieland T, Lichtner P, Beckmann BM, Clark T, Shaffer C, Benson DW, Kääb S, Meitinger T, Strom TM, Chazin WJ, Schwartz PJ, George AL Jr. Calmodulin mutations associated with recurrent cardiac arrest in infants. Circulation. 2013;127:1009–17. [PMC free article: PMC3834768] [PubMed: 23388215]

• Giudicessi JR, Ackerman MJ. Genotype- and phenotype-guided management of congenital long QT syndrome. Curr Probl Cardiol. 2013;38:417–55. [PMC free article: PMC3940076] [PubMed: 24093767]

• Goldenberg I, Horr S, Moss AJ, Lopes CM, Barsheshet A, McNitt S, Zareba W, Andrews ML, Robinson JL, Locati EH, Ackerman MJ, Benhorin J, Kaufman ES, Napolitano C, Platonov PG, Priori SG, Qi M, Schwartz PJ, Shimizu W, Towbin JA, Vincent GM, Wilde AA, Zhang L. Risk for life-threatening cardiac events in patients with genotype-confirmed long-QT syndrome and normal-range corrected QT intervals. J Am Coll Cardiol. 2011;57:51–9. [PMC free article: PMC3332533] [PubMed: 21185501]

• Goldenberg I, Zareba W, Moss AJ. Long QT syndrome. Curr Probl Cardiol. 2008;33:629–94. [PubMed: 18835466]

• Horner JM, Horner MM., Ackermann MJ. The diagnostic utility of recovery phase QTc during treadmill exercise stress testing in the evaluation of long QT syndrome. Heart Rhythm. 2011;8:1698–704. [PubMed: 21699858]

• Itoh H, Shimizu W, Hayashi K, Yamagata K, Sakaguchi T, Ohno S, Makiyama T, Akao M, Ai T, Noda T, Miyazaki A, Miyamoto Y, Yamagishi M, Kamakura S, Horie M. Long QT syndrome with compound mutations is associated with a more severe phenotype: a Japanese multicenter study. Heart Rhythm. 2010;7:1411–8. [PubMed: 20541041]

• Jervell A, Lange-Nielsen F. Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval and sudden death. Am Heart J. 1957;54:59–68. [PubMed: 13435203]

• Johnson JN, Ackerman MJ. Competitive sports participation in athletes with congenital long QT syndrome. JAMA. 2012;308:764–5. [PubMed: 22820673]

• Jons C, Moss AJ, Goldenberg I, Liu J, McNitt S, Zareba W, Qi M, Robinson JL. Risk of fatal arrhythmic events in long QT syndrome patients after syncope. J Am Coll Cardiol. 2010;55:783–8. [PubMed: 20170817]

• Kapplinger JD, Tester DJ, Salisbury BA, Carr JL, Harris-Kerr C, Pollevick GD, Wilde AA, Ackerman MJ. Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. Heart Rhythm. 2009;6:1297–303. [PMC free article: PMC3049907] [PubMed: 19716085]

• Kaufman ES, McNitt S, Moss AJ, Zareba W, Robinson JL, Hall WJ, Ackerman MJ, Benhorin J, Locati ET, Napolitano C, Priori SG, Schwartz PJ, Towbin JA, Vincent GM, Zhang L. Risk of death in the long QT syndrome when a sibling has died. Heart Rhythm. 2008;5:831–6. [PMC free article: PMC2486317] [PubMed: 18534367]

• Keating MT, Sanguinetti MC. Molecular and cellular mechanisms of cardiac arrhythmias. Cell. 2001;104:569–80. [PubMed: 11239413]

• Kimura H, Zhou J, Kawamura M, Itoh H, Mizusawa Y, Ding WG, Wu J, Ohno S, Makiyama T, Miyamoto A, Naiki N, Wang Q, Xie Y, Suzuki T, Tateno S, Nakamura Y, Zang WJ, Ito M, Matsuura H, Horie M. Phenotype variability in patients carrying KCNJ2 mutations. Circ Cardiovasc Genet. 2012;5:344–53. [PubMed: 22589293]

• Lieve KV, Wilde AA. Inherited ion channel diseases: a brief review. Europace. 2015;17 Suppl 2:ii1–ii6. [PubMed: 26842110]

• Lieve KV, Williams L, Daly A, Richard G, Bale S, Macaya D, Chung WK. Results of genetic testing in 855 consecutive unrelated patients referred for long QT syndrome in a clinical laboratory. Genet Test Mol Biomarkers. 2013;17:553–61. [PubMed: 23631430]

• Locati EH, Zareba W, Moss AJ, Schwartz PJ, Vincent GM, Lehmann MH, Towbin JA, Priori SG, Napolitano C, Robinson JL, Andrews M, Timothy K, Hall WJ. Age- and sex-related differences in clinical manifestations in patients with congenital long-QT syndrome: findings from the International LQTS Registry. Circulation. 1998;97:2237–44. [PubMed: 9631873]

• Mohler PJ, Le Scouarnec S, Denjoy I, Lowe JS, Guicheney P, Caron L, Driskell IM, Schott JJ, Norris K, Leenhardt A, Kim RB, Escande D, Roden DM. Defining the cellular phenotype of "ankyrin-B syndrome" variants: human ANK2 variants associated with clinical phenotypes display a spectrum of activities in cardiomyocytes. Circulation. 2007;115:432–41. [PubMed: 17242276]

• Mohler PJ, Schott JJ, Gramolini AO, Dilly KW, Guatimosim S, duBell WH, Song LS, Haurogne K, Kyndt F, Ali ME, Rogers TB, Lederer WJ, Escande D, Le Marec H, Bennett V. Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death. Nature. 2003;421:634–9. [PubMed: 12571597]

• Moss AJ, Zareba W, Hall WJ, Schwartz PJ, Crampton RS, Benhorin J, Vincent GM, Locati EH, Priori SG, Napolitano C, Medina A, Zhang L, Robinson JL, Timothy K, Towbin JA, Andrews ML. Effectiveness and limitations of beta-blocker therapy in congenital long-QT syndrome. Circulation. 2000;101:616–23. [PubMed: 10673253]

• Nannenberg EA, Sijbrands EJ, Dijksman LM, Alders M, van Tintelen JP, Birnie M, Van Langen IM, Wilde AA. Mortality of inherited arrhythmia syndromes: insight into their natural history. Circ Cardiovasc Genet. 2012;5:183–9. [PubMed: 22373669]

• Priest JR, Gawad C, Kahlig KM, Yu JK, O'Hara T, Boyle PM, Rajamani S, Clark MJ, Garcia ST, Ceresnak S, Harris J, Boyle S, Dewey FE, Malloy-Walton L, Dunn K, Grove M, Perez MV, Neff NF, Chen R, Maeda K, Dubin A, Belardinelli L, West J, Antolik C, Macaya D, Quertermous T, Trayanova NA, Quake SR, Ashley EA. Early somatic mosaicism is a rare cause of long-QT syndrome. Proc Natl Acad Sci U S A. 2016;113:11555–60. [PMC free article: PMC5068256] [PubMed: 27681629]

• Priori SG, Napolitano C, Schwartz PJ, Grillo M, Bloise R, Ronchetti E, Moncalvo C, Tulipani C, Veia A, Bottelli G, Nastoli J. Association of long QT syndrome loci and cardiac events among patients treated with beta-blockers. JAMA. 2004;292:1341–4. [PubMed: 15367556]

• Priori SG, Schwartz PJ, Napolitano C, Bloise R, Ronchetti E, Grillo M, Vicentini A, Spazzolini C, Nastoli J, Bottelli G, Folli R, Cappelletti D. Risk stratification in the long-QT syndrome. N Engl J Med. 2003;348:1866–74. [PubMed: 12736279]

• Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, Blom N, Brugada J, Chiang CE, Huikuri H, Kannankeril P, Krahn A, Leenhardt A, Moss A, Schwartz PJ, Shimizu W, Tomaselli G, Tracy C. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm. 2013;10:1932–63. [PubMed: 24011539]

• Schwartz PJ, Crotti L. QTc behavior during exercise and genetic testing for the long-QT syndrome. Circulation. 2011;124:2181–4. [PubMed: 22083145]

• Schwartz PJ, Crotti L, Insolia R. Long-QT syndrome: from genetics to management. Circ Arrhythm Electrophysiol. 2012;5:868–877. [PMC free article: PMC3461497] [PubMed: 22895603]

• Schwartz PJ, Moss AJ, Vincent GM, Crampton RS. Diagnostic criteria for the long QT syndrome. An update. Circulation. 1993;88:782–4. [PubMed: 8339437]

• Schwartz PJ, Priori SG, Cerrone M, Spazzolini C, Odero A, Napolitano C, Bloise R, De Ferrari GM, Klersy C, Moss AJ, Zareba W, Robinson JL, Hall WJ, Brink PA, Toivonen L, Epstein AE, Li C, Hu D. Left cardiac sympathetic denervation in the management of high-risk patients affected by the long-QT syndrome. Circulation. 2004;109:1826–33. [PubMed: 15051644]

• Schwartz PJ, Priori SG, Napolitano C. How really rare are rare diseases? J Cardiovasc Electrophysiol. 2003;14:1120–1. [PubMed: 14521668]

• Schwartz PJ, Priori SG, Spazzolini C, Moss AJ, Vincent GM, Napolitano C, Denjoy I, Guicheney P, Breithardt G, Keating MT, Towbin JA, Beggs AH, Brink P, Wilde AA, Toivonen L, Zareba W, Robinson JL, Timothy KW, Corfield V, Wattanasirichaigoon D, Corbett C, Haverkamp W, Schulze-Bahr E, Lehmann MH, Schwartz K, Coumel P, Bloise R. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation. 2001;103:89–95. [PubMed: 11136691]

• Schwartz PJ, Spazzolini C, Crotti L. All LQT3 patients need an ICD: true or false? Heart Rhythm. 2009;6:113–20. [PubMed: 19121811]

• Seth R, Moss AJ, McNitt S, Zareba W, Andrews ML, Qi M, Robinson JL, Goldenberg I, Ackerman MJ, Benhorin J, Kaufman ES, Locati EH, Napolitano C, Priori SG, Schwartz PJ, Towbin JA, Vincent GM, Zhang L. Long QT syndrome and pregnancy. J Am Coll Cardiol. 2007;49:1092–8. [PubMed: 17349890]

• Shigemizu D, Aiba T, Nakagawa H, Ozaki K, Miya F, Satake W, Toda T, Miyamoto Y, Fujimoto A, Suzuki Y, Kubo M, Tsunoda T, Shimizu W, Tanaka T. Exome analyses of long QT syndrome reveal candidate pathogenic mutations in calmodulin-interacting genes. PLoS One. 2015;10:e0130329. [PMC free article: PMC4488844] [PubMed: 26132555]

• Shimizu W, Noda T, Takaki H, Nagaya N, Satomi K, Kurita T, Suyama K, Aihara N, Sunagawa K, Echigo S, Miyamoto Y, Yoshimasa Y, Nakamura K, Ohe T, Towbin JA, Priori SG, Kamakura S. Diagnostic value of epinephrine test for genotyping LQT1, LQT2, and LQT3 forms of congenital long QT syndrome. Heart Rhythm. 2004;1:276–83. [PubMed: 15851169]

• Spazzolini C, Mullally J, Moss AJ, Schwartz PJ, McNitt S, Ouellet G, Fugate T, Goldenberg I, Jons C, Zareba W, Robinson JL, Ackerman MJ, Benhorin J, Crotti L, Kaufman ES, Locati EH, Qi M, Napolitano C, Priori SG, Towbin JA, Vincent GM. Clinical implications for patients with long QT syndrome who experience a cardiac event during infancy. J Am Coll Cardiol. 2009;54:832–7. [PMC free article: PMC3517782] [PubMed: 19695463]

• Swan H, Toivonen L, Viitasalo M. Rate adaptation of QT intervals during and after exercise in children with congenital long QT syndrome. Eur Heart J. 1998;19:508–13. [PubMed: 9568456]

• Sy RW, van der Werf C, Chattha IS, Chockalingam P, Adler A, Healey JS, Perrin M, Gollob MH, Skanes AC, Yee R, Gula LJ, Leong-Sit P, Viskin S, Klein GJ, Wilde AA, Krahn AD. Derivation and validation of a simple exercise-based algorithm for prediction of genetic testing in relatives of LQTS probands. Circulation. 2011;124:2187–94. [PubMed: 22042885]

• Tester DJ, Will ML, Haglund CM, Ackerman MJ. Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. Heart Rhythm. 2005;2:507–17. [PubMed: 15840476]

• Van Langen IM, Birnie E, Alders M, Jongbloed RJ, Le Marec H, Wilde AA. The use of genotype-phenotype correlations in mutation analysis for the long QT syndrome. J Med Genet. 2003;40:141–5. [PMC free article: PMC1735373] [PubMed: 12566525]

• Vatta M, Ackerman MJ, Ye B, Makielski JC, Ughanze EE, Taylor EW, Tester DJ, Balijepalli RC, Foell JD, Li Z, Kamp TJ, Towbin JA. Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome. Circulation. 2006;114:2104–12. [PubMed: 17060380]

• Vincent GM, Jaiswal D, Timothy KW. Effects of exercise on heart rate, QT, QTc and QT/QS2 in the Romano-Ward inherited long QT syndrome. Am J Cardiol. 1991;68:498–503. [PubMed: 1872278]

• Vincent GM, Schwartz PJ, Denjoy I, Swan H, Bithell C, Spazzolini C, Crotti L, Piippo K, Lupoglazoff JM, Villain E, Priori SG, Napolitano C, Zhang L. High efficacy of beta-blockers in long-QT syndrome type1; contribution of noncompliance and QT-prolonging drugs to the occurrence of beta-blocker treatment "failures". Circulation. 2009;119:215–21. [PubMed: 19118258]

• Vincent GM, Timothy KW, Leppert M, Keating M. The spectrum of symptoms and QT intervals in carriers of the gene for the long-QT syndrome. N Engl J Med. 1992;327:846–52. [PubMed: 1508244]

• Viskin S, Postema PG, Bhuiyan ZA, Rosso R, Kalman JM, Vohra JK, Guevara-Valdivia ME, Marquez MF, Kogan E, Belhassen B, Glikson M, Strasberg B, Antzelevitch C, Wilde AAM. The response of the QT interval to the brief tachycardia provoked by standing a bedside test for diagnosing long QT syndrome. JACC. 2010;55:1955–61. [PMC free article: PMC2862092] [PubMed: 20116193]

• Vyas H, Hejlik J, Ackerman MJ. Epinephrine QT stress testing in the evaluation of congenital long-QT syndrome: diagnostic accuracy of the paradoxical QT response. Circulation. 2006;113:1385–92. [PubMed: 16534005]

• Wedekind H, Bajanowski T, Friederich P, Breithardt G, Wülfing T, Siebrands C, Engeland B, Mönnig G, Haverkamp W, Brinkmann B, Schulze-Bahr E. Sudden infant death syndrome and long QT syndrome: an epidemiological and genetic study. Int J Legal Med. 2006;120:129–37. [PubMed: 16012827]

• Westenskow P, Splawski I, Timothy KW, Keating MT, Sanguinetti MC. Compound mutations: a common cause of severe long-QT syndrome. Circulation. 2004;109:1834–41. [PubMed: 15051636]

• Yang Y, Yang Y, Liang B, Liu J, Li J, Grunnet M, Olesen SP, Rasmussen HB, Ellinor PT, Gao L, Lin X, Li L, Wang L, Xiao J, Liu Y, Liu Y, Zhang S, Liang D, Peng L, Jespersen T, Chen YH. Identification of a Kir3.4 mutation in congenital long QT syndrome. Am J Hum Genet. 2010;86:872–80. [PMC free article: PMC3032079] [PubMed: 20560207]

• Zareba W, Moss AJ, Daubert JP, Hall WJ, Robinson JL, Andrews M. Implantable cardioverter defibrillator in high-risk long QT syndrome patients. J Cardiovasc Electrophysiol. 2003;14:337–41. [PubMed: 12741701]

• Zareba W, Moss AJ, Schwartz PJ, Vincent GM, Robinson JL, Priori SG, Benhorin J, Locati EH, Towbin JA, Keating MT, Lehmann MH, Hall WJ. Influence of genotype on the clinical course of the long-QT syndrome. International Long-QT Syndrome Registry Research Group. N Engl J Med. 1998;339:960–5. [PubMed: 9753711]

• Zhang L, Timothy KW, Vincent GM, Lehmann MH, Fox J, Giuli LC, Shen J, Splawski I, Priori SG, Compton SJ, Yanowitz F, Benhorin J, Moss AJ, Schwartz PJ, Robinson JL, Wang Q, Zareba W, Keating MT, Towbin JA, Napolitano C, Medina A. Spectrum of ST-T-wave patterns and repolarization parameters in congenital long-QT syndrome: ECG findings identify genotypes. Circulation. 2000;102:2849–55. [PubMed: 11104743]

Author History

Mariëlle Alders, PhD (2012-present)
Hennie Bikker, PhD (2018-present)
Imke Christiaans, PhD, MD (2015-present)
Marcel MAM Mannens, PhD; University of Amsterdam (2012-2015)
G Michael Vincent, MD; University of Utah School of Medicine (2003-2012)

Revision History

• 8 February 2018 (ha) Comprehensive update posted live
• 18 June 2015 (me) Comprehensive update posted live (title change)
• 31 May 2012 (me) Comprehensive update posted live
• 4 August 2009 (cd) Revision: prenatal diagnosis available for LQT1, LQT2, LQT3, LQT5, LQT6
• 7 May 2009 (gmv) Revision: deletion/duplication analysis available clinically for LQT2 and LQT3; additions to Management
• 21 May 2008 (me) Comprehensive update posted live
• 7 July 2005 (me) Comprehensive update posted live
• 28 February 2005 (gmv) Revision: sequence analysis clinically available; LQt4 moved to Differential Diagnosis
• 13 April 2004 (cd) Revision: ANK2 testing clinically available
• 11 February 2004 (bp/gmv) Revisions
• 18 November 2003 (gmv) Revisions
• 16 June 2003 (gmv) Revision: Table 4
• 20 February 2003 (me) Review posted live
• 25 October 2002 (gmv) Original submission