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Long QT Syndrome

, PhD, , PhD, and , PhD, MD.

Author Information

Initial Posting: ; Last Update: February 8, 2018.

Summary

Clinical characteristics.

Long QT syndrome (LQTS) is a cardiac electrophysiologic disorder, characterized by QT prolongation and T-wave abnormalities on the ECG 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 pregnancies at increased risk and preimplantation genetic diagnosis are possible once the pathogenic variant(s) have been identified in the family.

Diagnosis

Suggestive Findings

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

ECG Evaluation

Corrected QT (QTc) values on resting ECG. The QTc on resting ECG is neither completely sensitive nor specific for the diagnosis of LQTS. Approximately 25% of individuals with LQTS confirmed by the identification of a pathogenic variant in a LQTS-associated gene may have a normal range QTc (concealed LQTS) [Goldenberg et al 2011]. Also, several other factors can lengthen the QTc interval:

  • QT-prolonging drugs
  • Hypokalemia
  • Certain neurologic conditions including subarachnoid bleed
  • Structural heart disease

The following tests are helpful for further evaluation of individuals with "uncertain" QTc values on resting ECG:

Clinical History

A personal history of syncope, aborted cardiac arrest, or sudden death in a child or young adult may lead to suspicion of LQTS. 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 LQTS-associated syncope from seizures.

Family History

A family history of syncope, aborted cardiac arrest, or sudden death in a child or young adult and consistent with autosomal dominant inheritance or autosomal recessive inheritance supports the diagnosis of LQTS.

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

FindingsPoints
ECG 1QTc 2≥480 ms3
=460-479 ms2
=450-459 ms (in males)1
≥480 ms during 4th minute of recovery from exercise stress test1
Torsade de pointes 32
T wave alternans1
Notched T wave in 3 leads1
Low heart rate for age 40.5
Clinical historySyncope 3With stress2
Without stress1
Family historyFamily member(s) with definite LQTS 51
Unexplained sudden cardiac death at age <30 years in immediate family 50.5
Total score

Scoring:

≤1.0 point = low probability of LQTS

1.5-3.0 points = intermediate probability of LQTS

≥3.5 points = high probability of LQTS

Footnotes:

1.

In the absence of medications or disorders known to affect these electrocardiographic features

2.

QTc (corrected QT) calculated by Bazett's formula where QTc = QT/√RR

3.

Mutually exclusive

4.

Resting heart rate <2nd %ile for age

5.

The same family member cannot be counted for both criteria.

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 ECGs in the absence of a secondary cause for QT prolongation
  • The identification of a pathogenic variant in one of the 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 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 at the most reasonable cost 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

Gene 1,2LQTS Phenotype% of LQTS Attributed to Pathogenic Variants in This GeneProportion of Pathogenic Variants 3 Detectable by This Method
Sequence analysis 4Gene-targeted deletion/duplication analysis 5
KCNH2LQTS type 225%-30%97%-98%2%-3% 6
KCNQ1LQTS type 1 730%-35%97%-98%2%-3% 6
SCN5ALQTS type 35%-10%All variants reported to dateNone reported 8

Pathogenic variants of any one of the genes included in this table account for >1% of LQTS.

1.

Genes are listed in alphabetic order.

2.
3.

See Molecular Genetics for information on pathogenic variants detected.

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

Deletions or duplications involving KCNH1 or KCNQ2 have been shown to be causal for LQTS in ~3% of cases [Barc et al 2011].

7.

Biallelic pathogenic variants in KCNQ1 are associated with Jervell and Lange-Nielsen syndrome.

8.

The pathogenic variants in SCN5A that cause LQTS are gain-of-function variants (loss-of-function variants of SCN5A cause Brugada syndrome). Therefore, it is highly unlikely that large deletions or duplications in SCN5A will be identified as a cause of LQTS.

Table 2b.

Molecular Genetics of LQTS: Less Common Genetic Causes

Gene 1 ,2, 3LQTS PhenotypeComments
AKAP9LQTS type 11Limited 4
ANK2LQTS type 4<1% 5
CACNA1CLQTS type 8 6<1% 5
CALM1LQTS type 14<1% 7
CALM2LQTS type 15<1% 7
CAV3LQTS type 9<1% 5
KCNE1LQTS type 5 8<1% 9
KCNE2LQTS type 6<1% 9
KCNJ2LQTS type 7 10<1% 511
KCNJ5LQTS type 13<1% 12
SCN4BLQTS type 10Limited 5
SNTA1LQTS type 12<1% 13

Pathogenic variants of any one of the genes listed in this table are reported in only a few families (i.e., <1% of LQTS). See also the Clinical Genome Resource, which defines the clinical relevance of genes (work in progress).

1.

Genes are listed in alphabetic order.

2.
3.

Genes are not described in detail in Molecular Genetics, but are included here (pdf).

4.
5.
6.

LQTS type 8 is also referred to as Timothy syndrome.

7.
8.

Biallelic pathogenic variants in KCNE1 are associated with Jervell and Lange-Nielsen syndrome.

9.
10.

LQTS type 7 is also referred to as Andersen-Tawil syndrome.

11.
12.
13.

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 Characteristics

Clinical Description

Long QT syndrome (LQTS) 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 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

GenePhenotypeAverage QTcST-T-Wave MorphologyIncidence of Cardiac EventsCardiac Event TriggerSudden Death Risk
KCNH2LQTS type 2480 msecBifid T-waves46%Auditory stimuli, emotion, exercise, sleep6%-8%
KCNQ1LQTS type 1Broad-base T-wave63%Exercise, emotion6%-8%
SCN5ALQTS type 3~490 msecLong ST, small T18%Sleep6%-8%

Age-Related Risk

Cardiac events may occur from infancy through middle age but are most common from the preteen 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 LQTS type 3 phenotype.

Overall Risk for Cardiac Events

Of individuals who die of complications of LQTS, death is the first sign of the disorder in an estimated 10%-15%. It is difficult to establish numbers on the risk of cardiac events in LQTS since most individuals are treated.

  • Studies from the long QT syndrome registry including patients, individuals with a pathogenic variant (mostly treated), and also relatives who died suddenly show a cumulative mortality before age 40 years of 6%-8% in the LQTS type 1, type 2, and type 3 phenotypes [Zareba et al 1998, Goldenberg et al 2008].
    • In individuals between age 0 and 18 years, those with a LQTS type 1, type 2, or type 3 phenotype had a cumulative mortality of 2%, 3%, and 7%, respectively.
    • From age 19 to 40 years mortality rates were 5%, 7%, and 5%, respectively.
  • Although syncopal events are most common in the LQTS type 1 phenotype (63%), followed by the LQTS type 2 phenotype (46%) and LQTS type 3 phenotype (18%), the incidence of death is similar in all three.
  • A study using the family tree mortality rate method studied mortality in large families with LQTS, in times when disease was not known and individuals received no treatment, compared to the normal population.
    For the LQTS type 1 phenotype (one specific pathogenic variant), severely increased mortality was shown throughout childhood (ages 1-19 years), for the type 2 phenotype, increased mortality between ages 15 and 39 years was seen, and in the type 3 phenotype, increased mortality between ages 15 and 19 years was seen [Nannenberg et al 2012].

Non-Cardiac Features

Some types of LQTS are associated with a phenotype extending beyond cardiac arrhythmia:

  • Andersen-Tawil syndrome (LQTS type 7) is associated with prolonged QT interval, muscle weakness, and facial dysmorphism.
  • Timothy syndrome (LQTS type 8) is characterized by prolonged QT interval and hand/foot, facial, and neurodevelopmental features.
  • Jervell and Lange-Nielson syndrome (JLNS), an LQTS disorder associated with biallelic pathogenic KCNQ1 or KCNE1 variants, is associated with profound sensorineural hearing loss.

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 ECG changes and symptoms. Overall, approximately 25% of individuals with a pathogenic variant have a normal QTc (defined as <440 msec) on baseline ECG. 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.

Differential Diagnosis

Other causes of QTc interval prolongation to be considered:

  • QT-prolonging drugs
  • Hypokalemia
  • Certain neurologic conditions including subarachnoid bleed
  • Structural heart disease

Other causes of syncope or sudden death to be considered in children and young adults:

  • Sudden infant death syndrome (SIDS), commonly defined as unexpected sudden death within the first year of life. Death during the first year of life in families with LQTS appears to be rare, yet a percent of infants dying of SIDS have been shown to have pathogenic variants 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 pathogenic variants were the cause of the SIDS, the association is uncertain, and the frequency of pathogenic variants in SIDS cases has been questioned [Wedekind et al 2006].
  • Vasovagal (neurally mediated) syncope, orthostatic hypotension
  • Seizures
  • Familial ventricular fibrillation
  • Subtle cardiomyopathies (HCM, DCM, ARVC)
  • Anomalous coronary artery
  • Drug-induced QT prolongation (see drugs at CredibleMeds®)

Management

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:

  • ECG 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 ECG or ambulatory ECG;
    • 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 lifestyles. 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 ECG 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 ECG 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 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.

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 www.clinicaltrialsregister.eu in Europe for information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

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:

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 ECG evaluation including exercise ECG 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 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 is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

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

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • My46 Trait Profile
  • National Library of Medicine Genetics Home Reference
  • Canadian SADS Foundation
    9-6975 Meadowvale Town Centre Circle
    Suite 314
    Mississauga Ontario L5N 2V7
    Canada
    Phone: 877-525-5995 (toll-free); 905-826-6303
    Fax: 905-826-9068
    Email: info@sads.ca
  • SADS Australia
    Victoria
    Australia
  • Sudden Arrhythmia Death Syndromes (SADS) Foundation
    508 East South Temple
    Suite #202
    Salt Lake City UT 84102
    Phone: 800-786-7723 (toll-free); 801-531-0937
    Email: sads@sads.org
  • International Long QT Syndrome Registry
    Heart Research Follow-Up Program
    Box 653
    Rochester NY 14642-8653
    Phone: 585-276-0016
    Fax: 585-273-5283
    Email: heartajm@heart.rochester.edu

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Long QT Syndrome: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Long QT Syndrome (View All in OMIM)

106410ANKYRIN 2; ANK2
114180CALMODULIN 1; CALM1
114182CALMODULIN 2; CALM2
114205CALCIUM CHANNEL, VOLTAGE-DEPENDENT, L TYPE, ALPHA-1C SUBUNIT; CACNA1C
152427POTASSIUM CHANNEL, VOLTAGE-GATED, SUBFAMILY H, MEMBER 2; KCNH2
170390ANDERSEN CARDIODYSRHYTHMIC PERIODIC PARALYSIS
176261POTASSIUM CHANNEL, VOLTAGE-GATED, ISK-RELATED SUBFAMILY, MEMBER 1; KCNE1
192500LONG QT SYNDROME 1; LQT1
600163SODIUM CHANNEL, VOLTAGE-GATED, TYPE V, ALPHA SUBUNIT; SCN5A
600681POTASSIUM CHANNEL, INWARDLY RECTIFYING, SUBFAMILY J, MEMBER 2; KCNJ2
600734POTASSIUM CHANNEL, INWARDLY RECTIFYING, SUBFAMILY J, MEMBER 5; KCNJ5
600919CARDIAC ARRHYTHMIA, ANKYRIN-B-RELATED
601005TIMOTHY SYNDROME; TS
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; LQT5
616247LONG QT SYNDROME 14; LQT14
616249LONG QT SYNDROME 15; LQT15

Molecular Genetic 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.

KCNQ1

Gene structure. KCNQ1 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 encode a protein with an alternative N terminal domain (isoform 2) or non-coding transcripts.

Pathogenic variants. More than 500 pathogenic variants of KCNQ1 have been reported, including pathogenic missense, nonsense, splice site, and frameshift variants as well as large multiexon deletions.

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 function

KCNH2

Gene structure. KCNH2 spans approximately 19 kb. The longest isoform consists of 16 exons and produces a protein of 1,159 amino acids (NM_000238.3). Two shorter isoforms of KCNH2 exist.

Pathogenic variants. More than 700 pathogenic variants have been reported, including pathogenic missense, nonsense, splice site, and frameshift variants as well as large multiexon deletions.

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 function

SCN5A

Gene structure. SCN5A consists of 28 exons, spans approximately 80 kb; it encodes a protein of 2,016 amino acids (NM_198056.2). An isoform lacking amino acid Gln1077 exists.

Pathogenic variants. More than 200 pathogenic variants are known; they include pathogenic missense variants 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. Pathogenic gain-of-function variant resulting in a cardiac sodium channel with increased persistent inward current

For information on the genes listed in Table 2b, click here (pdf).

References

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 2-1-18. [PubMed: 16923744]
  • Vincent GM. Role of DNA testing for diagnosis, management, and genetic screening in long QT syndrome, hypertrophic cardiomyopathy, and Marfan syndrome. Heart. 86:12-4. Available online. 2001. Accessed 2-1-18. [PMC free article: PMC1729812] [PubMed: 11410552]

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Chapter Notes

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
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