Goal 1.

Briefly describe the clinical characteristics of LQTS.

Goal 2.

Review the genetic causes of LQTS.

Goal 3.

Review the differential diagnosis of LQTS with a focus on genetic conditions.

Goal 4.

Provide an evaluation strategy to identify the genetic cause of LQTS in a proband (when possible).

Goal 5.

Review management of LQTS including targeted pharmacologic treatment.

Goal 6.

Inform risk assessment and evaluation of at-risk relatives for early detection and treatment of LQTS.

Cardiac Features

T wave abnormalities include T wave alternans, notched T wave, broad-based and flattened T waves (see Adler et al [2020] and Wilde et al [2022] for concise examples and Tardo et al [2023] for a comprehensive review) and are associated with tachyarrhythmias, typically the ventricular tachycardia torsade de pointes (TdP). TdP is usually self-terminating and may cause palpitations, dizziness, or syncope, the most common symptom in individuals with LQTS. Syncope is typically precipitous and without warning. A careful evaluation of medical history can help distinguish LQTS-associated syncope from 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. The number of syncopal events in symptomatic individuals ranges from one to hundreds, averaging just a few. In some instances, TdP degenerates to ventricular fibrillation and aborted cardiac arrest (if the individual is defibrillated) or sudden death.

Cardiac events (i.e., syncope, cardiac arrest, or sudden cardiac death) 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. Cardiac events in individuals over age 40 years are more likely associated with SCN5A-related LQTS.

Pathogenic variants in KCNH2, KCNQ1, and SCN5A account for 90% of individuals with an identified molecular cause of LQTS. Three clinical phenotypes are recognized in individuals with pathogenic variants in these genes (see Table 2).

Although incidence of syncopal events is highest in those with KCNQ1-related LQTS and lowest in SCN5A-related LQTS, the incidence of sudden cardiac arrest or death was highest in individuals with SCN5A-related LQTS in a cohort of individuals with an identified genetic cause from the LQTS Registry receiving treatment (see Table 2). Of individuals who die of complications of LQTS, death is the first sign of the disorder in an estimated 10%-15%.

The risk of sudden cardiac death is dependent on history of syncope, proband status (i.e., being the first in the family in whom the genetic cause for LQTS has been identified), QTc interval, treatment, age, and gender. The age and sex dependency differs between the three main molecular causes of LQTS. Overall, boys are at relatively high risk before onset of adolescence, and girls after the onset of adolescence (age 13 to 14 years) [Wang et al 2022].

• KCNH2-related LQTS. Increased mortality occurred especially in women older than age 12 to 13 years, particularly up to nine months postpartum [Kutyifa et al 2018, Skinner et al 2019]. The risk for males aged one to 13 years can also be high [Wang et al 2022]. A common trigger is sudden arousal (e.g., auditory stimuli).
• KCNQ1-related LQTS. Severely increased mortality was observed for boys age five to 15 years [Kutyifa et al 2018, Skinner et al 2019], although the risk for girls age 13 to 20 years can also be high [Wang et al 2022]. Most sudden cardiac deaths occur during exercise (e.g., swimming) and emotion [Wilde et al 2022].
• SCN5A-related LQTS. Increased mortality is observed from childhood (especially in boys) throughout adulthood (both genders) [Wang et al 2022]. In contrast to KCNQ1- and KCNH2-related LQTS, QT prolongation in SCN5A-related LQTS is more pronounced during slow heart rate and events usually occur during sleep or rest.

LQTS exhibits incomplete penetrance for EKG changes and symptoms. Approximately 25% of individuals with an identified molecular cause of LQTS have a normal QTc (<440 ms) on baseline EKG. The percentage of individuals with a normal QTc was higher in those with KCNQ1-related LQTS (36%) than in those with KCNH2-related LQTS (19%) or SCN5A-related LQTS (10%) [Priori et al 2003, Goldenberg et al 2011]. With appropriate treatment, at least 56% of individuals with KCNQ1-related LQTS, 51% of those with KCNH2-related LQTS, and 59% of those with SCN5A-related LQTS remain asymptomatic (assessed at age 50 years) [Kutyifa et al 2018].

Non-Cardiac Features

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

• Andersen-Tawil syndrome, caused by a heterozygous pathogenic variant in KCNJ2, is associated with prolonged QT interval, episodic muscle paralysis, muscle weakness, facial dysmorphism, dental anomalies, and small hands and feet.
• Jervell and Lange-Nielsen syndrome, caused by biallelic KCNQ1 or KCNE1 pathogenic variants, is associated with congenital profound sensorineural hearing loss and QTc usually >500 ms.
• Timothy syndrome, caused by a heterozygous pathogenic variant in CACNA1C, is a multisystem disorder where QTc prolongation causes a high risk of arrhythmic events in neonates. Extracardiac features include hand/foot syndactyly, neurodevelopmental features including autism spectrum disorder and intellectual disability, and characteristic facial appearance.

Biallelic Pathogenic Variants / Digenic Inheritance

LQTS associated with biallelic pathogenic variants (in genes associated with autosomal dominant LQTS) 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, Mullally et al 2013].

Nomenclature

The designation "acquired long QT syndrome" may be used to distinguish QT interval prolongation associated with non-heritable causes and conditions from heritable predisposition to QTc prolongation. Of note, gene-environment interactions occur, and drug exposures and conditions associated with acquired LQTS may also be cardiac event triggers in individuals with a genetic predisposition to QT prolongation.

Prevalence

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

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with long QT syndrome (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 not performed as part of the evaluation that led to the diagnosis:

• EKG evaluation. Individuals with a QTc interval >500 ms are at higher risk for a cardiac 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 for an event. 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].
• To aid in risk stratification, an online calculator named 1-2-3-LQTS-Risk was validated for clinical use [Mazzanti et al 2022], predicting the risk of life-threatening cardiac events in five-year intervals. The prediction accounts for age, gender, QTc interval, history of syncope, and genotype (limited to the three most common genetic causes of LQTS). Further improvement of risk prediction using machine learning and functional imaging has been proposed [Marathe et al 2022].

Consultation with a clinical geneticist, certified genetic counselor, or certified advanced genetic nurse is recommended to inform affected individuals and their families about the nature, mode of inheritance, and implications of LQTS in order to facilitate medical and personal decision making.

Treatment of Manifestations

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 should have regular, periodic evaluations of the ICD 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.

Lifestyle modifications are advised based on genotype:

• Individuals with KCNQ1-related LQTS should avoid strenuous exercise, especially swimming without supervision.
• Individuals with KCNH2-related LQTS should avoid exposure to loud noises such as alarm clocks and phone ringing.
• Individuals at high risk for cardiac events or with exercise-induced symptoms (as in KCNH2- and KCNQ1-related LQTS) 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].

Pregnancy Management

The postpartum period is associated with increased risk for a cardiac event, especially in individuals with KCNH2-related LQTS. Beta-blocker treatment was associated with a reduction of events in the nine months after delivery [Seth et al 2007]. Recommendations for optimal care during and after pregnancy, including suitability of anti-arrhythmic drugs and surveillance measures, can be found in Roston et al [2020].

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

A current study is evaluating the drug ranolazine in individuals with SCN5A-related LQTS [Cano et al 2020].

For individuals with KCNH2-related LQTS due to a protein trafficking defect, combined treatment with lumacraftor and ivacraftor is under investigation [Schwartz et al 2019].

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.

Genetic Risk Assessment

Long QT syndrome (LQTS) without extracardiac features is typically inherited in an autosomal dominant manner. Timothy syndrome (caused by a heterozygous pathogenic variant in CACNA1C) and Andersen-Tawil syndrome (caused by heterozygous pathogenic variant in KCNJ2), types of LQTS that are associated with a phenotype extending beyond cardiac arrhythmia, are also inherited in an autosomal dominant manner. Jervell and Lange-Nielsen syndrome, a severe form of autosomal recessive LQTS with a high event risk at early age and deafness, is caused by biallelic pathogenic variants in KCNQ1 or KCNE1. Biallelic pathogenic variants in TRDN cause another very rare and severe form of autosomal recessive LQTS-catecholaminergic polymorphic ventricular tachycardia (CPVT) overlap syndrome (see Table 5).

LQTS associated with biallelic pathogenic variants (in genes associated with autosomal dominant LQTS) or heterozygosity for pathogenic variants in two different genes (i.e., digenic pathogenic variants) has also been reported (see Biallelic Pathogenic Variants / Digenic Inheritance).

Risk to Family Members (Autosomal Dominant Inheritance)

A basic view of autosomal dominant LQTS genetic risk assessment is presented in this section; issues that may be specific to a given family or genetic cause of LQTS are not comprehensively addressed. If a proband has a specific syndrome (e.g., Timothy syndrome or Andersen-Tawil syndrome), counseling for that condition is indicated. Genetic risk assessment in families with LQTS with extracardiac features is not discussed further in this section.

Parents of a proband

• The majority of individuals diagnosed with LQTS have inherited a pathogenic variant from a parent. Due to incomplete penetrance and variable expressivity, a parent who is heterozygous for an LQTS-related pathogenic variant may or may not have LQTS-related EKG changes and symptoms.
• A proband with LQTS may have the disorder as the result of a de novo pathogenic variant. The proportion of individuals with LQTS caused by a de novo pathogenic variant is small.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and facilitate the use of morbidity- and mortality-reducing interventions for parents found to be heterozygous for an LQTS-related pathogenic variant.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism (the incidence of germline mosaicism is very low: 0.1% [Acuna-Hidalgo et al 2015]). Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
• 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 does not exclude the possibility of an inherited pathogenic variant and molecular genetic testing is indicated.

Note: Biallelic and digenic pathogenic variants have been described. 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 et al 2018].
• 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 do not have signs of LQTS on cardiac evaluation but their genetic status is unknown, the risk to sibs of inheriting an LQTS-related pathogenic variant is estimated to be 50% because a heterozygous parent may be clinically unaffected due to reduced penetrance of LQTS-related EKG changes and symptoms. The likelihood that the proband has LQTS as the result of a pathogenic variant inherited from a heterozygous asymptomatic parent is far greater than the likelihood that the proband has LQTS as the result of a de novo pathogenic variant.

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 and/or has a pathogenic variant, the parent's family members are at risk.

Evaluation of Relatives 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.

Predictive genetic testing in family members of a proband with a molecular diagnosis of LQTS. If the LQTS-related pathogenic variant(s) has been identified in a proband, it is appropriate to clarify the genetic status of apparently asymptomatic relatives so that individuals found to be heterozygous for an LQTS-related pathogenic variant can benefit as early as possible from prompt initiation of targeted therapy, surveillance, and awareness of agents and circumstances to avoid (e.g., drugs that cause further prolongation of the QT interval and gene-specific cardiac event triggers). Predictive genetic testing is recommended for all at-risk family members of all ages from birth onward and especially for individuals age <18 years because the risk for cardiac events is greatest in childhood [Wilde et al 2022].

Predictive genetic testing can be used to identify relatives who are heterozygous for a familial LQTS-related pathogenic variant and at risk for LQTS-related manifestations but cannot be used to predict disease course (i.e., whether LQTS-related EKG changes and symptoms will occur and, if so, the age of onset and severity).

Evaluation of family members of a proband with a clinical diagnosis of LQTS. If the LQTS-related pathogenic variant in the proband is not known (as is the case in ≤25% of individuals with LQTS who undergo molecular genetic testing for known LQTS-related genes [Ingles & Semsarian 2020]) and the LQTS does not seem to be acquired, first-degree relatives should still be considered to be at risk. These relatives should undergo QTc analysis on resting EKG and, in those with normal QTc on resting EKG, QTc analysis on exercise EKG (the diagnostic accuracy by QTc analysis is considerably improved by evaluation of the exercise EKG in addition to the resting EKG, using the QTc measurements listed in Table 1). To date, there are no clear recommendations on when to repeat the EKG in individuals with normal findings.

Note: Because LQTS exhibits incomplete penetrance for EKG changes and symptoms, the absence of LQTS-related findings on EKG evaluation cannot be used to assess genetic status (i.e., an individual who is heterozygous for an LQTS-related pathogenic variant may have a normal QTc on baseline EKG).

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). For more information, see Huang et al [2022].

Author History

Mariëlle Alders, PhD; Amsterdam University Medical Center (2012-2024)
Hennie Bikker, PhD (2018-present)
Imke Christiaans, PhD, MD (2015-present)
Alexander J Groffen, PhD (2024-present)
Marcel MAM Mannens, PhD; University of Amsterdam (2012-2015)
G Michael Vincent, MD; University of Utah School of Medicine (2003-2012)

Revision History

• 21 March 2024 (sw) Comprehensive update posted live; scope changed to overview
• 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
• 21 May 2008 (me) Comprehensive update posted live
• 7 July 2005 (me) Comprehensive update posted live
• 20 February 2003 (me) Review posted live
• 25 October 2002 (gmv) Original submission

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 2-27-24.
• Fellmann F, van El CG, Charron P, Michaud K, Howard HC, Boers SN, Clarke AJ, Duguet AM, Forzano F, Kauferstein S, Kayserili H, Lucassen A, Mendes A, Patch C, Radojkovic D, Rial-Sebbag E, Sheppard MN, Tasse AM, Temel SG, Sajantila A, Basso C, Wilde AAM, Cornel MC, on behalf of European Society of Human Genetics ECoLMESoCwgom, pericardial diseases ERNfrlp, complex diseases of the heart AfECP. European recommendations integrating genetic testing into multidisciplinary management of sudden cardiac death. Eur J Hum Genet. 2019;27:1763-73.
• 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.
• Stiles MK, Wilde AAM, Abrams DJ, Ackerman MJ, Albert CM, Behr ER, Chugh SS, Cornel MC, Gardner K, Ingles J, James CA, Juang JJ, Kaab S, Kaufman ES, Krahn AD, Lubitz SA, MacLeod H, Morillo CA, Nademanee K, Probst V, Saarel EV, Sacilotto L, Semsarian C, Sheppard MN, Shimizu W, Skinner JR, Tfelt-Hansen J, Wang DW. 2020 APHRS/HRS expert consensus statement on the investigation of decedents with sudden unexplained death and patients with sudden cardiac arrest, and of their families. J Arrhythm. 2021;37:481-534.
• 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 2-27-24.
• Wilde AAM, Semsarian C, Marquez MF, Sepehri Shamloo A, Ackerman MJ, Ashley EA, Sternick EB, Barajas-Martinez H, Behr ER, Bezzina CR, Breckpot J, Charron P, Chockalingam P, Crotti L, Gollob MH, Lubitz S, Makita N, Ohno S, Ortiz-Genga M, Sacilotto L, Schulze-Bahr E, Shimizu W, Sotoodehnia N, Tadros R, Ware JS, Winlaw DS, Kaufman ES, Group ESCSD. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases. Europace. 2022;24:1307-67.
• Zeppenfeld K, Tfelt-Hansen J, de Riva M, Winkel BG, Behr ER, Blom NA, Charron P, Corrado D, Dagres N, de Chillou C, Eckardt L, Friede T, Haugaa KH, Hocini M, Lambiase PD, Marijon E, Merino JL, Peichl P, Priori SG, Reichlin T, Schulz-Menger J, Sticherling C, Tzeis S, Verstrael A, Volterrani M, Group ESCSD. 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J. 2022;43:3997-4126.

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