Long Qt Syndrome

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.

Suggestive Findings

Long QT syndrome (LQTS) should be suspected in individuals on the basis of ECG 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).

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 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 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.

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 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.

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.

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