Version May 2024
INTRODUCTION — This monograph discusses an approach to the results of genetic testing for the three major genes associated with congenital long QT syndrome (LQTS).
It does not discuss every LQTS-susceptibility gene, and it is not intended to replace clinical judgment in the decision to test or in the care of the individual who was tested. These subjects are discussed separately in UpToDate [1]. (See 'Resources' below.)
HOW TO READ THE REPORT
Review and verify — The table summarizes important considerations in reviewing a genetic test report (table 1).
All testing should be performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory or other nationally certified laboratory. For any concerning or unexpected finding obtained by direct-to-consumer testing or for research (positive result or negative result in an individual with suspected LQTS), testing should be repeated in a CLIA-certified laboratory with input from a specialist (genetic cardiologist, pediatric/adult heart rhythm expert, or genetic counselor with heart disease expertise).
Specialist input is also prudent to ensure that the appropriate testing is done (genetic testing and clinical evaluations) and the appropriate follow-up and interventions are in place. (See 'Implications for management' below.)
Patient and family history — Information from genetic testing should be reviewed in the context of personal and family history.
●Negative results or a variant of uncertain significance (VUS) cannot be ignored in a person with a positive personal or family history (unless the familial variant has been excluded and the electrocardiogram [ECG] is normal) [2]. This is because the test may not have covered all relevant variants and genes. (See 'Individuals with a VUS or a negative genetic test result' below.)
●A positive result may indicate an abnormal genetic finding that is important but does not explain the familial disorder. (See 'Genes' below.)
OVERVIEW OF CONGENITAL LQTS
Genes — Three LQTS-susceptibility genes account for approximately 80 percent of congenital LQTS cases/families:
●KCNQ1 (LQT1) – 35 to 45 percent
●KCNH2 (LQT2) – 25 to 35 percent
●SCN5A (LQT3) – 5 to 10 percent
KCNQ1 and KCNH2 encode pore-forming subunits of outward-rectifying potassium (K+) channels in cardiomyocytes. SCN5A encodes the alpha subunit of the cardiac sodium (Na+) channel. Their molecular roles have been well characterized [3].
Variant classification is summarized in the table (table 2). For pathogenic and likely pathogenic variants in LQTS genes, confidence is high that they produce gene products that interfere with channel formation and function and that can impair cardiomyocyte repolarization. (See 'Clinical features' below.)
However, variants in these genes are not exclusive to congenital LQTS; they can also cause other disorders.
As examples:
●Some KCNQ1 (LQT1) and KCNH2 (LQT2) variants cause congenital LQTS; others cause congenital short QT syndrome (SQT2 and SQT1, respectively).
●Some SCN5A variants cause congenital LQT3; others cause Brugada syndrome (BrS1).
A patient's disorder may not be immediately obvious from genetic test results or clinical history. (See "Pathophysiology and etiology of sudden cardiac arrest".)
Other genes account for a smaller proportion of congenital LQTS (table 3), and some cases remain genetically uncharacterized [4]. Transmission is typically autosomal dominant with incomplete penetrance (table 4); rare autosomal recessive forms occur.
The overall prevalence of congenital LQTS is estimated at approximately 1 in 2000; there may be a greater proportion of individuals who have an LQTS-causative variant and a normal electrocardiogram (ECG).
Clinical features — Cardiac repolarization abnormalities can cause polymorphic ventricular tachycardia (VT), also called torsades de pointes, which can degenerate to ventricular fibrillation (VF). Symptoms can include arrhythmogenic syncope, syncope-induced generalized seizures, sudden cardiac arrest, or sudden cardiac death. Bradycardia and atrial arrhythmias can occur.
Due to incomplete penetrance (table 4), 25 to 40 percent of individuals with an LQTS-causative variant (especially variant-positive family members) will have a normal ECG and a QTc value within the normal distribution for age and sex (this is also called genotype positive/phenotype negative LQTS or concealed LQTS). Due to variable expressivity, most individuals with a pathogenic or likely pathogenic LQTS variant may never become symptomatic.
Aside from symptoms attributable to LQTS, individuals with congenital LQTS-causative variants may come to medical attention for other reasons:
●An ECG done for screening or an unrelated purpose that shows QT prolongation.
●Genetic testing, often during evaluation of first-degree relatives of an affected individual, sometimes for other reasons.
●An extracardiac manifestation of a rare congenital LQTS disorder (eg, sensorineural deafness).
The ECG is an important test in any person with suspected LQTS, and many individuals with congenital LQTS have ECG abnormalities (see 'Evaluations' below). However, some patients with congenital LQTS have a normal ECG, and the absence of ECG findings does not exclude the diagnosis. If an LQTS-causative variant is established for a family, the only way a relative can have the diagnosis excluded is to have both a normal ECG and a negative test for the familial LQTS variant.
Documenting a pathogenic or likely pathogenic variant in a congenital LQTS gene is sufficient for diagnosis but not required. Other criteria include repeated documentation of an otherwise unexplained QTc of >500 milliseconds or a Schwartz LQTS score of >3.5 (table 5). Provocative testing with treadmill or bicycle stress testing may be used in selected individuals. (See "Congenital long QT syndrome: Diagnosis", section on 'Diagnosis'.)
IMPLICATIONS FOR MANAGEMENT
Individuals with a positive genetic test — Individuals with a pathogenic or likely pathogenic variant in an LQTS gene meet criteria for congenital LQTS. They require a full clinical evaluation and interventions to reduce the risk of symptoms and sudden cardiac arrest or sudden cardiac death. (See "Congenital long QT syndrome: Diagnosis".)
These evaluations and interventions are also necessary for individuals with negative genetic testing who meet other criteria for congenital LQTS (genotype negative/phenotype positive LQTS).
Evaluations — All individuals require review of a 12-lead electrocardiogram (ECG) and assessment of the rate-corrected QT interval (QTc) on more than one occasion by an experienced clinician. In most cases, especially if the initial ECG appears normal, more than one ECG should be serially reviewed.
Additional evaluations include:
●Careful symptom review and family history.
●Evaluation for secondary causes of QT prolongation, including electrolyte abnormalities and medications (table 6). (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes".)
●Ambulatory ECG monitoring.
●Treadmill ECG with review of QT response to exercise.
●ECG review for first-degree relatives.
●Review of genetic test results by a knowledgeable genetic cardiologist, pediatric/adult heart rhythm specialist, and/or cardiovascular genetic counselor.
Interventions — A number of approaches are available to reduce the risk of complications, ranging from relatively straightforward (avoidance of triggers for QT prolongation) to more invasive interventions. The table (table 7) summarizes a general approach to deciding among these interventions, with variations depending on genotype, patient values, and input from a heart rhythm disease expert [5-9].
●Avoid arrhythmia triggers – Triggers of arrhythmia are summarized in the table (table 6). Methods of reducing them include:
•Dehydration – Ensure adequate hydration, especially with exercise or gastrointestinal symptoms (nausea, anorexia, diarrhea).
•Hypokalemia/hypomagnesemia – Avoid medications that lower potassium or magnesium; use supplements if needed (especially for individuals with LQT2 [disease variants in KCNH2]).
•Catecholamines – Stay active and exercise recreationally. Participation in competitive sports should be guided by a genetic cardiologist or pediatric/adult heart rhythm specialist with experience in risk stratifying and treating patients with LQTS. Limit noise and stress as appropriate (individualized according to genotype and risk tolerance).
Specific activity restrictions may vary by genotype. As an example, arrhythmias triggered by swimming/diving are more common in LQT1 (disease variants in KCNQ1), while arrythmias triggered by noise and other auditory startles are more likely in patients with LQT2 (disease variants in KCNH2).
•Medications – Drugs that prolong the QT interval (www.crediblemeds.org) are generally avoided, especially if a suitable alternative is available [10]. The benefits of a medication may outweigh the risks in some cases (eg, attention deficit hyperactivity disorder [ADHD] or psychosis).
●Beta blockade – All individuals with a prolonged QTc are strongly urged to take a nonselective beta blocker (nadolol or propranolol) [11,12]; beta blocker use in people with a normal QTc is individualized. Occasionally, beta blockade is not tolerated or breakthrough events occur despite adherence to beta blockade, and other interventions may be used.
●ICD – Implantable cardiac defibrillators (ICDs) are recommended in only selected patients with congenital LQTS; they are often overprescribed. An ICD is recommended for an individual with a history of sudden cardiac arrest. An ICD is appropriate for those with breakthrough arrhythmic syncope or seizures while adherent to beta blocker therapy, or as primary prevention in some high-risk asymptomatic individuals (eg, women with LQT2 and QTc >500 ms or individuals with LQT2 or LQT3 [disease variants in SCN5A] and QTc >550 ms). Among the largest LQTS specialty centers in the world, an ICD is used in less than one-fifth of patients. (See "Implantable cardioverter-defibrillators: Overview of indications, components, and functions".)
●Other specialized interventions – Additional interventions that may be appropriate for selected individuals include other medications (mexiletine or spironolactone), left cardiac sympathetic denervation (LCSD) surgery, or intentional atrial pacing. However, this should be directed by a genetic cardiologist or a heart rhythm specialist with expertise in the risk stratification and treatment of patients with congenital LQTS.
Individuals with a VUS or a negative genetic test result — The implications of a variant of uncertain significance (VUS) or a negative test depend on the family history, personal history, and ECG findings:
●For an individual in a family with a known LQTS variant who has a reliable negative test for that variant (table 1) and a normal ECG, the diagnosis of congenital LQTS is excluded. If there is a family history of documented or suspected congenital LQTS, genetic testing should initially be performed on the affected family members so that other family members can have directed testing for the familial variant if possible.
●For an individual with a clinical suspicion for congenital LQTS, including suggestive symptoms or ECG abnormalities without an alternative explanation (see 'Overview of congenital LQTS' above), negative or VUS results should be reviewed by a genetic cardiologist, pediatric/adult heart rhythm specialist, or cardiovascular genetic counselor to determine whether additional testing is needed. This may include re-evaluation of existing results, genetic testing for other variants or other LQTS genes, and/or clinical evaluation with ECG and possibly provocative testing. (See 'Evaluations' above.)
As examples:
•If the patient was predicted to have LQT1 by phenotype and the genetic test reports a VUS in the gene KCNQ1, then that VUS is almost certainly an LQT1-causative pathogenic variant.
•If the patient has clinically definite LQTS (phenotype positive) but a negative genetic test for all known LQTS-susceptibility genes, then there is either a missing acquired explanation for QT prolongation or a previously undiscovered genetic variant (genotype negative/phenotype positive LQTS). Such patients should be offered research-based evaluation for LQTS gene discovery [3].
FIRST-DEGREE RELATIVES — The following individuals should be evaluated with an electrocardiogram (ECG) at a minimum and with genetic testing in most cases:
●First-degree relatives of a person with a pathogenic or likely pathogenic variant in a congenital LQTS gene.
●First-degree relatives of a person with a VUS that is potentially concerning (based on clinical history, family history, or ECG findings).
●First-degree relatives of a person with negative genetic testing but a clinical history or ECG findings consistent with congenital LQTS.
If a congenital LQTS variant has been documented in a family, at-risk relatives can be tested exclusively for that variant (algorithm 1). However, if a disease variant has not been identified in the proband, or if a variant of uncertain significance (VUS) or a variant associated with another heart rhythm disorder has been identified, more extensive genetic testing of family members may be indicated.
Evaluation and management of relatives who test positive for LQTS disease variants or have an abnormal ECG without another cause are the same as described above. (See 'Implications for management' above.)
RESOURCES
Drugs that prolong the QT interval are listed at https://crediblemeds.org/ (previously called QTdrugs.org).
Several UpToDate topics discuss congenital LQTS:
●Genetics – (See "Congenital long QT syndrome: Pathophysiology and genetics".)
●Symptoms – (See "Congenital long QT syndrome: Epidemiology and clinical manifestations".)
●Diagnosis – (See "Congenital long QT syndrome: Diagnosis".)
●Management – (See "Congenital long QT syndrome: Treatment".)
Databases of genetics professionals are available:
●Genetic counselors – National Society of Genetic Counselors (NSGC)
●Clinical geneticists – American College of Medical Genetics and Genomics (ACMG)
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