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Long QT syndrome (LQTS) is a genetic heart disorder due to malfunction of cardiac ion channels, resulting in 4,000 deaths annually in the United States (Vincent GM 1998). LQTS has an estimated prevalence of at least 1 in 3,000 and occurs in all ethnicities (Lehnart SE et al., 2007).  Affected individuals have delayed repolarization manifested by QT prolongation on the electrocardiogram (ECG), with an increased propensity to syncope, ventricular tachyarrhythmias and sudden cardiac death. Sudden death is the first and final symptom in 10-15% of fatal LQTS events. LQTS has genetic causes in at least 75% of individuals diagnosed with this condition, including mutations in more than 10 different genes. The disorder is usually inherited as an autosomal dominant trait, although a rare subtype with autosomal recessive inheritance (Jervell and Lange-Nielsen syndrome) has been reported.

Clinical Course The clinical course of LQTS is quite variable, even within the same family.  Patients with LQTS may be asymptomatic or present with syncope (fainting), life threatening ventricular tachyarrhythmia (e.g. torsade de pointes), aborted cardiac arrest, or sudden death. Some cases of Sudden Infant Death Syndrome (SIDS) are due to unrecognized LQTS.  The clinical variability is influenced by incomplete penetrance of the underlying mutation, functional status of interacting genes, age and gender, environmental factors, and therapeutic interventions.  Using the Long QT Syndrome Registry, Moss et al have delineated risk factors for adverse outcomes in patients with LQTS (e.g. aborted cardiac arrest and sudden cardiac death). The most powerful predictor of subsequent life-threatening cardiac events in LQTS patients is a history of syncope, whereby timing and frequency of previous syncopal events are crucial factors. Recent or recurrent syncopal events are associated more frequently with subsequent malignant events. A QTc (corrected QT interval) duration of >500 msec has consistently been associated with a worse prognosis.  Additionally, there is an age-dependent effect of gender on the clinical course of LQTS. Before 15 years of age, males have a higher risk of cardiac events such as syncope or sudden cardiac death compared to females. Over age 15, the risk reverses and females have higher risk than males.

Click on the image to enlarge. Figure 1: Illustration showing prolonged QT interval as compared to normal QT interval on an electrocardiogram (ECG)

Genetics of LQTS

LQTS is a genetic channelopathy of the heart, usually with autosomal dominant inheritance.  Therefore, an individual carrying a disease-causing LQTS mutation has a 50% chance of transmitting the mutation to a child, either male or female. A recessively inherited genetic syndrome involving LQTS and hereditary deafness (Jervell and Lange-Nielsen Syndrome) is rare.

Table 1: Genes Associated with Long QT Syndrome

Genotype	Gene Symbol	Gene Name
LQT1	KCNQ1	KQT-like voltage-gated potassium channel-1
LQT2	KCNH2	Potassium channel, voltage gated, H2
LQT3	SCN5A	Alpha polypeptide of voltage-gated sodium channel type V
LQT4	ANK2	Ankyrin-B
LQT5	KCNE1	Voltage-gated potassium channel , Isk-related subfamily, member 1
LQT6	KCNE2	Voltage-gated potassium channel , Isk-related subfamily, member 2
LQT7	KCNJ2	Inwardly rectifying potassium channel
LQT8	CACNA1C	Calcium channel, L type, alpha 1 polypeptide isoform
LQT9	CAV3	Caveolin-3
LQT10	SCN4B	Sodium channel, voltage gated, type IV beta subunit

LQTS is a genetically heterogeneous disorder that has been seen in all ethnicities. Mutations or deletions/duplications in more than 10 genes have been associated with LQTS, leading either to decreased repolarizing potassium currents or to inappropriate entry of sodium or calcium ions into cardiac myocytes due to defective sodium or calcium ion channels. As shown in Table 1, the vast majority of individuals with heritable LQTS have mutations in ion channel genes.


Genetic testing for Long QT Syndrome and its utility

There are several reasons an individual or family may be referred for genetic testing in LQTS. Genetic testing for LQTS encompasses 2 components: 1. DNA sequencing of the coding regions and splice junctions of the LQTS genes and 2. Testing for whole or partial gene deletions/duplications involving one of the LQTS genes. Diagnostic genetic testing may be considered for patients who clinically manifest with symptoms of LQTS and for asymptomatic family members of patients with a known mutation. Testing should be performed first on the family member who is symptomatic, i.e. has clinical manifestations of Long QT syndrome.  Preferably, the youngest of severely affected family members should be tested first. The three possible outcomes of genetic testing are: positive, negative, and variant of unknown clinical significance (VOUS). Genetic testing in a clinically affected patient with LQTS can reveal a disease-causing mutation and determine which of the different LQTS genes is involved, thus confirming the clinical diagnosis. Based on genotype-phenotype correlations, it is then possible to suggest triggers to be avoided. Genetic testing of affected individuals can also assist in the identification of other at-risk family members who will benefit from cardiac treatment and surveillance or, in individuals that test negative for a specific familial mutation, obviates the need for serial cardiac evaluations.
Results of genetic testing can also be used for prenatal/preimplantation genetic diagnosis.
 

Resources for Patients

Sudden Arrhythmia Death Syndrome (SADS) www.sads.org
 - Patient support organization

Cardiac Arrhythmias Research and Education Foundation (C.A.R.E.) www.longqt.org
- Patient support organization

The Canadian Sudden Arrhythmia Death Syndromes (SADS) Foundation www.sads.ca
 - Patient support organization

Sudden Cardiac Arrest Association www.suddencardiacarrest.org
- Patient support organization

National Society of Genetic Counselors: www.nsgc.org
- Search for a counselor/genetic center specializing in cardiology genetics

Genetic Heart Disease Program: www.geneticheartdisease.org

REFERENCES
 

1. Goldenberg I, Zareba W, Moss AJ Long QT Syndrome. Curr Probl Cardiol. 2008; 33:629-94 PMID 18835466
2. Goldenberg I, Moss AJ. Long QT syndrome. J Am Coll Cardiol 2008; 51: 2291-2300. PMID 18549912
3. A.J. Moss, W. Zareba and J. Benhorin et al., ECG T-wave patterns in genetically distinct forms of the hereditary long QT syndrome. Circulation 1995; 92:2929–2934. PMID 7586261
4. P.J. Schwartz, A.J. Moss, G.M. Vincent and R.S. Crampton, Diagnostic criteria for the long QT syndrome: an update, Circulation 1993; 88:782–784. PMID 8339437
5. Goldenberg, A.J. Moss and W. Zareba, QT interval: how to measure it and what is “normal.” J Cardiovasc Electrophysiol 2006; 17:333-336. PMID 16643414
6. Moss AJ, Kass RS. Long QT syndrome: from channels to cardiac arrhythmias. J Clin Invest 2005; 115:2018-2024. PMID 16075042
7. Moss AJ, Shimizu W, Wilde AA, et al. Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene. Circulation 2007; 115:2481-2489 PMID 17470695
8. Goldenberg I, Moss AJ, Zareba W, McNitt S, Robinson JL, Qi M, Towbin JA, Ackerman MJ, Murphy L. Clinical course and risk stratification of patients affected with the Jervell and Lange-Nielsen syndrome. J Cardiovasc Electrophysiol. 2006; Nov;17(11):1161-8 PMID 16911578
9. Vincent G.M. The molecular genetics of the long QT syndrome: genes causing fainting and sudden death. Ann Rev Med 1998; 49:263-274 PMID 9509262
10. Lehnart SE, Ackerman MG, Benson DW Jr. et al. Inherited arrhythmias: a National Heart, Lung, and Blood Institute and Office of Rare Diseases workshop consensus report about the diagnosis, phenotyping, molecular mechanisms, and therapeutic approaches for primary cardiomyopathies of gene mutations affecting ion channel function. Circulation 2007; 116(20):2325-45 PMID 17998470