Long QT Syndrome
Long QT Syndrome (LQTS) is a rare hereditary disease that is characterized by a prolonged QT-interval on the electrocardiogram (ECG) due to delayed repolarization of the heart. Affected individuals have an increased risk for ventricular tachycardia with syncope or even sudden death due to ventricular fibrillation.
The estimated prevalence of LQTS is one in 2000. The clinical symptoms of LQTS are quite variable depending on the causative mutation, age, gender, environmental factors and therapeutic interventions. The age of onset is usually younger than 40 years of age, however, the condition can occur as early as in infancy. The diagnosis and risk assessment of LQTS is based on patient’s clinical symptoms, including ECG findings, as well as family history. However, the diagnosis of LQTS can be challenging since around 2.5% of the healthy population have prolonged QT-interval while some of LQTS patients do not exhibit abnormal ECG findings. Therefore, genetic testing is a valuable component in the assessment of LQTS patients.
LQTS is caused by mutations in genes encoding for the subunits of various ion channels. To date, over 600 disease causing mutations have been recognized in at least 15 genes. It has been shown that mutations in known LQTS related genes can be detected in more than 75% of patients with clinical diagnosis. Most commonly the mutations are detected in KCNQ1 (LQT1), KCNH2 (LQT2) and SCN5A (LQT3) genes and account for about 95% of mutations in affected individuals. The disorder is inherited as an autosomal dominant trait, although a rare subtype with autosomal recessive inheritance has been reported (Jervell and Lange-Nielsen Syndrome).
Indications for genetic testing:
- Confirmation of clinical diagnosis
- Distinguishing different forms of LQTS to direct appropriate therapies
- Testing of family members of the affected individuals
- Carrier status detection of known mutation
- Genetic counseling
Lehnart SE 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 Nov 13;116(20):2325-45.
Moric-Janiszewska E et al. Challenges of diagnosis of long-QT syndrome in children. Pacing Clin Electrophysiol. 2007 Sep;30(9):1168-70.
Morita H et al. The QT syndromes: long and short. Lancet. 2008 Aug 30;372(9640):750-63.
Tester DJ, Ackerman MJ. Genetics of long QT syndrome. Methodist Debakey Cardiovasc J. 2014 Jan-Mar;10(1):29-33.
Schwartz PJ. Prevalence of the congenital long-QT syndrome. Circulation. 2009 Nov 3;120(18):1761-7.
Wang et al. The phenotype characteristics of type 13 long QT syndrome with mutation in KCNJ5 (Kir3.4-G387R). Heart Rhythm. 2013 Oct;10(10):1500-6.