Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

Long QT-Syndrome (LQTS), familial [I45.8]

OMIM numbers: 192500, 607542 (KCNQ1), 613688, 152427 (KCNH2), 603830, 600163 (SCN5A), 613695, 176261 (KCNE1), 613693, 603796 (KCNE2)

Dr. rer. nat. Christoph Marschall

Scientific Background

LQTS is a clinically and genetically heterogenous cardiac disease, characterized by prolonged ventricular repolarization. Long-term ECG shows a prolonged frequency-adjusted QT interval (QTc) of 440 to > 500 ms. Arrhythmia, which may lead to unresponsiveness and sudden cardiac death, occurs in dependence to the QTc. If the disease remains untreated, the 10-year survival rate is 50%. There are two types of LQTS: the common autosomal dominant Romano-Ward (RW) and the very rare autosomal recessive Jervell and Lange-Nielson form (JLN). The prevalence of LQTS among the Caucasian population is at least 1 in 2,500.

In approx. 75% of all clinically confirmed cases, mutations can be detected in one of the five myocardial ion channel genes. They encode potassium channels responsible for repolarization (KCNQ1, KCNH2, KCNE1, KCNE2) as well as one sodium channel (SCN5A). The molecular classification and nomenclature (LQTS type 1-12) derives from the affected genes.

  • KCNQ1 (LQTS type 1; 48% of all mutations, own data) encodes a voltage-gated cardiac potassium channel. Mutations with dominant or recessive phenotype (RW and JLN form) are known. Mutations in the KCNQ1 gene are usually associated with early manifestation of a severe phenotype with high risk of cardiac events.
  • KCNH2 (LQTS type 2; 31% of all mutations, own data) encodes another K+ channel. High risk of cardiac events. RW forms.
  • SCN5A (LQTS type 3; 18% of all mutations, own data) encodes a cardiac sodium channel. In contrast to type 1, cardiac events are rarer; the lethality rate, however, is five times higher. Clinically, LQTS type 3 is counted among the RW forms.
  • KCNE1 (LQTS type 5; 3% of all mutations, own data) encodes the regulatory β subunit of the KCNQ1 channel. Mutations may lead to the Romano-Ward or the JLN form.
  • KCNE2 (LQTS type 6, 1% of all mutations, own data) encodes MIRP1, a subunit of the HERG channel.

The identification of carriers of causative mutations allows early, possibly presymptomatic treatment. In this way, the risk of cardiac events in LQTS type 1 can be reduced by 62-95% and in LQTS type 2 by 74%. All carriers should receive instructions on how to adapt their lifestyle.

Furthermore, in rare special forms of LQTS, mutations were found in other genes: ANK2 (LQTS type 4), KCNJ2 (LQTS type 7), CAV3 (LQTS type 9), SCN4B (LQTS type 10), KCNE3, SNTA1 (LQTS type 12). These forms are characterized by sometimes highly complex phenotypes. Analysis in single families may be advisable.

Moreover, drugs of various classes may cause a prolonged QT interval. A prolonged metabolism of drugs caused by variants in the CYP2D6, CYP2C9 or CYP2C19 gene may increase this effect. Additional diagnostic testing of cytochrome P450 genes may be advisable in the case of medication-induced LQTS (see Cytochrome P450-induced drug intolerance, Pharmacogenetics).

Structural model and localization of mutations in the KCNQ1 protein (by courtesy of HUGO Long QT Database, Dr. Lars Allan Larsen)
Long QT syndrome distribution of mutations in KCNQ1