Causes of Long QT Syndrome

The exact prevalence of long QT syndrome (LQTS) is not known, but it is estimated to occur in 1 of every 2,000 to 2,500 individuals worldwide. LQTS is inherited in 90 percent of patients and occurs sporadically in 10 percent of patients. When LQTS is inherited, all family members have the same major gene mutation but the effects can be expressed differently by each individual in the family, a situation known as variable penetrance.

Much of the current discussion about the etiology of LQTS relates to the macromolecular complexes that comprise ion channel proteins and components of the cytoskeleton; cell signaling molecules, such as regulatory kinases and phosphatases; trafficking proteins; extracellular matrix proteins; and possibly, other ion channels. Alterations in these complexes can result in electrophysiological abnormalities that, through a variety of mechanisms, lead to the arrhythmias associated with LQTS (Moss and Kass, 2005; Meadows et al., 2005; Antzelevitch, 2007).

The Role of Ion Channels in LQTS

Ion channels are pores or openings in the cell membrane that allow charged particles called ions to pass in and out of the cell. There are many types of ion channels; they are classified based on their interaction with a specific ion and by their mechanism of action. Many ion channels are activated by depolarizing currents and electrochemical gradients, but other complex processes also modulate their function.

A number of genetic disorders known as channelopathies affect ion channels and the proteins that regulate them. If a channelopathy disrupts the normal function of an ion channel, it can result in disease. LQTS is a channelopathy in which a variety of ion channel malfunctions can result in QT interval prolongation and the development of associated arrhythmias.

LQTS is caused by a mutation in one of several genes that affect the structure or function of ion channels. A mutation in one of these genes can result in instability of the cellular ion channel system and lead to abnormal ionic currents. In cardiac cells, the abnormal currents produce electrical instability by prolonging the duration of the ventricular action potential, and as a result, the QT interval. Early after-depolarizations, often triggered by sympathetic stimulation, manifest as premature ventricular contractions (PVCs) and torsades de pointes or ventricular fibrillation.

The activity of ion channel currents relative to the cardiac action potential is shown in the figure below. Depolarization occurs in association with rapid influx of the sodium current, INa. Repolarization is a result of the opening of potassium channels at various times during the action potential sequence. There are two potassium currents represented here, the slow delayed potassium rectifier channel current, IKs, and the rapid delayed potassium rectifier channel current, IKr.

Genes Associated With LQTS

Potassium (K+), sodium (Na+), and calcium (Ca++) ion channels are involved in the heart's normal function. Recent genetic studies have identified mutations in several genes that encode for proteins that regulate or modulate these ion channels. These mutations can lead to LQTS by altering cardiac repolarization and increasing the risk for ventricular arrhythmias.

Currently, mutations shown to be causative for LQTS have been identified in 12 genes. Together, these genes explain approximately 75 percent of LQTS cases. The remainder of cases are presumably caused by mutations in additional genes not yet identified as conferring risk to LQTS, or from mutations in known risk genes that evade detection. Genetic tests that identify mutations in known LQTS-related genes can help diagnose the disorder.

LQTS Subtypes: Jervell and Lange-Nielson and Romano-Ward Syndromes

When LQTS was initially described, the genetic etiologies and electrophysiologic mechanisms underlying the disorder were not known. Those with LQTS were classified according to the type of inheritance and the presence or absence of associated hearing deficits. Once genetic mutations associated with LQTS were identified, LQTS subtypes were described according to a specific gene mutation, when known. Both Jervell and Lange-Nielson and Romano-Ward syndrome are now categorized as LQTS subtypes and classified by their specific ion current-associated gene mutation spectra.

The condition associated with an autosomal recessive inheritance and hearing deficit was named Jervell and Lange-Nielson syndrome after the authors of the first description of the disorder, which was published in 1957. This form is now associated with mutations in the KCNE1 and KCNQ1 genes. Jervell and Lange-Nielson syndrome is sometimes still used to describe LQTS with an associated hearing deficit. There are two subtypes of Jervell and Lange-Neilson syndrome, JLN1 occurs when a person has two abnormal KCNQ1 genes and JLN2 occurs when a person has two abnormal forms of the KCNE1 gene.

Similarly, a second form associated with normal hearing and inheritance in an autosomal dominant manner was described in 1963 and 1964 and subsequently named Romano-Ward syndrome. Most cases of LQTS can be considered Romano-Ward syndrome, which describes any LQTS with normal hearing; however, this classification is less commonly used than other LQTS subtype names.

Genetic Defects That Cause QT Interval Prolongation

Most of what is known about mutations that result in LQTS relates to the first five LQTS genes identified, listed here with commonly used gene aliases: KCNQ1 (KVLQT1); KCNH2 (HERG); SCN5A (hH1 and NaV1.5); KCNE1 (minK); and KCNE2 (MiRP1). Observed mutations in these genes include missense (72 percent), frameshift (10 percent), splice-site (7 percent), and nonsense mutations (6 percent), and in-frame deletions (5 percent) (Splawski et al., 2000).

Reduced slow delayed potassium rectifier channel current (IKs), rapid delayed potassium rectifier channel current (IKr), or increased sodium current (INa) will result in a prolongation of the action potential and thus the QT interval, which subsequently increases the risk of ventricular arrhythmias. KCNQ1 and KCNH2 have been reported to account for 50 to 60 percent and 30 to 40 percent of all identified mutations found in LQTS, respectively. SCN5A account for an additional 5-10 percent of mutations, KCNE1 for 3 percent, and KCNE2 for 2 percent. These mutations were located in various protein domains, including the intracellular (52 percent), transmembrane (30 percent), pore (12 percent), and extracellular (6 percent) segments.

Table 1. Ionic Currents, Proteins, and Genes Associated With LQTS
LQTS Type Protein Protein Type Gene Current1 Prevalence of genotyped cases2
LQT1 Kv7.1 K+ channel (IKs) α subunit KCNQ1 IKs 50-60%
LQT2 Kv11.1 K+ channel (IKr) α subunit KCNH2 IKr 30%-40%
LQT3 Nav1.5 Na2+ channel (INa) α subunit SCN5A INa 5%-10%
LQT4 Ankyrin-B Membrane anchoring/adapter protein ANK2 Loss of function <1%
LQT5 minK K+ channel (IKs) β subunit KCNE1 IKs ~1%
LQT6 MiRP1 K+ channel (IKr) β subunit KCNE2 IKr <1%
  Andersen-Tawil Syndrome
LQT7
(ATS1)
Kir2.1 K+ channel (IK1) α subunits KCNJ2 IK1 50% of Andersen-Tawil cases
  Timothy Syndrome
LQT8 Cav1.2 L type Ca2+ channel (ICa,L) α subunit CACNA1C ICa-L <1% of Timothy syndrome cases
LQT9 Caveolin-3 Caveolae coat protein CAV3 INa <1%
LQT10 NaVβ4 Na2+ channel β subunit SCN4B INa rare
LQT11 Yotiao A-kinase anchor protein 9/adapter protein AKAP9 Loss of function rare
LQT12 α-1-syntrophin Membrane scaffold SNTA1 INa rare
  Jervell and Lange-Nielsen Syndrome
JLN1 Kv7.1 K+ channel (IKs) α subunit KCNQ1 IKs 80% of Jervell and Lange-Nielsen cases
JLN2 MinK K+ channel (IKs) β subunit KCNE1 IKs 20%
1 Arrows indicate increased current or gain of function (up arrow) or decreased current or loss of function (down arrow) relative to normal function
2 For LQT1 through LQT6, prevalence values are relative to all LQTS cases that can be genotyped; for named subtypes, prevalence values are relative to all cases within that subtype

More information on these genes can be found in Napoliatano et al (2006) and in the information below.



Potassium Channel Disorders

LQT1 and LQT5

Long QT syndrome 1 (LQT1) and long QT syndrome 5 (LQT5) are both a result of an abnormality in the IKs channel, one of two channels responsible for termination of the plateau phase of the action potential. LQT1 is caused by mutations in the KCNQ1 gene, also known as KVLQT1, which encodes the voltage-gated K+ channel subunit. LQT5, a relatively uncommon form of LQTS that transmits as an autosomal dominant trait, is caused by mutations in KCNE1, a gene that encodes a much smaller K+ channel β subunit.

Four KCNQ1 subunits assemble with the KCNE1-encoded β subunit to form the channels that underlie the slowly activating IKs current in the heart (Sanguinetti et al., 1996). Abnormalities of the KCNQ1 and KCNE1 genes prolong repolarization through a dominant-negative effect and reduce K+ channel function by more than 50 percent (Keating and Sanguinetti, 2001).

The molecular mechanism resulting in reduced IKs function occurs from synthesis of abnormal subunits. The abnormal subunits either cannot join with normal subunits or have other structural abnormalities that result in a reduction in the number of functional channels and loss of function.

Homozygous mutations of the KCNQ1 gene occur when both parents transmit the same or similar mutations and lead to severe prolongation of the QT interval due to near-complete loss of the IKs ion channel. They are also associated with increased risk of ventricular arrhythmias and congenital deafness. Disease caused by this autosomal recessive variant of KCNQ1 is known as the Jervell and Lange-Nielsen syndrome, specifically the subtype called JLN1. Homozygous mutations of the KCNE1 gene are rare, but when they do occur, the homozygous form of LQT5 can lead to the subtype of Jervell and Lange-Nielsen syndrome called JLN2.

Both KCNQ1 and KCNE1 are expressed in the inner ear. Patients harboring mutations in both KVNQ1 and KCNE1 alleles have no functional IKs channels, which leads to inadequate endolymph production, deterioration of the organ of Corti, and neural deafness.

LQT2 and LQT6

Long QT syndrome 2 (LQT2) and long QT syndrome 6 (LQT6) are both caused by abnormalities in subunits involved in the IKr current.

The genetic basis of LQT2 was identified in 1994 when Jiang and colleagues showed genetic linkage to a chromosome 7 locus in a cohort of families with LQTS. This form of LQTS involves mutations of the human ether-a-go-go-related gene (HERG), officially named KCNH2. KCNH2 mutations represent 30 to 40 percent of the total number of LQTS mutations found to date, which makes it the second most prevalent LQTS subtype.

KCNH2 encodes for the subunits that form the cardiac IKr channel, the second of two channels responsible for termination of the plateau phase of the action potential. The IKr current is mainly responsible for the termination of the cardiac action potential, and therefore the length of the QT interval. Mutations in this gene result in a decreased outward K+ current that prevents termination of the plateau phase of the action potential. A normally functioning KCNH2 protein allows for protection against early after-depolarization.

LQT6 is caused by mutations in the gene KCNE2, which encodes for a K+ channel beta subunit that constitutes part of the IKr repolarizing K+ current. KCNH2 subunits assemble with subunits encoded by the KCNE2 gene, also known as the minK-related protein 1(MiRP1) gene, to form cardiac IKr channels. LQT6 is a relatively uncommon form of LQTS.

The KCNH2 channel is the K+ channel that is most frequently blocked by drugs. The KCNH2 K+ channel appears be predisposed to unintended blockage by multiple drugs due to two aromatic amino acids, a tyrosine at position 652 and a phenylalanine at position 656. These amino acid residues are positioned such that drug molecules binding to either residue will block the channel from conducting current. Other potassium channels do not have the same amino acids at these positions and are therefore not as prone to blockage.

Multiple drugs are known to prolong the QT interval and potentially induce arrhythmias by blocking the IKr current via the KCNH2 protein. These drugs include erythromycin, terfenadine, and ketoconazole. Drugs that block IKr are often associated with pause-dependent torsades de pointes.

LQT7

Long QT syndrome 7 (LQT7), also known as Andersen-Tawil syndrome, is associated with skeletal deformities and periodic paralysis. LQT7 involves a mutation in the gene KCNJ2, also known as Kir2.1, which encodes a potassium channel protein for the IK1 current.

The syndrome is characterized by LQTS with ventricular arrhythmias, periodic paralysis, and skeletal developmental abnormalities, including clinodactyly, low-set ears, and micrognathia. The phenotypic manifestations of LQT7 are highly variable.

LQT11

Long QT syndrome 11 (LQT11) is a rare LQTS subtype associated with A-kinase-anchoring proteins (AKAPs), scaffolding proteins that determine the subcellular localization of protein kinase A, and pathway regulating enzymes. One family was described as having a mutation in the gene that encodes for the Yotiao domain of AKAP9, which forms macromaolecular complexes with the slowly activating cardiac potassium channel IKs.

Sodium Channel Disorders

LQT3

Long QT syndrome 3 (LQT3) involves a mutation of the SCN5A gene, also known as hH1 or NaV1.5, which encodes the α subunit of the ion channel that controls the Na+ current in the heart. In 1995, Wang and colleagues reported a group of LQTS families who revealed a genetic linkage between LQT3 and chromosome band 3p21. The responsible locus was shown to encode the subunit of the cardiac Na+ channel responsible for initiating cardiac action potentials.

Mutations of SCN5A slow the inactivation of the Na+ channel, resulting in prolongation of Na+ influx during depolarization. Paradoxically, mutant Na+ channels inactivate more quickly and may open repetitively during the action potential. Increased activity is reported to be due to gain of function mutations, especially in the inactivation gate between domains III and IV of the Na+ channel. This results in continued late inward Na+ current (gain of function) that prolongs the action potential and predisposes to ventricular arrhythmias.

Ca++ has been suggested as a regulator of SCN5A, and the effects of Ca++ on SCN5A may begin to explain the mechanism by which some these mutations cause LQT3. Furthermore, mutations in SCN5A can cause Brugada syndrome, cardiac conduction disease, and dilated cardiomyopathy. Rarely, some affected individuals can have combinations of these diseases.

LQT9

Long QT syndrome 9 (LQT9) is a more recently discovered LQTS subtype, caused by mutations in the membrane structural protein caveolin-3 (CAV3). Caveolins form specific membrane domains called caveolae, in which ion channels such as the NaV1.5 voltage-gated Na+ channel are situated. Similar to LQT3, mutations in CAV3 increase the "late" Na+ current that impairs cellular repolarization.

LQT10

Long QT syndrome 10 (LQT10) is a newly discovered LQTS subtype caused by mutations in the gene SCN4B. This gene encodes NaVB4, an auxiliary subunit to the pore-forming NaV1.5 subunit of the cardiac-specific voltage-gated Na+ channel, encoded by SCN5A. Mutations of SCN4B lead to a positive shift in inactivation of the Na+ current, thus increasing Na+ current. This is a rare mutation.

LQT12

Long QT syndrome 12 (LQT12) is another rare subtype of LQTS. It is caused by mutations in the SNTA1 gene, which encodes the α-1-syntrophin scaffolding protein, a scaffolding protein that interacts with the subunit of the cardiac sodium channel and impacts regulation of the sodium current. This mutation is rare.

Calcium Channel and Other Disorders

LQT8

Long QT syndrome 8 (LQT8), also known as Timothy syndrome, is due to mutations in the Ca++ channel encoded by the gene CACNA1C (Cav1.2). Since CACNA1C is abundantly expressed in many tissues, patients with LQT8 have many clinical manifestations, including congenital heart disease, autism, syndactyly, and immune deficiency.

LQT4

Long QT syndrome 4 (LQT4) is associated with mutations in the ANK2 gene also called ankyrin-B or ankyrin 2, in the family of membrane adapters. Mutations in this gene result in alterations of the Na+ pump and Na+/ Ca++ exchanger and can also lead to altered Ca++ signaling in adult cardiomyocytes that results in extrasystoles.

More information regarding the spectrum of mutations in LQTS predisposition genes has been reported by Splawski and colleagues, and by Ackerman and Mohler.

Non-Genetic Factors Associated With QT Interval Prolongation

LQTS is not the only cause of prolonged QT intervals. Medications, electrolyte abnormalities, and additional factors or other medical conditions can lead to prolongation of the QT interval. Evaluation of these factors is essential when a diagnosis of LQTS is being considered.

References