Long QT Syndrome classification

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]

Overview

There are multiple genetic mutations that account for long QT syndrome (LQTS), but LQT1, LQT2, and LQT3 account for 75% of cases of LQT. Both LQT1 and LQT2 result from a mutation in the potassium channels; however, LQT1 results from a mutation in the alpha subunit of the slow delayed rectifier potassium channel while LQT2 is caused by a mutation in the alpha subunit of the slow delayed rectifier potassium channel. LQT3 is due to an abnormality in the sodium channels.

Classification Based Upon Genotype

The following is a list of the most common mutations:

Type	OMIM	Mutation	Notes
LQT1	192500	alpha subunit of the slow delayed rectifier potassium channel (KvLQT1 or KCNQ1)	The current through the heteromeric channel (KvLQT1 + minK) is known as IKs. These mutations often cause LQT by reducing the amount of repolarizing current that is required to terminate the action potential, leading to an increase in the action potential duration (APD). These mutations tend to be the most common yet least severe.
LQT2	152427	alpha subunit of the slow delayed rectifier potassium channel (HERG + MiRP1)	Current through this channel is known as IKr. This phenotype is also probably caused by a reduction in repolarizing current.
LQT3	603830	alpha subunit of the sodium channel (SCN5A)	Current through this channel is commonly referred to as INa. Depolarizing current through the channel late in the action potential is thought to prolong APD. The late current is due to failure of the channel to remain inactivated and hence enter a bursting mode in which significant current can enter when it should not. These mutations are more lethal but less common.
LQT4	600919	anchor protein Ankyrin B	LQT4 is very rare. Ankyrin B anchors the ion channels in the cell.
LQT5	176261	beta subunit MinK (or KCNE1) which coassembles withKvLQT1	-
LQT6	603796	beta subunit MiRP1 (or KCNE2) which coassembles with HERG	-
LQT7	170390	potassium channel KCNJ2 (or Kir2.1)	The current through this channel and KCNJ12 (Kir2.2) is called IK1. LQT7 leads to Andersen-Tawil syndrome.
LQT8	601005	alpha subunit of the calcium channel Cav1.2 encoded by the gene CACNA1c.	Leads to Timothy's syndrome.
LQT9		Caveolin 3
LQT10		SCN4B

LQT1

LQT1 is the most common type of long QT syndrome, making up about 40 to 55 percent of all cases. This variant will sometimes come to the attention of the cardiologist following a cardiac event during exercise like swimming. The LQT1 gene is KCNQ1 which has been isolated to chromosome 11p15.5. KCNQ1 codes for the voltage-gated potassium channel KvLQT1 that is highly expressed in the heart. It is believed that the product of the KCNQ1 gene produces an alpha subunit that interacts with other proteins (particularly the minK beta subunit) to create the I_Ks ion channel, which is responsible for the delayed potassium rectifier current of the cardiac action potential.

Mutations to the KCNQ1 gene can be inherited in an autosomal dominant or an autosomal recessive pattern in the same family. In the autosomal recessive mutation of this gene,homozygous mutations in KVLQT1 leads to severe prolongation of the QT interval (due to near-complete loss of the I_Ks ion channel), and is associated with increased risk of ventricular arrhythmias and congenital deafness. This variant of LQT1 is known as the Jervell and Lange-Nielsen syndrome.

Most individuals with LQT1 show paradoxical prolongation of the QT interval with infusion of epinephrine. This can also unmark latent carriers of the LQT1 gene.

Many missense mutations of the LQT1 gene have been identified. These are often associated with a high risk percentage of symptomatic carriers and sudden death.

LQT2

The LQT2 type is the second most common gene location that is affected in long QT syndrome, making up about 35 to 45 percent of all cases. This variant will sometimes come to the attention of the cardiologist as a result of a cardiac event during the post partum period or after being triggered by an alarm clock. This form of long QT syndrome most likely involves mutations of the human ether-a-go-go related gene (HERG) on chromosome 7. The HERG gene (also known as KCNH2) is part of the rapid component of the potassium rectifying current (I_Kr). (The I_Kr current is mainly responsible for the termination of the cardiac action potential, and therefore the length of the QT interval.) The normally functioning HERG gene allows protection against early after depolarizations (EADs).

Most drugs that cause long QT syndrome do so by blocking the I_Kr current via the HERG gene. These include erythromycin, terfenadine, andketoconazole. The HERG channel is very sensitive to unintended drug binding due to two aromatic amino acids, the tyrosine at position 652 and the phenylalanine at position 656. These amino acid residues are poised so drug binding to them will block the channel from conducting current. Other potassium channels do not have these residues in these positions and are therefore not as prone to blockage.

LQT3

The LQT3 type of long QT syndrome accounts for 5-10% of cases, and cardiac events can occur during sleep. This variant involves a mutation of the gene that encodes the alpha subunit of the Na⁺ ion channel. This gene is located on chromosome 3p21-24, and is known as SCN5A (also hH1 and Na_V1.5). The mutations involved in LQT3 slow the inactivation of the Na⁺ channel, resulting in prolongation of the Na⁺ influx during depolarization. Paradoxically, the mutant sodium channels inactivate more quickly, and may open repetitively during the action potential.

A large number of mutations have been characterized as leading to or predisposing LQT3. Calcium has been suggested as a regulator of SCN5A, and the effects of calcium 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 anddilated cardiomyopathy. Rarely some affected individuals can have combinations of these diseases.

LQT4

The LQT4 genes are ANK2 and ANKB, and code for proteins called ankyrins. They are proteins which bind to several important ion channel proteins such as the chloride-bicarbonate anion exchanger, ATPase, calcium release channels, and the voltage gated sodium channel. A mutation in the LTQ4 genes that code for ankyrins can cause increased intracellular concentrations of calcium, and can therefore cause fatal arrhythmias.

LQT5

is an autosomal dominant relatively uncommon form of LQTS. It involves mutations in the gene KCNE1 which encodes for the potassium channel beta subunit MinK. In its rare homozygous forms it can lead to Jervell and Lange-Nielsen syndrome

LQT6

is an autosomal dominant relatively uncommon form of LQTS. It involves mutations in the gene KCNE2 which encodes for the potassium channel beta subunit MiRP1, constituting part of the I_Kr repolarizing K⁺ current.

LQT7

Andersen-Tawil syndrome is an autosomal dominant form of LQTS associated with skeletal deformities. It involves mutation in the gene KCNJ2 which encodes for the potassium channel protein Kir 2.1. The syndrome is characterized by Long QT syndrome with ventricular arrhythmias, periodic paralysis and skeletal developmental abnormalities as clinodactyly, low-set ears and micrognathia. The manifestations are highly variable.

LQT8

Timothy's syndrome is due to mutations in the calcium channel Cav1.2 encoded by the gene CACNA1c. Since the Calcium channel Cav1.2 is abundant in many tissues, patients with Timothy's syndrome have many clinical manifestations including congenital heart disease, autism, syndactyly and immune deficiency.

LQT9

This newly discovered variant is caused by mutations in the membrane structural protein,caveolin-3. Caveolins form specific membrane domains calledcaveolae in which among others the Na_V1.5 voltage-gated sodium channelsits. Similar to LQT3, these particular mutations increase so-called 'late' sodium current which impairs cellular repolarization.

LQT10

This novel susceptibility gene for LQT is SCN4B encoding the protein Na_Vβ4, an auxiliary subunit to the pore-forming Na_V1.5 (gene: SCN5A) subunit of the voltage-gated sodium channel of the heart. The mutation leads to a positive shift in inactivation of the sodium current, thus increasing sodium current. Only one mutation in one patient has so far been found.