<unk>  is a descriptive term for a group of subtypes of long QT syndrome, specifically subtypes LQT1-6 and LQT9-16. Several subtypes of<unk>  have been described based on the underlying genetic variant. These subtypes differ in clinical presentation and their response to treatment. There is robust evidence that the genetic variants associated with the three most common subtypes (LQT1, LQT2 and LQT3) are truly causative of the syndrome. However, there is uncertainty as to whether some of the other rarer subtypes are truly disease-causing by themselves or instead make individuals more susceptible to QT prolongation in response to other factors such as medication or low blood potassium levels (hypokalaemia). LQT1 LQT1 is the most common subtype of<unk> , responsible for 30 to 35% of all cases. The gene responsible, KCNQ1, has been isolated to chromosome 11p15.5 and encodes the alpha subunit of the KvLQT1 potassium channel. This subunit interacts with other proteins (in particular, the minK beta subunit) to create the channel, which carries the delayed potassium rectifier current IKs responsible for the repolarisation phase of the cardiac action potential. Variants in KCNQ1 cause the LQT1 subtype of<unk>  when a single copy of the variant is inherited (heterozygous, autosomal dominant inheritance). When two copies of the variant are inherited (homozygous, autosomal recessive inheritance) the more severe Jervell and Lange-Nielsen syndrome is found, associated with more marked QT prolongation, congenital sensorineural deafness, and a greater risk of arrhythmias. LQT1 is associated with a high risk of faints but lower risk of sudden death than LQT2. LQT1 may also affect glucose regulation. After ingesting glucose, those with LQT1 produce more insulin than would be expected, which is followed by a period of insulin resistance. When the resistance diminishes, abnormally low blood glucose levels (hypoglycaemia) are sometimes seen. LQT2 The LQT2 subtype is the second-most common form of<unk> , responsible for 25 to 30% of all cases. This form of<unk>  is caused by variants in the KCNH2 gene on chromosome 7. KCNH2 (also known as hERG) encodes the potassium channel which carries the rapid inward rectifier current IKr. This current contributes to the terminal repolarisation phase of the cardiac action potential, and therefore the length of the QT interval. LQT3 The LQT3 subtype of<unk>  is caused by variants in the SCN5A gene located on chromosome 3p21-24. SCN5A encodes the alpha subunit of the cardiac sodium channel, NaV1.5, responsible for the sodium current INa which depolarises cardiac cells at the start of the action potential. Cardiac sodium channels normally inactivate rapidly, but the mutations involved in LQT3 slow their inactivation leading to a small sustained 'late' sodium current. This continued inward current prolongs the action potential and thereby the QT interval. A large number of mutations have been characterized as leading to or predisposing to LQT3. Calcium has been suggested as a regulator of SCN5A protein, and the effects of calcium on SCN5A may begin to explain the mechanism by which some of these mutations cause LQT3. Furthermore, mutations in SCN5A can cause Brugada syndrome, cardiac conduction disease, and dilated cardiomyopathy. In rare situations, some affected individuals can have combinations of these diseases. Other subtypes LQT5 is caused by variants in the KCNE1 gene. This gene is responsible for the potassium channel beta subunit MinK which, in conjunction with the alpha subunit encoded by KCNQ1, is responsible for the potassium current IKs, and variants associated with prolonged QT intervals decrease this current. The same variants in KCNE1 can cause the more severe Jervell and Lange-Nielsen syndrome when two copies are inherited (homozygous inheritance) and the milder LQT5 subtype of<unk>  when a single copy of the variant is inherited (heterozygous inheritance). The LQT6 subtype is caused by variants in the KCNE2 gene. This gene is responsible for the potassium channel beta subunit MiRP1 which generates the potassium current IKr, and variant that decrease this current have been associated with prolongation of the QT interval. However, subsequent evidence such as the relatively common finding of variants in the gene in those without long QT syndrome, and the general need for a second stressor such as hypokalaemia to be present to reveal the QT prolongation, has suggested that this gene instead represents a modifier to susceptibility to QT prolongation. Some, therefore, dispute whether variants in the gene are sufficient to cause<unk>  by themselves. LQT9 is caused by variants in the membrane structural protein, caveolin. Caveolins form specific membrane domains called caveolae in which voltage-gated sodium channels sit. Similar to LQT3, these caveolin variants increase the late sustained sodium current, which impairs cellular repolarization. LQT10 is an extremely rare subtype, caused by variants in the SCN4B gene. The product of this gene is an auxiliary beta-subunit (NaVβ4) forming cardiac sodium channels, variants in which increase the late sustained sodium current. LQT13 is caused by variants in GIRK4, a protein involved in the parasympathetic modulation of the heart. Clinically, the patients are characterized by only modest QT prolongation, but an increased propensity for atrial arrhythmias. LQT14, LQT15 and LQT16 are caused by variants in the genes responsible for calmodulin (CALM1, CALM2, and CALM3 respectively). Calmodulin interacts with several ion channels and its roles include modulation of the L-type calcium current in response to calcium concentrations, and trafficking the proteins produced by KCNQ1 and thereby influencing potassium currents. The precise mechanisms by which means these genetic variants prolong the QT interval remain uncertain. Table of causative genes Type OMIM Gene Notes LQT1 KCNQ1 Encodes the α-subunit of the slow delayed rectifier potassium channel KV7.1 carrying the potassium current IKs. LQT2 KCNH2 Also known as hERG. Encodes the α-subunit of the rapid delayed rectifier potassium channel KV11.1 carrying the potassium current IKr. LQT3 SCN5A Encodes the e α-subunit of the cardiac sodium channel NaV1.5 carrying the sodium current INa. LQT4 ANK2 Encodes Ankyrin B which anchors the ion channels in the cell. Disputed true association with QT prolongation. LQT5 KCNE1 Encodes MinK, a potassium channel β-subunit. LQT6 KCNE2 Encodes MiRP1, a potassium channel β-subunit. LQT9 CAV3 Encodes Caveolin-3 responsible for forming membrane pouches known as caveolae. Mutations in this gene may increase the late sodium INa. LQT10 SCN4B Encodes the β4-subunit of the cardiac sodium channel. LQT11 AKAP9 Encode A-kinase associated protein which interacts with KV7.1. LQT12 SNTA1 Encodes syntrophin-α1. Mutations in this gene may increase the late sodium current INa. LQT13 KCNJ5 Also known as GIRK4, encodes G protein-sensitive inwardly rectifying potassium channels (Kir3.4) which carry the potassium current IK(ACh). LQT14 CALM1 Encodes calmodulin-1, a calcium-binding messenger protein that interacts with the calcium current ICa(L). LQT15 CALM2 Encodes calmodulin-2, a calcium-binding messenger protein that interacts with the calcium current ICa(L). LQT16 CALM3 Encodes calmodulin-3, a calcium-binding messenger protein that interacts with the calcium current ICa(L).
Romano–Ward syndrome
Brugada syndrome
Witteveen–Kolk syndrome
Andersen–Tawil syndrome
Townes–Brocks syndrome
Laugier–Hunziker syndrome
Baggio–Yoshinari syndrome
Morgagni Stewart Morel syndrome