There are several subtypes of<unk> . These can be broadly split into those caused by genetic mutations which those affected are born with, carry throughout their lives, and can pass on to their children (inherited or congenital<unk> , and those caused by other factors which cannot be passed on and are often reversible (acquired<unk> . Inherited Romano Ward syndrome (middle) and Jervell and Lange-Nielsen syndrome (bottom). Inherited, or congenital<unk> , is caused by genetic abnormalities.<unk>  can arise from variants in several genes, leading in some cases to quite different features. The common thread linking these variants is that they affect one or more ion currents leading to prolongation of the ventricular action potential, thus lengthening the<unk>  interval. Classification systems have been proposed to distinguish between subtypes of the condition based on the clinical features (and named after those who first described the condition) and subdivided by the underlying genetic variant. The commonest of these, accounting for 99% of cases, is Romano–Ward syndrome (genetically<unk> 1-6 and<unk> 9-16), an autosomal dominant form in which the electrical activity of the heart is affected without involving other organs. A less commonly seen form is Jervell and Lange-Nielsen syndrome, an autosomal recessive form of<unk>  combining a prolonged<unk>  interval with congenital deafness. Other rare forms include Anderson–Tawil syndrome <unk> 7) with features including a prolonged<unk>  interval, periodic paralysis, and abnormalities of the face and skeleton; and Timothy syndrome <unk> 8) in which a prolonged<unk>  interval is associated with abnormalities in the structure of the heart and autism spectrum disorder. Romano–Ward syndrome<unk> 1 is the most common subtype of Romano–Ward syndrome, 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 that decrease IKs (loss of function variants) slow the repolarisation of the action potential. This causes the<unk> 1 subtype of Romano–Ward syndrome when a single copy of the variant is inherited (heterozygous, autosomal dominant inheritance). Inheriting two copies of the variant (homozygous, autosomal recessive inheritance) leads to the more severe Jervell and Lange–Nielsen syndrome. Conversely, variants in KCNQ1 that increase IKs lead to more rapid repolarisation and the short<unk> . The<unk> 2 subtype is the second-most common form of Romano–Ward syndrome, responsible for 25 to 30% of all cases. It is caused by variants in the KCNH2 gene (also known as hERG) on chromosome 7 which encodes the potassium channel that 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<unk>  interval. The<unk> 3 subtype of Romano–Ward syndrome 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<unk> 3 slow their inactivation leading to a small sustained 'late' sodium current. This continued inward current prolongs the action potential and thereby the<unk>  interval. While some variants in SCN5A cause<unk> 3, other variants can cause quite different conditions. Variants causing a reduction in the early peak current can cause Brugada syndrome and cardiac conduction disease, while other variants have been associated with dilated cardiomyopathy. Some variants which affect both the early and late sodium current can cause overlap syndromes which combine aspects of both<unk> 3 and Brugada syndrome. Rare Romano–Ward subtypes <unk> 4-6 and<unk> 9-16)<unk> 5 is caused by variants in the KCNE1 gene responsible for the potassium channel beta subunit MinK. This subunit, in conjunction with the alpha subunit encoded by KCNQ1, is responsible for the potassium current IKs which is decreased in<unk> .<unk> 6 is caused by variants in the KCNE2 gene responsible for the potassium channel beta subunit MiRP1 which generates the potassium current IKr. Variants that decrease this current have been associated with prolongation of the<unk>  interval. However, subsequent evidence such as the relatively common finding of variants in the gene in those without<unk> , and the general need for a second stressor such as hypokalaemia to be present to reveal the<unk>  prolongation, has suggested that this gene instead represents a modifier to susceptibility to<unk>  prolongation. Some therefore dispute whether variants in KCNE2 are sufficient to cause Romano-Ward syndrome by themselves.<unk> 9 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<unk> 3, these caveolin variants increase the late sustained sodium current, which impairs cellular repolarization.<unk> 10 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.<unk> 13 is caused by variants in GIRK4, a protein involved in the parasympathetic modulation of the heart. Clinically, the patients are characterized by only modest<unk>  prolongation, but an increased propensity for atrial arrhythmias.<unk> 14,<unk> 15 and<unk> 16 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<unk>  interval remain uncertain. Jervell and Lange–Nielsen syndrome Jervell and Lange–Nielsen syndrome (JLNS) is a rare form of<unk>  inherited in an autosomal recessive manner. In addition to severe prolongation of the<unk>  interval, those affected are born with severe sensorineural deafness affecting both ears. The syndrome is caused by inheriting two copies of certain variant in the KCNE1 or KCNQ1 genes. The same genetic variants lead to the<unk> 1 and<unk> 5 forms of Romano-Ward syndrome if only a single copy of the variant is inherited. JLNS is generally associated with a higher risk of arrhythmias than most other forms of<unk> . Andersen–Tawil syndrome <unk> 7)<unk> 7, also known as Andersen–Tawil syndrome, is characterised by a triad of features – in addition to a prolonged<unk>  interval, those affected may experience intermittent weakness often occurring at times when blood potassium concentrations are low (hypokalaemic periodic paralysis), and characteristic facial and skeletal abnormalities such as a small lower jaw (micrognathia), low set ears, and fused or abnormally angled fingers and toes (syndactyly and clinodactyly). The condition is inherited in an autosomal-dominant manner and is caused by mutations in the KCNJ2 gene which encodes the potassium channel protein Kir2.1. Timothy syndrome <unk> 8)<unk> 8, also known as Timothy syndrome combines a prolonged<unk>  interval with fused fingers or toes (syndactyly). Abnormalities of the structure of the heart are commonly seen including ventricular septal defect, tetralogy of Fallot, and hypertrophic cardiomyopathy. The condition presents early in life and the average life expectancy is 2.5 years with death most commonly caused by ventricular arrhythmias. Many children with Timothy syndrome who survive<unk> er than this have features of autism spectrum disorder. Timothy syndrome is caused by variants in the calcium channel Cav1.2 encoded by the gene CACNA1c. Table of associated genes The following is a list of genes associated with<unk> : Type OMIM Gene Notes<unk> 1 KCNQ1 Encodes the α-subunit of the slow delayed rectifier potassium channel KV7.1 carrying the potassium current IKs.<unk> 2 KCNH2 Also known as hERG. Encodes the α-subunit of the rapid delayed rectifier potassium channel KV11.1 carrying the potassium current IKr.<unk> 3 SCN5A Encodes the α-subunit of the cardiac sodium channel NaV1.5 carrying the sodium current INa.<unk> 4 ANK2 Encodes Ankyrin B which anchors the ion channels in the cell. Disputed whether truly disease causing versus minor<unk>  susceptibility gene.<unk> 5 KCNE1 Encodes MinK, a potassium channel β-subunit. Heterozygous inheritance causes Romano–Ward, homozygous inheritance causes Jervell and Lange–Nielsen syndrome.<unk> 6 KCNE2 Encodes MiRP1, a potassium channel β-subunit. Disputed whether truly disease causing versus minor<unk>  susceptibility gene.<unk> 7 KCNJ2 Encodes inward rectifying potassium current Kir2.1 carrying the potassium current IK1. Causes Andersen–Tawil syndrome.<unk> 8 CACNA1c Encodes the α-subunit CaV1.2 of the calcium channel Cav1.2 carrying the calcium current ICa(L). Causes Timothy syndrome.<unk> 9 CAV3 Encodes Caveolin-3, responsible for forming membrane pouches known as caveolae. Mutations in this gene may increase the late sodium current INa.<unk> 10 SCN4B Encodes the β4-subunit of the cardiac sodium channel.<unk> 11 AKAP9 Encodes A-kinase associated protein which interacts with KV7.1.<unk> 12 SNTA1 Encodes syntrophin-α1. Mutations in this gene may increase the late sodium current INa.<unk> 13 KCNJ5 Also known as GIRK4, encodes G protein-sensitive inwardly rectifying potassium channels (Kir3.4) which carry the potassium current IK(ACh).<unk> 14 CALM1 Encodes calmodulin-1, a calcium-binding messenger protein that interacts
Long QT syndrome
Brugada syndrome
Short QT syndrome
Arrhythmogenic cardiomyopathy
Catecholaminergic polymorphic ventricular tachycardia
Opitz G/BBB syndrome
Jervell and Lange-Nielsen syndrome
Familial atrial fibrillation