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 LQT3 and Brugada syndrome. Rare Romano–Ward subtypes (LQT4-6 and LQT9-16)
LQT5 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 LQTS. LQT6 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 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 KCNE2 are sufficient to cause Romano-Ward syndrome by themselves.LQT9 is caused by variants in the membrane structural protein, caveolin-3. 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.
LQTS 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 QT 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 LQT1-6 and LQT9-16), 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 LQTS combining a prolonged QT interval with congenital deafness. Other rare forms include Anderson–Tawil syndrome (LQT7) with features including a prolonged QT interval, periodic paralysis, and abnormalities of the face and skeleton; and Timothy syndrome (LQT8) in which a prolonged QT interval is associated with abnormalities in the structure of the heart and autism spectrum disorder. Romano–Ward syndrome
LQT1 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.