Variants in KCNQ1 that decrease IKs (loss of function variants) slow the repolarisation of the action potential. This causes the LQT1 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 QT syndrome.The LQT2 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 QT interval.The LQT3 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 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. While some variants in SCN5A cause LQT3, 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 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.