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 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 Romano–Ward syndrome when a single copy of the variant is inherited (heterozygous inheritance).The LQT6 subtype is caused by variants in the KCNE2 gene.
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 Romano–Ward syndrome 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 Romano–Ward syndrome, responsible for 25 to 30% of all cases. This form of Romano–Ward syndrome 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 Romano–Ward syndrome is caused by variants in the SCN5A gene located on chromosome 3p21-24.