Certain situations are more likely to precipitate arrhythmias such as exercise or mental stress in the LQT1 subtype, sudden loud noise in the LQT2 subtype, and during sleep or immediately upon waking in the LQT3 subtype.Romano–Ward syndrome can be differentiated from other forms of long QT syndrome by Romano-Wards sole involvement of the heart. While other forms of long QT syndrome are associated with deafness (Jervell and Lange-Nielsen syndrome), intermittent weakness and bone abormailities (LQT7, Andersen–Tawil syndrome), and autism spectrum disorder (LQT8, Timothy syndrome), these extra-cardiac manifestations are not seen in Romano-Ward. Causes
Romano–Ward syndrome is a descriptive term for a group of subtypes of long QT syndrome, specifically subtypes LQT1-6 and LQT9-16. Several subtypes of Romano–Ward syndrome 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 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 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 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. 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).