Phenotypic variability and unusual clinical severity of congenital long-QT syndrome in a founder population

Background-In the congenital long-QT syndrome (LQTS), there can be a marked phenotypic heterogeneity. Founder effects, by which many individuals share a mutation identical by descent, represent a powerful tool to further understand the underlying mechanisms and to predict the natural history of mutation-associated effects. We are investigating one such founder effect, originating in South Africa in approximately AD 1700 and segregating the same KCNQ1 mutation ( A341V). Methods and Results-The study population involved 320 subjects, 166 mutation carriers (MCs) and 154 noncarriers. When not taking beta-blocker therapy, MCs had a wide range of QTc values ( 406 to 676 ms), and 12% of individuals had a normal QTc ( <= 440 ms). A QTc > 500 ms was associated with increased risk for cardiac events ( OR = 4.22; 95% CI, 1.12 to 15.80; P = 0.033). We also found that MCs with a heart rate < 73 bpm were at significantly lower risk ( OR = 0.23; 95% CI, 0.06 to 0.86; P = 0.035). This study also unexpectedly determined that KCNQ1-A341V is associated with greater risk than that reported for large databases of LQT1 patients: A341V MCs are more symptomatic by age 40 years (79% versus 30%) and become symptomatic earlier ( 7 +/- 4 versus 13 +/- 9 years, both P < 0.001). Accordingly, functional studies of KCNQ1-A341V in CHO cells stably expressing IKs were conducted and identified a dominant negative effect of the mutation on wild-type channels. Conclusions-KCNQ1-A341V is a mutation associated with an unusually severe phenotype, most likely caused by the dominant negative effect of the mutation. The availability of an extended kindred with a common mutation allowed us to identify heart rate, an autonomic marker, as a novel risk factor.