The KCNQ1-A341V mutation was associated with an unusually severe phenotype, with 79% of carriers becoming symptomatic by age 40 compared to 30% in other LQT1 patients (P<0.001).
Observational (n=320)
Does the KCNQ1-A341V mutation increase the risk and severity of cardiac events in a founder population compared to noncarriers and typical LQT1 patients?
The KCNQ1-A341V mutation is associated with an unusually severe long-QT phenotype, and heart rate is identified as a novel risk factor for cardiac events in this population.
Absolute Event Rate: 79% vs 30%
p-value: p=<0.001
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 (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.
Brink et al. (Tue,) conducted a observational in Congenital long-QT syndrome (LQTS) (n=320). KCNQ1-A341V mutation vs. Other LQT1 patients (from large databases) was evaluated on Symptomatic by age 40 years (p=<0.001). The KCNQ1-A341V mutation was associated with an unusually severe phenotype, with 79% of carriers becoming symptomatic by age 40 compared to 30% in other LQT1 patients (P<0.001).