Combined assessment of sex- and mutation-specific information for risk stratification in type 1 long QT syndrome

Background: Men and women with type 1 long QT syndrome (LQT1) exhibit time-dependent differences in the risk for cardiac events. Objective: We hypothesized that sex-specific risk for LQT1 is related to the location and function of the disease-causing mutation in the KCNQ1 gene. Methods: The risk for life-threatening cardiac events (comprising aborted cardiac arrest [ACA] or sudden cardiac death [SCD]) from birth through age 40 years was assessed among 1051 individuals with LQT1 (450 men and 601 women) by the location and function of the LQT1-causing mutation (prespecified as mutations in the intracellular domains linking the membrane-spanning segments [ie, S2-S3 and S4-S5 cytoplasmic loops] involved in adrenergic channel regulation vs other mutations). Results: Multivariate analysis showed that during childhood (age group: 0-13 years) men had >2-fold (P <.003) increased risk for ACA/SCD than did women, whereas after the onset of adolescence the risk for ACA/SCD was similar between men and women (hazard ratio = 0.89 [P =.64]). The presence of cytoplasmic-loop mutations was associated with a 2.7-fold (P <.001) increased risk for ACA/SCD among women, but it did not affect the risk among men (hazard ratio 1.37; P =.26). Time-dependent syncope was associated with a more pronounced risk-increase among men than among women (hazard ratio 4.73 [P <.001] and 2.43 [P =.02], respectively), whereas a prolonged corrected QT interval (<500 ms) was associated with a higher risk among women than among men. Conclusion: Our findings suggest that the combined assessment of clinical and mutation location/functional data can be used to identify sex-specific risk factors for life-threatening events for patients with LQT1.