title: Mutation-specific risk in two genetic forms of type 3 long QT syndrome.
abstract: The clinical course of patients with 2 relatively common long QT syndrome type 3 mutations has not been well described. In the present study, we investigated the mutational-specific risk in patients with deletional (DeltaKPQ) and missense (D1790G) mutations involving the SCN5A gene. The study population involved 50 patients with the DeltaKPQ mutation and 35 patients with the D1790G mutation. The cumulative probability of a first cardiac event (syncope, aborted cardiac arrest, or long QT syndrome-related sudden death) was evaluated using the Kaplan-Meier method. The Cox proportional hazards survivorship model was used to determine the independent contribution of clinical and genetic factors to the first occurrence of cardiac events from birth through 40 years of age. The Andersen-Gill proportional intensity regression model was used to analyze the factors associated with recurrent syncope. Patients with a DeltaKPQ mutation had a significantly greater probability of a first cardiac event from birth through 40 years of age (34%) than those with the D1790G mutation (20%; p <0.001). Multivariate analysis demonstrated an increased risk of cardiac events among DeltaKPQ carriers compared to D1790G carriers (hazard ratio 2.42, p <0.0001) after adjustment for gender and QTc duration. Patients with DeltaKPQ mutations also had an increased risk of recurrent syncope (hazard ratio 5.20, p <0.001). In conclusion, the clinical course of patients with long QT syndrome type with DeltaKPQ mutations was shown to be more virulent than those with D1790G mutations, and this effect was independent of QTc duration. The findings highlight the importance of knowing the specific mutation in risk stratification of patients with long QT syndrome type 3.
authors.affiliation: Heart Research Follow-up Program, Cardiology Division, Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Judy F
authors.initials: JF
authors.lastname: Liu
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Moss
authors.forename: Christian
authors.initials: C
authors.lastname: Jons
authors.forename: Jesaia
authors.initials: J
authors.lastname: Benhorin
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Schwartz
authors.forename: Carla
authors.initials: C
authors.lastname: Spazzolini
authors.forename: Lia
authors.initials: L
authors.lastname: Crotti
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
authors.forename: Scott
authors.initials: S
authors.lastname: McNitt
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Robinson
authors.forename: Ming
authors.initials: M
authors.lastname: Qi
authors.forename: Ilan
authors.initials: I
authors.lastname: Goldenberg
authors.forename: Wojciech
authors.initials: W
authors.lastname: Zareba
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004562:Electrocardiography; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D008133:Long QT Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality*; D008297:Male; D009124:Muscle Proteins / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D012042:Registries; D012189:Retrospective Studies; D017384:Sequence Deletion / Q000235:genetics*; D015222:Sodium Channels / Q000235:genetics*; D016019:Survival Analysis; D055815:Young Adult
chemical_list: D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels