title: Risk of syncope in family members who are genotype-negative for a family-associated long-QT syndrome mutation.
abstract: BACKGROUND
  Current clinical diagnosis of long-QT syndrome (LQTS) includes genetic testing of family members of mutation-positive patients. The present study was designed to assess the clinical course of individuals who are found negative for the LQTS-causing mutation in their families.
  
  
  RESULTS
  Multivariate Cox proportional hazards model was used to assess the risk for cardiac events (comprising syncope, aborted cardiac arrest [ACA], or sudden cardiac death [SCD]) from birth through age 40 years among 1828 subjects from the LQTS Registry who were found negative for their family LQTS-causing mutation. The median QTc of study subjects was 423 ms (interquartile range, 402-442 ms). The cumulative probability of a first syncope through age 40 years was 15%. However, only 2 patients (0.1%) had ACA, and none died suddenly during follow-up. Independent risk factors for syncope in genotype-negative subjects included female sex (hazard ratio [HR], 1.60; P=0.002), prolonged QTc (HR=1.63 per 100 ms increment, P=0.02), family history of ACA or SCD (HR=1.89, P=0.002), and LQT2 versus LQT1 family mutation (HR=1.41, P=0.03). Subgroup analysis showed that the presence of the K897T polymorphism in the LQT2 gene in an affected family was associated with an 11-fold (P=0.001) increase in the risk of recurrent syncope in genotype-negative subjects.
  
  
  CONCLUSIONS
  Our findings suggest that cardiac events among genotype-negative family members of LQTS patients are dominated by nonfatal syncopal episodes without occurrence of sudden cardiac death. The risk for nonfatal events in this population may be mediated by the presence of common polymorphisms in LQTS genes.
authors.affiliation: Cardiology Division, University of Rochester Medical Center, Rochester, NY 14642, USA. alon.barsheshet@heart.rochester.edu
authors.forename: Alon
authors.initials: A
authors.lastname: Barsheshet
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Moss
authors.forename: Scott
authors.initials: S
authors.lastname: McNitt
authors.forename: Slava
authors.initials: S
authors.lastname: Polonsky
authors.forename: Coeli M
authors.initials: CM
authors.lastname: Lopes
authors.forename: Wojciech
authors.initials: W
authors.lastname: Zareba
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Robinson
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
authors.forename: Jesaia
authors.initials: J
authors.lastname: Benhorin
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Kaufman
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Towbin
authors.forename: G Michael
authors.initials: GM
authors.lastname: Vincent
authors.forename: Ming
authors.initials: M
authors.lastname: Qi
authors.forename: Ilan
authors.initials: I
authors.lastname: Goldenberg
mesh_terms: D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D002648:Child; D002675:Child, Preschool; D016757:Death, Sudden, Cardiac / Q000209:etiology; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics; D005190:Family; D005260:Female; D005838:Genotype; D006323:Heart Arrest / Q000209:etiology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D051657:KCNQ1 Potassium Channel / Q000235:genetics; D008133:Long QT Syndrome / Q000235:genetics*; D008297:Male; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010641:Phenotype; D011110:Polymorphism, Genetic; D016016:Proportional Hazards Models; D012307:Risk Factors; D015222:Sodium Channels / Q000235:genetics; D013575:Syncope / Q000209:etiology*
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels