title: Phenotypic variability and unusual clinical severity of congenital long-QT syndrome in a founder population.
abstract: 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).
  
  
  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 (< or =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.
authors.affiliation: Department of Internal Medicine, University of Stellenbosch, South Africa.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Brink
authors.forename: Lia
authors.initials: L
authors.lastname: Crotti
authors.forename: Valerie
authors.initials: V
authors.lastname: Corfield
authors.forename: Althea
authors.initials: A
authors.lastname: Goosen
authors.forename: Glenda
authors.initials: G
authors.lastname: Durrheim
authors.forename: Paula
authors.initials: P
authors.lastname: Hedley
authors.forename: Marshall
authors.initials: M
authors.lastname: Heradien
authors.forename: Gerhard
authors.initials: G
authors.lastname: Geldenhuys
authors.forename: Emilio
authors.initials: E
authors.lastname: Vanoli
authors.forename: Sara
authors.initials: S
authors.lastname: Bacchini
authors.forename: Carla
authors.initials: C
authors.lastname: Spazzolini
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Lundquist
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
authors.forename: Alfred L
authors.initials: AL
authors.lastname: George
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Schwartz
mesh_terms: D015331:Cohort Studies; D018703:Founder Effect; D006580:Genetic Carrier Screening; D014644:Genetic Variation; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D008133:Long QT Syndrome / Q000151:congenital / Q000235:genetics* / Q000503:physiopathology*; D009154:Mutation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
chemical_list: D051657:KCNQ1 Potassium Channel