title: The common long-QT syndrome mutation KCNQ1/A341V causes unusually severe clinical manifestations in patients with different ethnic backgrounds: toward a mutation-specific risk stratification.
abstract: BACKGROUND
  The impressive clinical heterogeneity of the long-QT syndrome (LQTS) remains partially unexplained. In a South African (SA) founder population, we identified a common LQTS type 1 (LQT1)-causing mutation (KCNQ1-A341V) associated with high clinical severity. We tested whether the arrhythmic risk was caused directly by A341V or by its presence in the specific ethnic setting of the SA families.
  
  
  RESULTS
  Seventy-eight patients, all with a single KCNQ1-A341V mutation, from 21 families and 8 countries were compared with 166 SA patients with A341V and with 205 non-A341V LQT1 patients. In the 2 A341V populations (SA and non-SA), the probability of a first event through 40 years of age was similar (76% and 82%), and the QTc was 484+/-42 versus 485+/-45 ms (P=NS). Compared with the 205 non-A341V patients with the same median follow-up (30 versus 32 years), the 244 A341V patients were more likely to have cardiac events (75% versus 24%), were younger at first event (6 versus 11 years), and had a longer QTc (485+/-43 versus 465+/-38 ms) (all P<0.001). Arrhythmic risk remained higher (P<0.0001) even when the A341V patients were compared with non-A341V patients with mutations either localized to transmembrane domains or exhibiting a dominant-negative effect. A341V patients had more events despite beta-blocker therapy.
  
  
  CONCLUSIONS
  The hot spot KCNQ1-A341V predicts high clinical severity independently of the ethnic origin of the families. This higher risk of cardiac events also persists when compared with LQT1 patients with either transmembrane or dominant-negative mutations. The identification of this high-risk mutation and possibly others may improve the risk stratification and management of LQTS.
authors.affiliation: Section of Cardiology, Department of Lung, Blood and Heart, University of Pavia, Pavia, Italy.
authors.forename: Lia
authors.initials: L
authors.lastname: Crotti
authors.forename: Carla
authors.initials: C
authors.lastname: Spazzolini
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Schwartz
authors.forename: Wataru
authors.initials: W
authors.lastname: Shimizu
authors.forename: Isabelle
authors.initials: I
authors.lastname: Denjoy
authors.forename: Eric
authors.initials: E
authors.lastname: Schulze-Bahr
authors.forename: Elena V
authors.initials: EV
authors.lastname: Zaklyazminskaya
authors.forename: Heikki
authors.initials: H
authors.lastname: Swan
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Moss
authors.forename: Arthur A M
authors.initials: AA
authors.lastname: Wilde
authors.forename: Minoru
authors.initials: M
authors.lastname: Horie
authors.forename: Paul A
authors.initials: PA
authors.lastname: Brink
authors.forename: Roberto
authors.initials: R
authors.lastname: Insolia
authors.forename: Gaetano M
authors.initials: GM
authors.lastname: De Ferrari
authors.forename: Gabriele
authors.initials: G
authors.lastname: Crimi
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005006:Ethnicity / Q000235:genetics*; D005260:Female; D006801:Humans; D007391:International Cooperation; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D008133:Long QT Syndrome / Q000235:genetics* / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012307:Risk Factors; D012720:Severity of Illness Index
chemical_list: D051657:KCNQ1 Potassium Channel