Phenotypic variability and unusual clinical severity of congenital long-QT syndrome in a founder population.
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.
Brink
Paul A
PA
Department of Internal Medicine, University of Stellenbosch, South Africa.
Crotti
Lia
L
Corfield
Valerie
V
Goosen
Althea
A
Durrheim
Glenda
G
Hedley
Paula
P
Heradien
Marshall
M
Geldenhuys
Gerhard
G
Vanoli
Emilio
E
Bacchini
Sara
S
Spazzolini
Carla
C
Lundquist
Andrew L
AL
Roden
Dan M
DM
George
Alfred L
AL
Schwartz
Peter J
PJ
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
D051657:KCNQ1 Potassium Channel