Origin of the Swedish long QT syndrome Y111C/KCNQ1 founder mutation

BackgroundThe Y111C/KCNQ1 mutation causes a dominant-negative effect in vitro but a benign clinical phenotype in a Swedish long QT syndrome population.ObjectiveThe purpose of this study was to investigate the origin (genealogic, geographic, genetic, and age) of the Y111C/KCNQ1 mutation in Sweden.MethodsWe identified 170 carriers of the Y111C/KCNQ1 mutation in 37 Swedish proband families. Genealogic investigation was performed for all families. Haplotype analysis was performed in 26 probands, 21 family members, and 84 healthy Swedish controls, using 15 satellite markers flanking the KCNQ1 gene. Mutation age was estimated using ESTIAGE and DMLE computer software and regional population demographic data.ResultsAll probands were traced back to a northern river valley region. A founder couple born in 1605/1614 connected 26 of 37 families. Haplotyped probands shared 2–14 (median 10) uncommon alleles, with frequencies ranging between 0.01 and 0.41 (median 0.16) in the controls. The age of the mutation was estimated to 24 generations (95% confidence interval 18; 34), that is, 600 years (95% confidence interval 450; 850) assuming 25 years per generation. The number of now living Swedish Y111C mutation carriers was estimated to approximately 200–400 individuals for the mutation age span 22–24 generations and population growth rates 25%–27%.ConclusionThe Y111C/KCNQ1 mutation is a Swedish long QT syndrome founder mutation that was introduced in the northern population approximately 600 years ago. Enrichment of the mutation was enabled by a mild clinical phenotype and strong regional founder effects during population development of the northern inland. The Y111C/KCNQ1 founder population constitutes an important asset for future genetic and clinical studies.