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

• BACKGROUND: The Y111C/KCNQ1 mutation causes a dominant-negative effect in vitro albeit a benign clinical phenotype in a Swedish Long QT Syndrome population.OBJECTIVE: To investigate the origin (genealogic, geographic, genetic and age) of the Y111C/KCNQ1 mutation in Sweden.METHODS: We identified 170 carriers of the Y111C/KCNQ1 mutation in 37 Swedish proband families. Genealogical investigation was performed in 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 the ESTIAGE and DMLE computer softwares and regional population demographics data.RESULTS: All probands were traced back to a northern river valley region. A founder couple born in 1605/1614 connected 26/37 families. Haplotyped probands shared 2-14 (median 10) uncommon alleles, with frequencies ranging between 0.01-0.41 (median 0.16) in the controls. The age of the mutation was estimated to 24 generations (95% CI 18; 34), i.e. 600 years (95% CI 450; 850) if assuming 25 years per generation. The number of now living Swedish Y111C mutation-carriers was estimated to ~200-400 individuals for the mutation age span 22-24 generations and population growth rates 25-27%.CONCLUSIONS: The Y111C/KCNQ1 mutation is a Swedish LQTS founder mutation, introduced in the northern population approximately 600 years ago. The enrichment of the mutation was enabled by a mild clinical phenotype and strong regional founder effects during the population development of the northern inland. The Y111C/KCNQ1 founder population constitutes an important asset for future genetic and clinical studies.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Kardiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cardiac and Cardiovascular Systems (hsv//eng)

Nyckelord

Dominant-negative mutation

Founder mutation

Gene mutation

Ion channel

Long QT syndrome

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