title: Phenotype, origin and estimated prevalence of a common long QT syndrome mutation: a clinical, genealogical and molecular genetics study including Swedish R518X/KCNQ1 families.
abstract: BACKGROUND
  The R518X/KCNQ1 mutation is a common cause of autosomal recessive (Jervell and Lange Nielsen Syndrome- JLNS) and autosomal dominant long QT syndrome (LQTS) worldwide. In Sweden p.R518X accounts for the majority of JLNS cases and is the second most common cause of LQTS. Here we investigate the clinical phenotype and origin of Swedish carriers of the p.R518X mutation.
  
  
  METHODS
  The study included 19 Swedish p.R518X index families, ascertained by molecular genetics methods (101 mutation-carriers, whereof 15 JLNS cases and 86 LQTS cases). In all families analyses included assessment of clinical data (symptoms, medications and manually measured electrocardiograms), genealogy (census records), haplotype (microsatellite markers) as well as assessment of mutation age and associated prevalence (ESTIAGE and DMLE computer software).
  
  
  RESULTS
  Clinical phenotype ranged from expectedly severe in JLNS to surprisingly benign in LQTS (QTc 576 ± 61 ms vs. 462 ± 34 ms, cumulative incidence of (aborted) cardiac arrest 47% vs. 1%, annual non-medicated incidence rate (aborted) cardiac arrest 4% vs. 0.04%).A common northern origin was found for 1701/1929 ancestors born 1650-1950. Historical geographical clustering in the coastal area of the Pite River valley was shown. A shared haplotype spanning the KCNQ1 gene was seen in 17/19 families. Mutation age was estimated to 28 generations (95% CI 19;41). A high prevalence of Swedish p.R518X heterozygotes was suggested (~1:2000-4000).
  
  
  CONCLUSIONS
  R518X/KCNQ1 occurs as a common founder mutation in Sweden and is associated with an unexpectedly benign phenotype in heterozygous carriers.
authors.affiliation: Department of Clinical Sciences, Pediatrics, Umeå University, Umeå, Sweden. Annika.Winbo@pediatri.umu.se.
authors.forename: Annika
authors.initials: A
authors.lastname: Winbo
authors.forename: Eva-Lena
authors.initials: EL
authors.lastname: Stattin
authors.forename: Charlotte
authors.initials: C
authors.lastname: Nordin
authors.forename: Ulla-Britt
authors.initials: UB
authors.lastname: Diamant
authors.forename: Johan
authors.initials: J
authors.lastname: Persson
authors.forename: Steen M
authors.initials: SM
authors.lastname: Jensen
authors.forename: Annika
authors.initials: A
authors.lastname: Rydberg
mesh_terms: D000328:Adult; D004252:DNA Mutational Analysis; D004562:Electrocardiography; D005260:Female; D018703:Founder Effect; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006323:Heart Arrest / Q000453:epidemiology / Q000235:genetics; D040941:Heredity; D006579:Heterozygote; D006801:Humans; D029593:Jervell-Lange Nielsen Syndrome / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D008297:Male; D008967:Molecular Biology; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011379:Prognosis; D012307:Risk Factors; D012720:Severity of Illness Index; D013548:Sweden / Q000453:epidemiology; D013997:Time Factors; D055815:Young Adult
chemical_list: D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human