The Swedish long QT syndrome R518X/KCNQ1 founder population- origin and clinical phenotype: phenotypic variability partly explained by gender-specific effects of sequence variants in the NOS1AP gene
(English)Manuscript (preprint) (Other academic)
Background: Genetic modifiers have been proposed to explain phenotypic variability in the long QT syndrome (LQTS). We investigate the origin and phenotype of the worldwide common R518X/KCNQ1 mutation in Sweden, as well as possible associations between p.R518X-LQTS phenotype and previously reported modifying sequence variants in the NOS1AP, KCNH2, KCNE1, SCN5A and KCNQ1(3’UTR) genes.
Methods and Results: We identified 19 p.R518X families (101 mutation-carriers, whereof 15 Jervell and Lange-Nielsen (JLNS) cases and 86 LQTS cases). Analyses of microsatellite markers, genealogy and mutation age (ESTIAGE) identified a common northern origin ~700 years ago for 17/19 families and a high prevalence of Swedish p.R518X heterozygotes was suggested (DMLE).
Clinical phenotype ranged from severe in JLNS to relatively 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%).
In p.R518X-LQTS males, two NOS1AP variants rs12143842 and rs16847548 were associated with a 29 ms QT prolongation (p=0.004), explaining 27% of QTc variability.
Three derived 3’UTR-KCNQ1 variants, previously shown to suppress gene expression in an allele-specific manner, were found to segregate with the founder mutation.
Conclusion: The R518X/KCNQ1 mutation is a Swedish founder mutation presenting with an expectedly severe phenotype in JLNS and an unusually mild phenotype in LQTS, although intra-familial variability remained. Gender-specific effects of NOS1AP sequence variants explained over a fourth of QTc variance in p.R518X-LQTS males, warranting further studies. Repressive 3’UTR-KCNQ1 sequence variants segregating within the founder haplotype could possibly contribute to its relative benignancy.
Long QT Syndrome, Jervell and Lange-Nielsen Syndrome, founder effects, genealogy, genetics, origin, haplotype analysis, mutation age, clinical phenotype, KCNQ1 gene, modifier genes, sequence variants, risk stratification
Research subject Pediatrics
IdentifiersURN: urn:nbn:se:umu:diva-57723OAI: oai:DiVA.org:umu-57723DiVA: diva2:544319
Manuskriptets titel i avhandlingen: Phenotype and origin of the Swedish long QT syndrome R518X/KCNQ1 founder population - phenotypic variability partly explained by gender-specific effects of genetic modifiers.2012-08-142012-08-142012-08-15Bibliographically approved