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The Swedish long QT...
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
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- Winbo, Annika, 1978- (författare)
- Umeå universitet,Pediatrik
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- Stattin, Eva-Lena (författare)
- Umeå universitet,Medicinsk och klinisk genetik
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- Norberg, Anna (författare)
- Umeå universitet,Medicinsk och klinisk genetik
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visa fler...
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- Nordin, Charlotte (författare)
- Umeå universitet,Pediatrik
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- Diamant, Ulla-Britt (författare)
- Umeå universitet,Klinisk fysiologi
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- Persson, Johan (författare)
- Umeå universitet,Pediatrik
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- Jensen, Steen M (författare)
- Umeå universitet,Medicin
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- Rydberg, Annika (författare)
- Umeå universitet,Pediatrik
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visa färre...
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(creator_code:org_t)
- Engelska.
- Relaterad länk:
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https://urn.kb.se/re...
Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Pediatrik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Pediatrics (hsv//eng)
Nyckelord
- 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
- pediatrik
- Pediatrics
Publikations- och innehållstyp
- vet (ämneskategori)
- ovr (ämneskategori)