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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
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

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.

Keyword [en]
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
National Category
Pediatrics
Research subject
Pediatrics
Identifiers
URN: urn:nbn:se:umu:diva-57723OAI: oai:DiVA.org:umu-57723DiVA: diva2:544319
Note
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.Available from: 2012-08-14 Created: 2012-08-14 Last updated: 2012-08-15Bibliographically approved
In thesis
1. Long QT syndrome in Sweden: founder effects and associated cardiac phenotypes
Open this publication in new window or tab >>Long QT syndrome in Sweden: founder effects and associated cardiac phenotypes
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Långt QT syndrom i Sverige : foundereffekter och associerade kardiella fenotyper
Abstract [en]

Background: We aimed to increase the knowledge regarding the familial arrhythmogenic disorder Long QT Syndrome (LQTS) and its recessive variant Jervell and Lange-Nielsen Syndrome (JLNS) in Sweden, including prevalences and clinical phenotypes. A specific focus was directed towards two KCNQ1 mutations –p.Y111C and p.R518X- commonly identified in Swedish LQTS index cases.

Methods: Cases and families with LQTS (p.Y111C or p.R518X) and JLNS were recruited via regional clinical practices, national referrals to the Clinical Genetics laboratory, Umeå University Hospital, and a national inventory. Molecular genetics methods were used for case ascertainment. Clinical data was obtained via medical records, a questionnaire, and/or an interview. Electrocardiograms were manually assessed. In p.R518X heterozygotes intra-familial phenotypic variability (QTc and cardiac events) was assessed by analysis of sequence variants (modifier genes). The origins of the mutations p.Y111C and p.R518X were investigated using genealogical and haplotype analysis (microsatellite markers). In families sharing a common haplotype mutation age and associated prevalence was analyzed using ESTIAGE and DMLE computer software.

Results: We identified p.Y111C (170 mutation-carriers) and p.R518X (101 mutation-carriers) as two major causes of LQTS/JLNS in Sweden. LQTS phenotype was revealed to be relatively benign in p.Y111C and p.R518X (annual incidence of life-threatening cardiac events, before therapy 0.05% and 0.04%, respectively). Gender-specific effects of genetic modifiers on phenotypic expression were seen. A founder origin, approximately 600-700 years ago in two northern river valleys was established for p.Y111C and p.R518X, and a high prevalence of LQTS founder descendants suggested. A minimum JLNS prevalence of 1:200 000 in preadolescent Swedish children was revealed. JLNS phenotype was mainly severe, with a cumulative incidence of life-threatening cardiac events of 53% (annual incidence rate before therapy 5%) and four sudden deaths. Possible founder effects regarding four KCNQ1 mutations; p.Y111C (8%), p.R518X (50%), c.572_576del (17%) and p.Q530X (8%) together explained 83% of the JLNS mutation-spectrum in Sweden, consisting of 8 KCNQ1 mutations.

Conclusion: The high prevalence of p.Y111C- and p.R518X-related LQTS as well as JLNS revealed in Sweden could be explained by the combination of mild clinical phenotypes in heterozygotes and strong founder effects present during the population development of northern Sweden. Increased knowledge regarding the occurrence of LQTS and JLNS as well as mutation- and/or genotype-specific data constitute prerequisites for possible improvement of patient management.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2012. 98 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1515
Keyword
Long QT Syndrome, Jervell and Lange-Nielsen Syndrome, inherited arrhythmia, founder effects, clinical genetics, haplotype analysis, mutation age, founder mutation, clinical phenotype, life-threatening cardiac events, mutation-specific, KCNQ1 gene, modifier genes, sequence variants, risk stratification, risk factor, gender
National Category
Pediatrics
Research subject
Pediatrics
Identifiers
urn:nbn:se:umu:diva-57724 (URN)978-91-7459-460-7 (ISBN)
Public defence
2012-09-07, E04, Biomedicinhusets suterrängplan, byggnad 6E, Norrlands Universitetssjukhus, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2012-08-15 Created: 2012-08-14 Last updated: 2012-08-15Bibliographically approved

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Winbo, AnnikaDiamant, Ulla-BrittJensen, Steen MRydberg, Annika

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