Long QT syndrome in Sweden: founder effects and associated cardiac phenotypes

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Winbo, Annika,1978-Umeå universitet,Pediatrik (författare)

Long QT syndrome in Sweden : founder effects and associated cardiac phenotypes

BokEngelska2012

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Umeå :Umeå universitet,2012
98 s.
electronicrdacarrier

Nummerbeteckningar

LIBRIS-ID:oai:DiVA.org:umu-57724
ISBN:9789174594607
https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-57724URI

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Språk:engelska
Sammanfattning på:engelska

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Ämneskategori:vet swepub-contenttype
Ämneskategori:dok swepub-publicationtype

Varianttitlar

Långt QT syndrom i Sverige :foundereffekter och associerade kardiella fenotyper

Serie

Umeå University medical dissertations,0346-6612 ;1515

Anmärkningar

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.

Ämnesord och genrebeteckningar

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Pediatrik hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Pediatrics hsv//eng
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
pediatrik
Pediatrics

Biuppslag (personer, institutioner, konferenser, titlar ...)

Rydberg, Annika,DocentUmeå universitet,Pediatrik(Swepub:umu)anry0014 (preses)
Schulze-Bahr, Eric,ProfessorInstitut für Genetik von Herzerkrankungen, Universitätsklinikum Münster, Münster, Tyskland (opponent)
Umeå universitetPediatrik (creator_code:org_t)

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MEDICIN OCH HÄLSOVETENSKAP: MEDICIN OCH HÄLS ...; och Klinisk medicin; och Pediatrik

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Av lärosätet: Umeå universitet

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