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Low incidence of sudden cardiac death in a Swedish Y111C type 1 long-QT syndrome population
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. 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 Public Health and Clinical Medicine, Medicine.
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2009 (English)In: Circulation: Cardiovascular Genetics, ISSN 1942-325X, Vol. 2, no 6, 558-564 p.Article in journal (Refereed) Published
Abstract [en]

Background: A 10% cumulative incidence and a 0.3% per year incidence rate of sudden cardiac death in patients younger than 40 years and without therapy have been reported in type 1 long-QT syndrome. The Y111C-KCNQ1 mutation causes a severe phenotype in vitro, suggesting a high-risk mutation. This study investigated the phenotype among Y111C-KCNQ1 mutation carriers in the Swedish population with a focus on life-threatening cardiac events.

Methods and Results: We identified 80 mutation carriers in 15 index families, segregating the Y111C-KCNQ1 mutation during a national inventory of mutations causing the long-QT syndrome. Twenty-four mutation carriers <40 years experienced syncope (30%). One mutation carrier had an aborted cardiac arrest (1.25%). No case of sudden cardiac death was reported during a mean nonmedicated follow-up of 25±20 years. This corresponds to a low incidence rate of life-threatening cardiac events (0.05%/year versus 0.3%/year, P=0.025). In 8 Y111C families connected by a common ancestor, the natural history of the mutation was assessed by investigating the survival over the age of 40 years for 107 nonmedicated ascertained mutation carriers (n=24) and family members (n=83) born between 1873 and 1968. In total, 4 deaths in individuals younger than 40 years were noted: 1 case of noncardiac death and 3 infant deaths between 1873 and 1915.

Conclusions: The dominant-negative Y111C-KCNQ1 mutation, associated with a severe phenotype in vitro, presents with a low incidence of life-threatening cardiac events in a Swedish population. This finding of discrepancy emphasizes the importance of clinical observations in the risk stratification of long-QT syndrome.

Place, publisher, year, edition, pages
Philadelphia, PA: Lippincott Williams & Wilkins , 2009. Vol. 2, no 6, 558-564 p.
Keyword [en]
death, sudden, genetics, ion channels, long-QT syndrome, survival
National Category
Medical and Health Sciences
URN: urn:nbn:se:umu:diva-32464DOI: 10.1161/CIRCGENETICS.108.825547PubMedID: 20031635OAI: diva2:303286
Available from: 2010-03-11 Created: 2010-03-11 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.
Umeå University medical dissertations, ISSN 0346-6612 ; 1515
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
Research subject
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)
Available from: 2012-08-15 Created: 2012-08-14 Last updated: 2012-08-15Bibliographically approved

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