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Prevalence, mutation spectrum, and cardiac phenotype of the Jervell and Lange-Nielsen syndrome in Sweden
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, Cardiology.
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
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2012 (English)In: Europace, ISSN 1099-5129, E-ISSN 1532-2092, Vol. 14, no 12, 1799-1806 p.Article in journal (Refereed) Published
Abstract [en]

AIMS: To explore the national prevalence, mutation spectrum, cardiac phenotype, and outcome of the uncommon Jervell and Lange-Nielsen syndrome (JLNS), associated with a high risk of sudden cardiac death.

METHODS AND RESULTS: A national inventory of clinical JLNS cases was performed. Genotype and area of origin were ascertained in index families. Retrospective clinical data were collected from medical records and interviews. We identified 19 cases in 13 Swedish families. A JLNS prevalence >1:200 000 was revealed (five living cases <10 years of age). The mutation spectrum consisted of eight KCNQ1 mutations, whereof p.R518X in 12/24 alleles. Geographic clustering of four mutations (20/24 alleles) and similarities to Norway's mutation spectrum were seen. A high prevalence of heterozygotes was suggested. Three paediatric cases on β-blockers since birth were as yet asymptomatic. Seven symptomatic cases had suffered an aborted cardiac arrest and four had died suddenly. QTc prolongation was significantly longer in symptomatic cases (mean 605 ± 62 vs. 518 ± 50 ms, P = 0.016). β-Blockers reduced, but did not abolish, cardiac events in any previously symptomatic case. β-Blocker type, dosage, and compliance probably affect outcome significantly. Implantable cardioverter-defibrillator therapy (ICD, n = 6) was associated with certain complications; however, no case of sudden death.

CONCLUSION: Founder effects could explain 83% of the Swedish JLNS mutation spectrum and probably contribute to the high JLNS prevalence found in preadolescent Swedish children. Due to the severe cardiac phenotype in JLNS, the importance of stringent β-blocker therapy and compliance, and consideration of ICD implantation in the case of therapy failure is stressed.

Place, publisher, year, edition, pages
2012. Vol. 14, no 12, 1799-1806 p.
Keyword [en]
Jervell and Lange-Nielsen syndrome, Founder effects, KCNQ1 gene, Cardiac phenotype, Therapy efficacy
National Category
Cardiac and Cardiovascular Systems
URN: urn:nbn:se:umu:diva-56903DOI: 10.1093/europace/eus111PubMedID: 22539601OAI: diva2:538108
Available from: 2012-06-28 Created: 2012-06-28 Last updated: 2014-03-19Bibliographically 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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