期刊
BMC CARDIOVASCULAR DISORDERS
卷 14, 期 -, 页码 -出版社
BIOMED CENTRAL LTD
DOI: 10.1186/1471-2261-14-22
关键词
Long QT Syndrome; Genotype-phenotype correlations; Clinical phenotype; Founder mutation; Mutation age; Prevalence estimate
资金
- Swedish Heart-Lung Foundation
- Heart Foundation of Northern Sweden
- Umea University
- Northern County Councils Cooperation Committee
Background: The R518X/KCNQ1 mutation is a common cause of autosomal recessive (Jervell and Lange Nielsen Syndrome-JLNS) and autosomal dominant long QT syndrome (LQTS) worldwide. In Sweden p.R518X accounts for the majority of JLNS cases and is the second most common cause of LQTS. Here we investigate the clinical phenotype and origin of Swedish carriers of the p. R518X mutation. Methods: The study included 19 Swedish p. R518X index families, ascertained by molecular genetics methods (101 mutation-carriers, whereof 15 JLNS cases and 86 LQTS cases). In all families analyses included assessment of clinical data (symptoms, medications and manually measured electrocardiograms), genealogy (census records), haplotype (microsatellite markers) as well as assessment of mutation age and associated prevalence (ESTIAGE and DMLE computer software). Results: Clinical phenotype ranged from expectedly severe in JLNS to surprisingly 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%). A common northern origin was found for 1701/1929 ancestors born 1650-1950. Historical geographical clustering in the coastal area of the Pite River valley was shown. A shared haplotype spanning the KCNQ1 gene was seen in 17/19 families. Mutation age was estimated to 28 generations (95% CI 19;41). A high prevalence of Swedish p. R518X heterozygotes was suggested (similar to 1: 2000-4000). Conclusions: R518X/KCNQ1 occurs as a common founder mutation in Sweden and is associated with an unexpectedly benign phenotype in heterozygous carriers.
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