Phenotype, origin and estimated prevalence of a common long QT syndrome mutation: a clinical, genealogical and molecular genetics study including Swedish R518X/KCNQ1families

Annika Winbo,Eva-Lena Stattin,Annika Rydberg,Johan Persson,Steen M Jensen,Charlotte Nordin,Ulla-Britt Diamant

doi:10.1186/1471-2261-14-22

Abstract

BackgroundThe 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.MethodsThe 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).ResultsClinical 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 (~1:2000-4000).ConclusionsR518X/KCNQ1 occurs as a common founder mutation in Sweden and is associated with an unexpectedly benign phenotype in heterozygous carriers.

Highlights

The R518X/KCNQ1 mutation is a common cause of autosomal recessive (Jervell and Lange Nielsen Syndrome- Jervell and Lange-Nielsen syndrome (JLNS)) and autosomal dominant long QT syndrome (LQTS) worldwide
In this study, we identified 101 Swedish cases (15 JLNS, 86 LQTS) in 19 index families segregating the R518X/ KCNQ1 mutation, and revealed that the common occurrence of this specific mutation in the Swedish population is related to founder effects
A benign phenotype and remaining variability While the p.R518X-associated phenotype in JLNS cases was expectedly severe, an unexpectedly benign phenotype was seen in LQTS cases

Summary

Introduction

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. Loss-of-function mutations in the KCNQ1 gene cause both the autosomal recessive Jervell and Lange-Nielsen syndrome (JLNS) and the autosomal dominant type 1 long QT syndrome (LQTS), known as the Romano-Ward syndrome [1]. The p.R518X and p.Y111C mutations account for over 25% of Swedish LQTS index cases with identified mutations [3], and p.R518X alone has been identified as the major cause of JLNS in Sweden [4]. Regarding p.Y111C, strong founder effects during the population development of a northern river valley region have previously been shown to result in the enrichment of this specific founder mutation in the population [5,6]

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