Molecular genetic analysis of long QT syndrome in Norway indicating a high prevalence of heterozygous mutation carriers

Medical Genetics Laboratory, Department of Medical Genetics, Rikshospitalet-Radiumhospitalet Medical Centre, Oslo, Norway.
Scandinavian Journal of Clinical and Laboratory Investigation (Impact Factor: 1.9). 02/2008; 68(5):362-8. DOI: 10.1080/00365510701765643
Source: PubMed


Mutations in the KCNQ1, HERG, SCN5A, minK and MiRP1 genes cause long QT syndrome (LQTS), of which there are two forms: the Romano Ward syndrome and the Jervell and Lange-Nielsen syndrome. We have performed DNA sequencing of the LQTS-associated genes in 169 unrelated patients referred for genetic testing with respect to Romano Ward syndrome and in 13 unrelated patients referred for genetic testing with respect to Jervell and Lange-Nielsen syndrome. A total of 37 different mutations in the 5 genes, of which 20 were novel, were identified. Among patients with the most stringent clinical criteria of Romano Ward syndrome, a mutation was identified in 71%. Twelve of the 13 unrelated patients referred for genetic testing with respect to Jervell and Lange-Nielsen syndrome were provided with a molecular genetic diagnosis. Cascade genetic screening of 505 relatives of index patients with molecularly defined LQTS identified 251 mutation carriers. The observed penetrance was 41%. Although caution must be exerted, the prevalence of heterozygotes for mutations in the LQTS-associated genes in Norway could be in the range 1/100-1/300, based on the prevalence of patients with Jervell and Lange-Nielsen syndrome.

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    • "Consequently, it is very difficult to establish a success rate for the genetic screening across this period. But it is probably comparable to the 70% reported from Norway in a much smaller collection of mutations [67]. Likewise, we cannot really state anything about the cost-effectiveness of including more genes in the basic screen or the suitability or cost-effectiveness of MLPA analysis of the five genes. "
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    ABSTRACT: Long QT syndrome (LQTS) is a cardiac ion channelopathy which presents clinically with palpitations, syncope or sudden death. More than 700 LQTS-causing mutations have been identified in 13 genes, all of which encode proteins involved in the execution of the cardiac action potential. The most frequently affected genes, covering > 90% of cases, are KCNQ1, KCNH2 and SCN5A. We describe 64 different mutations in 70 unrelated Danish families using a routine five-gene screen, comprising KCNQ1, KCNH2 and SCN5A as well as KCNE1 and KCNE2. Twenty-two mutations were found in KCNQ1, 28 in KCNH2, 9 in SCN5A, 3 in KCNE1 and 2 in KCNE2. Twenty-six of these have only been described in the Danish population and 18 are novel. One double heterozygote (1.4% of families) was found. A founder mutation, p.F29L in KCNH2, was identified in 5 "unrelated" families. Disease association, in 31.2% of cases, was based on the type of mutation identified (nonsense, insertion/deletion, frameshift or splice-site). Functional data was available for 22.7% of the missense mutations. None of the mutations were found in 364 Danish alleles and only three, all functionally characterised, were recorded in the Exome Variation Server, albeit at a frequency of < 1:1000. The genetic etiology of LQTS in Denmark is similar to that found in other populations. A large founder family with p.F29L in KCNH2 was identified. In 48.4% of the mutations disease causation was based on mutation type or functional analysis.
    BMC Medical Genetics 03/2014; 15(1):31. DOI:10.1186/1471-2350-15-31 · 2.08 Impact Factor
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    • "Here we investigate the clinical phenotype and founder nature of the R518X/KCNQ1 mutation, a worldwide known hotspot mutation and a common cause of JLNS and LQTS [2,7-9], in the Swedish population. "
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    ABSTRACT: 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. 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). 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 (~1:2000-4000). R518X/KCNQ1 occurs as a common founder mutation in Sweden and is associated with an unexpectedly benign phenotype in heterozygous carriers.
    BMC Cardiovascular Disorders 02/2014; 14(1):22. DOI:10.1186/1471-2261-14-22 · 1.88 Impact Factor
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    • "This percentage of CNV in these three major genes accounts for more LQTS cases than mutations in all other known genes (Barc et al., 2011; Tester et al., 2010). No common mutations or hot-spots have been found in any of the genes of interest, except in a few populations due to a founder effect (Berge et al., 2008; Brink and Schwartz, 2009; Winbo et al., 2011). Mutations in these genes can alter the duration of repolarization , leading to either prolongation or shortening of the QT interval . "
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    ABSTRACT: Channelopathies are diseases caused by dysfunctional ion channels, due to either genetic or acquired pathological factors. Inherited cardiac arrhythmic syndromes are among the most studied human disorders involving ion channels. Since seminal observations made in 1995, thousands of mutations have been found in many of the different genes that code for cardiac ion channel subunits and proteins that regulate the cardiac ion channels. The main phenotypes observed in patients carrying these mutations are congenital long QT syndrome (LQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), short QT syndrome (SQTS) and variable types of conduction defects (CD). The goal of this review is to present an update of the main genetic and molecular mechanisms, as well as the associated phenotypes of cardiac channelopathies as of 2012.
    Gene 12/2012; 517(1). DOI:10.1016/j.gene.2012.12.061 · 2.14 Impact Factor
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