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: 2.01). 02/2008; 68(5):362-8. DOI: 10.1080/00365510701765643
Source: PubMed

ABSTRACT 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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Sudden cardiac death (SCD) is responsible for a large proportion of non-traumatic, sudden and unexpected deaths in young individuals. Sudden cardiac death is a known manifestation of several inherited cardiac diseases. In post-mortem examinations, about two-thirds of the SCD cases show structural abnormalities at autopsy. The remaining cases stay unexplained after thorough investigations and are referred to as sudden unexplained deaths. A routine forensic investigation of the SCD victims in combination with genetic testing makes it possible to establish a likely diagnosis in some of the deaths previously characterized as unexplained. Additionally, a genetic diagnose in a SCD victim with a structural disease may not only add to the differential diagnosis, but also be of importance for pre-symptomatic family screening. In the case of SCD, the optimal establishment of the cause of death and management of the family call for standardized post-mortem procedures, genetic screening, and family screening. Studies of genetic testing in patients with primary arrhythmia disorders or cardiomyopathies and of victims of SCD presumed to be due to primary arrhythmia disorders or cardiomyopathies, were systematically identified and reviewed. The frequencies of disease-causing mutation were on average between 16 and 48% in the cardiac patient studies, compared with ∼10% in the post-mortem studies. The frequency of pathogenic mutations in heart genes in cardiac patients is up to four-fold higher than that in SCD victims in a forensic setting. Still, genetic investigation of SCD victims is important for the diagnosis and the possible investigation of relatives at risk.
    Europace 10/2014; 17(3). DOI:10.1093/europace/euu210 · 3.05 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Sudden cardiac death (SCD) is responsible for a large proportion of sudden deaths in young individuals. In forensic medicine, many cases remain unexplained after routine postmortem autopsy and conventional investigations. These cases are called sudden unexplained deaths (SUD). Genetic testing has been suggested useful in forensic medicine, although in general with a significantly lower success rate compared to the clinical setting. The purpose of the study was to estimate the frequency of pathogenic variants in the genes most frequently associated with SCD in SUD cases and compare the frequency to that in patients with inherited cardiac channelopathies. Fifteen forensic SUD cases and 29 patients with channelopathies were investigated. DNA from 34 of the genes most frequently associated with SCD were captured using NimbleGen SeqCap EZ library build and were sequenced with next-generation sequencing (NGS) on an Illumina MiSeq. Likely pathogenic variants were identified in three out of 15 (20 %) forensic SUD cases compared to 12 out of 29 (41 %) patients with channelopathies. The difference was not statistically significant (p = 0.1). Additionally, two larger deletions of entire exons were identified in two of the patients (7 %). The frequency of likely pathogenic variants was >2-fold higher in the clinical setting as compared to SUD cases. However, the demonstration of likely pathogenic variants in three out of 15 forensic SUD cases indicates that NGS investigations will contribute to the clinical investigations. Hence, this has the potential to increase the diagnostic rate significantly in the forensic as well as in the clinical setting.
    International Journal of Legal Medicine 12/2014; DOI:10.1007/s00414-014-1105-y · 2.69 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic tinnitus is a highly prevalent and often incapacitating condition frequently associated with sensorineural hearing loss. While its etiology remains incompletely understood there is a growing awareness of genetic factors that predispose to, or aggravate chronic tinnitus. Candidate genes for the disorder include KCNE1, a potassium channel subunit gene that has been implicated in maturation defects of central vestibular neurons, in Menière's disease, and in noise-induced hearing loss. 201 Caucasian outpatients with a diagnosis of chronic tinnitus were systematically screened for mutations in the KCNE1 open reading frame and in the adjacent sequence by direct sequencing. Allele frequencies were determined for 46 known variants, plus two novel KCNE1 mutations. These comprised one missense substitution (V47I) in the highly conserved region encoding the KCNE1 transmembrane domain, and one rare variant in the gene's 3'UTR. When genotypes were grouped assuming dominance of the minor alleles, no significant genotype or compound genotype effects were observed on tinnitus severity. The newly identified V47I substitution argues in favor of an enlarged spectrum of mutations in hearing disorders. However, with regard to allele frequencies in healthy control populations from earlier studies, more common KCNE1 variants are unlikely to play a major role in chronic tinnitus. Further investigations are invited to address variation in additional channel subunits as possible risk factors in tinnitus.
    06/2010; 1(1):23-37. DOI:10.3390/genes1010023