Christiansen, Michael8; Hedley, Paula L22; Theilade, Juliane10; Stoevring, Birgitte8; Leren, Trond P11; Eschen, Ole1; Sørensen, Karina M8; Tybjærg-Hansen, Anne12; Ousager, Lilian Bomme13; Pedersen, Lisbeth N14; Frikke-Schmidt, Ruth12; Aidt, Frederik Heurlin8; Hansen, Michael G15; Hansen, Jim16; Thomsen, Poul Erik Bloch4; Toft, Egon17; Henriksen, Finn Lund18; Bundgaard, Henning19; Jensen, Henrik Kjærulf20; Kanters, Jørgen K.21
1 Aalborg University Hospital, The Faculty of Medicine, Aalborg University, VBN2 Department of Clinical Medicine, The Faculty of Medicine, Aalborg University, VBN3 The Faculty of Medicine, Aalborg University, VBN4 Klinik Hjerte-Lunge, The Faculty of Medicine, Aalborg University, VBN5 Hjertemedicin (Kardiologi), The Faculty of Medicine, Aalborg University, VBN6 Center for Sensory-Motor Interaction, The Faculty of Medicine, Aalborg University, VBN7 Department of Health Science and Technology, The Faculty of Medicine, Aalborg University, VBN8 Depatment of Clinical Biochemistry, Statens Serum Institut, Copenhagen9 University of Stellenbosch10 The Heart Center, Rigshospitalet, Copenhagen11 Department of Medical Genetics, University Hospital Rikshospitalet, Oslo12 Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen13 Human Genetik14 Institut for Klinisk Medicin - Molekylær medicinsk afdeling (MOMA)15 Department of Internal Medicine, Haderslev Hospital, Haderslev16 Institut for Klinisk Medicin17 Forskningscenter for etik i praksis, The Faculty of Humanities, Aalborg University, VBN18 Kardiologi19 The Heart Centre, Rigshospitalet, University of Copenhagen20 Institut for Klinisk Medicin - Hjertemedicinsk Afdeling B, SKS21 Afd. for Hjerte- og Kredsløbsforskning22 University of Stellenbosch
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
B M C Medical Genetics, 2014, Vol 15, Issue 1
Case-Control Studies; DNA Mutational Analysis; Denmark; Ether-A-Go-Go Potassium Channels; Female; Founder Effect; Genetic Association Studies; Genetic Predisposition to Disease; Haplotypes; Humans; KCNQ1 Potassium Channel; Long QT Syndrome; Male; Microsatellite Repeats; Mutation, Missense; NAV1.5 Voltage-Gated Sodium Channel; Potassium Channels, Voltage-Gated; Journal Article; Research Support, Non-U.S. Gov't