title: Multiplex ligation-dependent probe amplification copy number variant analysis in patients with acquired long QT syndrome.
abstract: OBJECTIVE
  Thirteen genetic loci map to families with congenital long QT syndrome (cLQT) and multiple single nucleotide mutations have been functionally implicated in cLQT. Studies have investigated copy number variations (CNVs) in the cLQT genes to ascertain their involvement in cLQT. In these studies 3-12% of cLQT patients who were mutation negative by all other methods carried CNVs in cLQT genes. Prolongation of the QT interval can also be acquired after exposure to certain drugs [acquired LQT (aLQT)]. Single nucleotide mutations in cLQT genes have also been associated with and functionally implicated in aLQT, but to date no studies have explored CNVs as an additional susceptibility factor in aLQT. The aim of this study was to explore the contribution of CNVs in determining susceptibility to aLQT.
  
  
  RESULTS
  In this study we screened the commonest cLQT genes (KCNQ1; KCNH2; SCN5A; KCNE1, and KCNE2) in a general population of healthy volunteers and in a cohort of subjects presenting with aLQT for CNVs using the multiplex ligation-dependent probe amplification method. Copy number variants were detected and confirmed in 1 of 197 of the healthy volunteers and in 1 of 90 subjects with aLQT. The CNV in the aLQT subject was functionally characterized and demonstrated impaired channel function.
  
  
  CONCLUSIONS
  Copy number variation is a possible additional risk factor for aLQT and should be considered for incorporation into pharmacogenetic screening of LQTS genes in addition to mutation detection to improve the safety of medication administration.
authors.affiliation: AstraZeneca, Personalised Healthcare and Biomarkers, R&D Genetics, Alderley Park, UK.
authors.forename: Victoria S
authors.initials: VS
authors.lastname: Williams
authors.affiliation: AstraZeneca, Personalised Healthcare and Biomarkers, R&D Genetics, Alderley Park, UK.
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Cresswell
authors.affiliation: School of Biomedical Sciences, King's College London, London, UK.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Ruspi
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, TN, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, TN, USA.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Atak
authors.affiliation: AstraZeneca, Personalised Healthcare and Biomarkers, R&D Genetics, Alderley Park, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: McLoughlin
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, TN, USA.
authors.forename: Christiana D
authors.initials: CD
authors.lastname: Ingram
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, TN, USA.
authors.forename: Andrea H
authors.initials: AH
authors.lastname: Ramirez
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, TN, USA Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Roden
authors.affiliation: AstraZeneca, Personalised Healthcare and Biomarkers, R&D Genetics, Alderley Park, UK Shire AG, Business Park Terre-Bonne, Route de Crassier 7, 1262 Eysins, Switzerland victoria.williams@astrazeneca.com.
authors.forename: Martin
authors.initials: M
authors.lastname: Armstrong
mesh_terms: D000328:Adult; D056915:DNA Copy Number Variations / Q000235:genetics*; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000453:epidemiology* / Q000235:genetics*; D006801:Humans; D008133:Long QT Syndrome / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics*; D008297:Male; D060885:Multiplex Polymerase Chain Reaction; D009154:Mutation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015221:Potassium Channels / Q000235:genetics*; D015995:Prevalence; D012307:Risk Factors; D006113:United Kingdom / Q000453:epidemiology
chemical_list: D005819:Genetic Markers; D015221:Potassium Channels
keywords: Copy number variation; Genes; Long QT syndrome; MLPA; Multiplex ligation-dependent probe amplification