title: Screening for copy number variation in genes associated with the long QT syndrome: clinical relevance.
abstract: OBJECTIVE
  The aim of this study was to investigate, in a set of 93 mutation-negative long QT syndrome (LQTS) probands, the frequency of copy number variants (CNVs) in LQTS genes.
  
  
  BACKGROUND
  LQTS is an inherited cardiac arrhythmia characterized by a prolonged heart rate-corrected QT (QTc) interval associated with sudden cardiac death. Recent studies suggested the involvement of duplications or deletions in the occurrence of LQTS. However, their frequency remains unknown in LQTS patients.
  
  
  METHODS
  Point mutations in KCNQ1, KCNH2, and SCN5A genes were excluded by denaturing high-performance liquid chromatography or direct sequencing. We applied Multiplex Ligation-dependent Probe Amplification (MLPA) to detect CNVs in exons of these 3 genes. Abnormal exon copy numbers were confirmed by quantitative multiplex PCR of short fluorescent fragment (QMPSF). Array-based comparative genomic hybridization (array CGH) analysis was performed using Agilent Human Genome 244K Microarrays to further map the genomic rearrangements.
  
  
  RESULTS
  We identified 3 different deletions in 3 unrelated families: 1 in KCNQ1 and 2 involving KCNH2. We showed in the largest family that the deletion involving KCNH2 is fully penetrant and segregates with the long QT phenotype in 7 affected members.
  
  
  CONCLUSIONS
  Our study demonstrates that CNVs in KCNQ1 and KCNH2 explain around 3% of LQTS in patients with no point mutation in these genes. This percentage is likely higher than the frequency of point mutations in ANKB, KCNE1, KCNE2, KCNJ2, CACNA1C, CAV3, SCN4B, AKAP9, and SNTA1 together. Thus, we propose that CNV screening in KCNQ1 and KCNH2 may be performed routinely in LQTS patients.
authors.affiliation: INSERM, UMR915, l'institut du thorax, Service de cardiologie Nantes, Nantes, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Barc
authors.forename: François
authors.initials: F
authors.lastname: Briec
authors.forename: Sébastien
authors.initials: S
authors.lastname: Schmitt
authors.forename: Florence
authors.initials: F
authors.lastname: Kyndt
authors.forename: Martine
authors.initials: M
authors.lastname: Le Cunff
authors.forename: Estelle
authors.initials: E
authors.lastname: Baron
authors.forename: Claude
authors.initials: C
authors.lastname: Vieyres
authors.forename: Frédéric
authors.initials: F
authors.lastname: Sacher
authors.forename: Richard
authors.initials: R
authors.lastname: Redon
authors.forename: Cédric
authors.initials: C
authors.lastname: Le Caignec
authors.forename: Hervé
authors.initials: H
authors.lastname: Le Marec
authors.forename: Vincent
authors.initials: V
authors.lastname: Probst
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Schott
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D004247:DNA / Q000235:genetics*; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D005820:Genetic Testing; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D008133:Long QT Syndrome / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010375:Pedigree; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D015222:Sodium Channels / Q000235:genetics*; D055815:Young Adult
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels; D004247:DNA