title: Long QT syndrome caused by a large duplication in the KCNH2 (HERG) gene undetectable by current polymerase chain reaction-based exon-scanning methodologies.
abstract: BACKGROUND
  The numerous mutations in the long QT syndrome (LQTS)-associated genes reported to date are point mutations or small insertions and deletions in coding regions or at splice junctions.
  
  
  OBJECTIVE
  The purpose of this study was to determine the relative copy number of gene exons in a series of mutation-negative LQTS probands.
  
  
  METHODS
  We used a quantitative multiplex approach because the polymerase chain reaction (PCR)-based exon-scanning methodologies routinely utilized in mutation analysis are unable to detect large genomic alterations.
  
  
  RESULTS
  We identified the first large gene rearrangement consisting of a tandem duplication of 3.7 kb in KCNH2 responsible for LQTS in a Dutch family. This large duplication is expected to lead to nonfunctional or severely debilitated channels, thereby decreasing I(Kr).
  
  
  CONCLUSIONS
  Our findings have implications for genetic testing in the approximately 30% of LQTS patients in whom conventional mutation screening fails to uncover a mutation. Analysis for large gene alterations such as the one described herein in routine genetic testing may provide a genetic diagnosis in a number of these patients.
authors.affiliation: Experimental and Molecular Cardiology Group, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Tamara T
authors.initials: TT
authors.lastname: Koopmann
authors.forename: Marielle
authors.initials: M
authors.lastname: Alders
authors.forename: Roselie J
authors.initials: RJ
authors.lastname: Jongbloed
authors.forename: Silvia
authors.initials: S
authors.lastname: Guerrero
authors.forename: Marcel M A M
authors.initials: MM
authors.lastname: Mannens
authors.forename: Arthur A M
authors.initials: AA
authors.lastname: Wilde
authors.forename: Connie R
authors.initials: CR
authors.lastname: Bezzina
mesh_terms: D000293:Adolescent; D000328:Adult; D004252:DNA Mutational Analysis; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics*; D005091:Exons; D005260:Female; D020440:Gene Duplication; D015321:Gene Rearrangement; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics; D008133:Long QT Syndrome / Q000235:genetics*; D009426:Netherlands; D021141:Nucleic Acid Amplification Techniques / Q000379:methods
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