title: Identification of large gene deletions and duplications in KCNQ1 and KCNH2 in patients with long QT syndrome.
abstract: BACKGROUND
  Sequencing or denaturing high-performance liquid chromatography (dHPLC) analysis of the known genes associated with the long QT syndrome (LQTS) fails to identify mutations in approximately 25% of subjects with inherited LQTS. Large gene deletions and duplications can be missed with these methodologies.
  
  
  OBJECTIVE
  The purpose of this study was to determine whether deletions and/or duplications of one or more exons of the main LQTS genes were present in an LQTS mutation-negative cohort.
  
  
  METHODS
  Multiplex ligation-dependent probe amplification (MLPA), a quantitative fluorescent approach, was used to screen 26 mutation-negative probands with an unequivocal LQTS phenotype (Schwartz score >4). The appropriate MLPA kit contained probes for selected exons in LQTS genes KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2. Real-time polymerase chain reaction was used to validate the MLPA findings.
  
  
  RESULTS
  Altered exon copy number was detected in 3 (11.5%) patients: (1) an ex13-14del of the KCNQ1 gene in an 11-year-old boy with exercise-induced collapse (QTc 580 ms); (2) an ex6-14del of the KCNH2 gene in a 22-year-old woman misdiagnosed with epilepsy since age 9 years (QTc 560 ms) and a sibling with sudden death at age 13 years; and (3) an ex9-14dup of the KCNH2 gene in a 12 year-old boy (QTc 550 ms) following sudden nocturnal death of his 32-year-old mother.
  
  
  CONCLUSIONS
  If replicated, this study demonstrates that more than 10% of patients with LQTS and a negative current generation genetic test have large gene deletions or duplications among the major known LQTS susceptibility genes. As such, these findings suggest that sequencing-based mutation detection strategies should be followed by deletion/duplication screening in all LQTS mutation-negative patients.
authors.affiliation: Cardiac Inherited Diseases Group (CIDG), Auckland City Hospital/Starship Children's Hospital, Auckland, New Zealand. c.eddy@auckland.ac.nz
authors.forename: Carey-Anne
authors.initials: CA
authors.lastname: Eddy
authors.forename: Judith M
authors.initials: JM
authors.lastname: MacCormick
authors.forename: Seo-Kyung
authors.initials: SK
authors.lastname: Chung
authors.forename: Jackie R
authors.initials: JR
authors.lastname: Crawford
authors.forename: Donald R
authors.initials: DR
authors.lastname: Love
authors.forename: Mark I
authors.initials: MI
authors.lastname: Rees
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Skinner
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Shelling
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D005838:Genotype; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D008133:Long QT Syndrome / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D021141:Nucleic Acid Amplification Techniques; D010375:Pedigree; D010865:Pilot Projects; D012307:Risk Factors; 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