title: Exclusion of multiple candidate genes and large genomic rearrangements in SCN5A in a Dutch Brugada syndrome cohort.
abstract: BACKGROUND
  The Brugada syndrome is an inherited cardiac electrical disorder associated with a high incidence of life-threatening arrhythmias. Screening for mutations in the cardiac Na+ channel-encoding gene SCN5A uncovers a mutation in approximately 20% of Brugada syndrome cases. Genetic heterogeneity and/or undetected SCN5A mutations, such as exon duplications and deletions, could be involved in the remaining 80% mutation-negative patients.
  
  
  OBJECTIVE
  Thirty-eight SCN5A mutation-negative Dutch Brugada syndrome probands were studied. The SCN5A gene was investigated for exon duplication and deletion, and a number of candidate genes (Caveolin-3, Irx-3, Irx-4, Irx-5, Irx-6, Plakoglobin, Plakophilin-2, SCN1B, SCN2B, SCN3B, and SCN4B) were tested for the occurrence of point mutations and small insertions/deletions.
  
  
  METHODS
  We used a quantitative multiplex approach to determine SCN5A exon copy numbers. Mutation analysis of the candidate genes was performed by direct sequencing of polymerase chain reaction-amplified coding regions.
  
  
  RESULTS
  No large genomic rearrangements in SCN5A were identified. No mutations were found in the candidate genes. Twenty novel polymorphisms were identified in these genes.
  
  
  CONCLUSIONS
  Large genomic rearrangements in SCN5A are not a common cause of Brugada syndrome. Similarly, the studied candidate genes are unlikely to be major causal genes of Brugada syndrome. Further studies are required to identify other genes responsible for this syndrome.
authors.affiliation: Center for Heart Failure Research, Experimental and Molecular Cardiology Group, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Tamara T
authors.initials: TT
authors.lastname: Koopmann
authors.forename: Leander
authors.initials: L
authors.lastname: Beekman
authors.forename: Marielle
authors.initials: M
authors.lastname: Alders
authors.forename: Paola G
authors.initials: PG
authors.lastname: Meregalli
authors.forename: Marcel M A M
authors.initials: MM
authors.lastname: Mannens
authors.forename: Antoon F M
authors.initials: AF
authors.lastname: Moorman
authors.forename: Arthur A M
authors.initials: AA
authors.lastname: Wilde
authors.forename: Connie R
authors.initials: CR
authors.lastname: Bezzina
mesh_terms: D053840:Brugada Syndrome / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D017353:Gene Deletion; D006801:Humans; D009124:Muscle Proteins / Q000235:genetics*; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D009426:Netherlands / Q000453:epidemiology; D011110:Polymorphism, Genetic; D012307:Risk Factors; D015222:Sodium Channels / Q000235:genetics*
chemical_list: D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels