title: Novel pore mutation in SCN5A manifests as a spectrum of phenotypes ranging from atrial flutter, conduction disease, and Brugada syndrome to sudden cardiac death.
abstract: OBJECTIVE
  The purpose of this study was to determine the clinical and biophysical characteristics of a novel SCN5A mutation.
  
  
  BACKGROUND
  Brugada syndrome and isolated cardiac conduction defect have been linked to SCN5A mutations.
  
  
  METHODS
  Eleven members of a western European family underwent electrophysiologic investigations and mutation analysis of the SCN5A gene. Wild-type and mutant SCN5A channels were expressed in HEK293 cells, and whole cell currents were studied using patch clamp procedures.
  
  
  RESULTS
  A novel mutation, R376H, in the first pore segment of SCN5A variably causes Brugada syndrome and/or conduction disease in a single family. Biophysical analysis demonstrated a significant current reduction for the mutant, a pathophysiologic profile consistent with Brugada syndrome and isolated cardiac conduction defect. Among 11 family members, 9 were carriers of the mutation. The proband's initial presentation was a saddleback Brugada ECG, atrial flutter, and diffuse conduction disturbances. He had no inducible ventricular arrhythmias but experienced sudden cardiac death. His brother was affected by atrial flutter and had a clear conduction disorder, but he did not display baseline or evocable ECG signs of Brugada syndrome. He received an implantable cardioverter-defibrillator that delivered one appropriate shock after 1 year of follow-up. The phenotype in the family members was highly variable and ranged from noninducible and inducible asymptomatic carriers of the mutations to isolated conduction disease and to symptomatic Brugada syndrome.
  
  
  CONCLUSIONS
  We describe the functional characterization of a novel SCN5A pore mutation, R376H, with variable clinical expression in the same family. Differentiating between electrophysiologic entities (Brugada syndrome-isolated cardiac conduction defect) is more challenging. Recognition of factors modifying the clinical presentation may be important for clinical decision making.
authors.affiliation: Center for Transgene Technology and Gene Therapy, Flanders Interuniversitary Institute for Biotechnology, KULeuven, Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: Rossenbacker
authors.forename: Sheila J
authors.initials: SJ
authors.lastname: Carroll
authors.forename: Huajun
authors.initials: H
authors.lastname: Liu
authors.forename: Cuno
authors.initials: C
authors.lastname: Kuipéri
authors.forename: Thomy J L
authors.initials: TJ
authors.lastname: de Ravel
authors.forename: Koen
authors.initials: K
authors.lastname: Devriendt
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kass
authors.forename: Hein
authors.initials: H
authors.lastname: Heidbüchel
mesh_terms: D000293:Adolescent; D000328:Adult; D001282:Atrial Flutter / Q000235:genetics*; D002037:Bundle-Branch Block / Q000235:genetics*; D004252:DNA Mutational Analysis; D004562:Electrocardiography; D005260:Female; D006329:Heart Conduction System / Q000503:physiopathology*; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010641:Phenotype; D015222:Sodium Channels / Q000235:genetics*; D013577:Syndrome; D014693:Ventricular Fibrillation / Q000235:genetics*
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels