title: Flecainide provocation reveals concealed brugada syndrome in a long QT syndrome family with a novel L1786Q mutation in SCN5A.
abstract: BACKGROUND
  Mutations in SCN5A can result in both long QT type 3 (LQT3) and Brugada syndrome (BrS), and a few mutations have been found to have an overlapping phenotype. Long QT syndrome is characterized by prolonged QT interval, and a prerequisite for a BrS diagnosis is ST elevation in the right precordial leads of the electrocardiogram.
  
  
  RESULTS
  In a Danish family suffering from long QT syndrome, a novel missense mutation in SCN5A, changing a leucine residue into a glutamine residue at position 1786 (L1786Q), was found to be present in heterozygous form co-segregating with prolonged QT interval. The proband presented with an aborted cardiac arrest, and his mother died suddenly and unexpectedly at the age of 65. Flecainide treatment revealed coved ST elevation in all mutation carriers. Electrophysiological investigations of the mutant in HEK293 cells indicated a reduced peak current, a negative shift in inactivation properties and a positive shift in activation properties, compatible with BrS. Furthermore, the sustained (I(Na,late)) tetrodotoxin-sensitive sodium current was found to be drastically increased, explaining the association between the mutation and LQT syndrome.
  
  
  CONCLUSIONS
  The L1786Q mutation is associated with a combined LQT3 and concealed BrS phenotype explained by gating characteristics of the mutated ion channel protein. Hence, sodium channel blockade should be considered in clinical evaluation of apparent LQT3 patients.
authors.affiliation: Danish National Foundation Research Centre in Arrhythmias (DARC), Laboratory of Experimental Cardiology, Department of Biomedical Sciences.
authors.forename: Jørgen K
authors.initials: JK
authors.lastname: Kanters
authors.forename: Lei
authors.initials: L
authors.lastname: Yuan
authors.forename: Paula L
authors.initials: PL
authors.lastname: Hedley
authors.forename: Birgitte
authors.initials: B
authors.lastname: Stoevring
authors.forename: Christian
authors.initials: C
authors.lastname: Jons
authors.forename: Poul Erik
authors.initials: PE
authors.lastname: Bloch Thomsen
authors.forename: Morten
authors.initials: M
authors.lastname: Grunnet
authors.forename: Michael
authors.initials: M
authors.lastname: Christiansen
authors.forename: Thomas
authors.initials: T
authors.lastname: Jespersen
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage*; D053840:Brugada Syndrome / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D005190:Family; D005260:Female; D005424:Flecainide / Q000008:administration & dosage*; D057809:HEK293 Cells; D006579:Heterozygote; D006801:Humans; D008133:Long QT Syndrome / Q000178:diet therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D020125:Mutation, Missense; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism
chemical_list: D000889:Anti-Arrhythmia Agents; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D005424:Flecainide