title: Type of SCN5A mutation determines clinical severity and degree of conduction slowing in loss-of-function sodium channelopathies.
abstract: BACKGROUND
  Patients carrying loss-of-function SCN5A mutations linked to Brugada syndrome (BrS) or progressive cardiac conduction disease (PCCD) are at risk of sudden cardiac death at a young age. The penetrance and expressivity of the disease are highly variable, and new tools for risk stratification are needed.
  
  
  OBJECTIVE
  We aimed to establish whether the type of SCN5A mutation correlates with the clinical and electrocardiographic phenotype.
  
  
  METHODS
  We studied BrS or PCCD probands and their relatives who carried a SCN5A mutation. Mutations were divided into 2 main groups: missense mutations (M) or mutations leading to premature truncation of the protein (T). The M group was subdivided according to available biophysical properties: M mutations with <or=90% (M(active)) or >90% (M(inactive)) peak I(Na) reduction were analyzed separately.
  
  
  RESULTS
  The study group was composed of 147 individuals with 32 different mutations. No differences in age and sex distribution were found between the groups. Subjects carrying a T mutation had significantly more syncopes than those with an M(active) mutation (19 of 75 versus 2 of 35, P = .03). Also, mutations associated with drastic peak I(Na) reduction (T and M(inactive) mutants) had a significantly longer PR interval, compared with M(active) mutations. All other electrocardiographic parameters were comparable. After drug provocation testing, both PR and QRS intervals were significantly longer in the T and M(inactive) groups than in the M(active) group.
  
  
  CONCLUSIONS
  In loss-of-function SCN5A channelopathies, patients carrying T and M(inactive) mutations develop a more severe phenotype than those with M(active) mutations. This is associated with more severe conduction disorders. This is the first time that genetic data are proposed for risk stratification in BrS.
authors.affiliation: Department of Cardiology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Paola G
authors.initials: PG
authors.lastname: Meregalli
authors.forename: Hanno L
authors.initials: HL
authors.lastname: Tan
authors.forename: Vincent
authors.initials: V
authors.lastname: Probst
authors.forename: Tamara T
authors.initials: TT
authors.lastname: Koopmann
authors.forename: Michael W
authors.initials: MW
authors.lastname: Tanck
authors.forename: Zahurul A
authors.initials: ZA
authors.lastname: Bhuiyan
authors.forename: Frederic
authors.initials: F
authors.lastname: Sacher
authors.forename: Florence
authors.initials: F
authors.lastname: Kyndt
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Schott
authors.forename: J
authors.initials: J
authors.lastname: Albuisson
authors.forename: Philippe
authors.initials: P
authors.lastname: Mabo
authors.forename: Connie R
authors.initials: CR
authors.lastname: Bezzina
authors.forename: Herve
authors.initials: H
authors.lastname: Le Marec
authors.forename: Arthur A M
authors.initials: AA
authors.lastname: Wilde
mesh_terms: D000328:Adult; D001145:Arrhythmias, Cardiac / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D053840:Brugada Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D018388:Codon, Terminator / Q000235:genetics; D016757:Death, Sudden, Cardiac / Q000209:etiology; D005260:Female; D006329:Heart Conduction System / Q000503:physiopathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics*; D009154:Mutation; D020125:Mutation, Missense; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010641:Phenotype; D018570:Risk Assessment; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000235:genetics*
chemical_list: D018388:Codon, Terminator; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D026941:Sodium Channel Blockers; D015222:Sodium Channels