title: Contribution of Cardiac Sodium Channel β-Subunit Variants to Brugada Syndrome.
abstract: BACKGROUND
  Brugada syndrome (BrS) is an inheritable cardiac disease associated with syncope, malignant ventricular arrhythmias and sudden cardiac death. The largest proportion of mutations in BrS is found in the SCN5A gene encoding the α-subunit of cardiac sodium channels (Nav1.5). Causal SCN5A mutations are present in 18-30% of BrS patients. The additional genetic diagnostic yield of variants in cardiac sodium channel β-subunits in BrS patients was explored and functional studies on 3 novel candidate variants were performed.
  
  
  RESULTS
  TheSCN1B-SCN4B genes were screened, which encode the 5 sodium channel β-subunits, in a SCN5A negative BrS population (n=74). Five novel variants were detected; in silico pathogenicity prediction classified 4 variants as possibly disease causing. Three variants were selected for functional study. These variants caused only limited alterations of Nav1.5 function. Next generation sequencing of a panel of 88 arrhythmia genes could not identify other major causal mutations.
  
  
  CONCLUSIONS
  It was hypothesized that the studied variants are not the primary cause of BrS in these patients. However, because small functional effects of these β-subunit variants can be discriminated, they might contribute to the BrS phenotype and be considered a risk factor. The existence of these risk factors can give an explanation to the reduced penetrance and variable expressivity seen in this syndrome. We therefore recommend including the SCN1-4B genes in a next generation sequencing-based gene panel.
authors.affiliation: Centre for Medical Genetics, Reproduction and Genetics; Reproduction, Genetics and Regenerative Medicine, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel).
authors.forename: Uschi
authors.initials: U
authors.lastname: Peeters
authors.forename: Fabiana
authors.initials: F
authors.lastname: Scornik
authors.forename: Helena
authors.initials: H
authors.lastname: Riuró
authors.forename: Guillermo
authors.initials: G
authors.lastname: Pérez
authors.forename: Evrim
authors.initials: E
authors.lastname: Komurcu-Bayrak
authors.forename: Sophie
authors.initials: S
authors.lastname: Van Malderen
authors.forename: Gudrun
authors.initials: G
authors.lastname: Pappaert
authors.forename: Anna
authors.initials: A
authors.lastname: Tarradas
authors.forename: Sara
authors.initials: S
authors.lastname: Pagans
authors.forename: Dorien
authors.initials: D
authors.lastname: Daneels
authors.forename: Karine
authors.initials: K
authors.lastname: Breckpot
authors.forename: Pedro
authors.initials: P
authors.lastname: Brugada
authors.forename: Maryse
authors.initials: M
authors.lastname: Bonduelle
authors.forename: Ramon
authors.initials: R
authors.lastname: Brugada
authors.forename: Sonia
authors.initials: S
authors.lastname: Van Dooren
mesh_terms: D000328:Adult; D000368:Aged; D053840:Brugada Syndrome / Q000235:genetics / Q000401:mortality / Q000503:physiopathology; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism; D062546:Voltage-Gated Sodium Channel beta Subunits / Q000235:genetics* / Q000378:metabolism*
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D062546:Voltage-Gated Sodium Channel beta Subunits