title: Cardiac conduction defects and Brugada syndrome: A family with overlap syndrome carrying a nonsense SCN5A mutation.
abstract: BACKGROUND
  Phenotypes often differ even within family members carrying the sameSCN5Amutation. We aimed to evaluate the genetic modifiers in a family with Brugada syndrome (BrS) and sick sinus syndrome (SSS) with anSCN5Amutation that causes the truncated alpha-subunit of cardiac Na channel protein.
  
  
  METHODS
  To detect the genetic modifiers, we performed targeted panel sequencing of the coding region of 46 genes that are related to primary arrhythmia syndrome, by using a bench-top, next generation sequencer. Phenotype-genotype relationships were evaluated among the family members.
  
  
  RESULTS
  Index proband was a 13-year old (yo) boy with cardiac conduction defect as well as BrS. Genetic analysis revealed that he and his three asymptomatic family members carried a novel nonsense mutation:SCN5A-Q779X. Both genotype-positive mother and sister exhibited coved type ST elevation and his sister had SSS, whereas his elder brother exhibited saddleback type ST elevation induced by pilsicainide administration. We detected four non-synonymous variants (DSG2-R773K,SCN1B-L210P, -S248R, and -R250T) in the proband, his mother and his sister, but not in his brother.
  
  
  CONCLUSIONS
  Phenotypic differences between the proband and his brother carrying the same nonsenseSCN5Amutation could be explained by modifiers such asSCN1B, andDSG2gene variants.
authors.affiliation: Department of Pediatrics, Kinki University, Faculty of Medicine, Osaka, Japan.
authors.forename: Hisaaki
authors.initials: H
authors.lastname: Aoki
authors.affiliation: Department of Pediatrics, Kinki University, Faculty of Medicine, Osaka, Japan.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Ohtsu, Shiga, Japan.
authors.forename: Seiko
authors.initials: S
authors.lastname: Ohno
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Takeru
authors.initials: T
authors.lastname: Makiyama
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Ohtsu, Shiga, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Horie
keywords: Children; Overlap syndrome; Pilsicainide challenge test; SCN5A