Mutation Analysis of the SCN5A Gene in 122 Brugada Syndrome Probands

Dorien Daneels, Uschi Peeters, Pedro Brugada, Mary-Louise Bonduelle, A. Gazzo, Daniele Raimondi, Liszl Peirsman, Inge Timmermans, Gudrun Pappaert, Sophie Van Malderen, Martine Biervliet, Daisy Verdonck, Sonia Van Dooren

Research output: Chapter in Book/Report/Conference proceedingMeeting abstract (Book)

Abstract

Brugada syndrome (BrS) is a cardiac channelopathy manifesting in structural normal hearts and inherited as an autosomal dominant trait with incomplete penetrance and variable expression. The clinical diagnosis is based on the appearance of a type 2 ST-segment ECG elevation of at least 2mm in more than one of the V1-V3 precordial leads either spontaneous or induced after sodium-blocker exposure. Genetic diagnosis is currently based on the mutation analysis of the pore-forming alpha-subunit of the sodium channel gene (SCN5A), resulting in a genetic diagnostic yield of approximately 30%. We performed SCN5A mutation analysis of all 28 exons and flanking intron-exon boundaries in 122 BrS probands of our outclinic patient population. We identified 23 variants possibly associated with cardiac channelopathies, which resulted in a genetic diagnostic yield of 18.8%. When only taking into account the patients with a baseline type I ECG (23.7%), which is the most convincing diagnostic criterion for BrS, the genetic diagnostic yield increased to 34.4%. If possible, segregation analysis was performed in the families of the SCN5A positive BrS probands to determine genotype-phenotype correlations. In more than 50% of tested families there was an incomplete segregation of the discovered variant. Revision of all ECG data revealed that some ajmaline or baseline ECG negative BrS patients with SCN5A mutations did not meet the stringent diagnostic criteria but demonstrated conduction disease. Given this incompete variant segregation pattern in some families, studies are on going to better predict in silico the effect of the discovered variants on the protein structure, which might give some more insight into their pathologic nature and their role in the disease. These results also urge for the need to revise the clinical diagnositc criteria for BrS, in order to stratify BrS patients groups based on more detailed phenotypic data necessary to discover novel major disease associated genes.
Original languageEnglish
Title of host publicationThird PhD Day at the Medical Campus VUB, Brussels, Belgium
Pages7-7
Number of pages1
Publication statusPublished - 2014
Event3rd PhD Day Medical Campus - Research Unlimited - Brussels
Duration: 1 Apr 20141 Apr 2014

Conference

Conference3rd PhD Day Medical Campus - Research Unlimited
Period1/04/141/04/14

Keywords

  • Brugada Syndrome
  • SCN5A
  • segregation

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