Whole exome sequencing as a tool to identify novel causal variants and genes for Brugada syndrome

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

Abstract

Brugada syndrome (BrS) is a cardiac channelopathy inherited as an autosomal dominant trait with incomplete penetrance and variable expression. All published BrS-associated genes have been identified by a classical candidate gene approach, leading to a total genetic diagnostic yield of 30% (with 20% of mutations in the SCN5A gene). Currently available genomics and bioinformatics technologies allow us to identify novel and potentially major genes involved in BrS. Hence we can better address the urgent question to what extent BrS can be regarded as a pure Mendelian, monogenic disorder or as an oligo- to polygenic syndrome modulating disease expression.

We report the results of a first panel of exome sequence data of 8 stringently selected, large BrS families. Multiple candidate causal variants in genes already linked with cardiac arrhythmias and in novel cardiac genes were identified and validated with Sanger sequencing. In three families we observed that novel, in silico disease-causing variants in known cardiac arrhythmia genes did not show complete correlation with the clinical diagnosis by segregation analysis in all available family members. This phenomenon is also seen in our diagnostics lab for SCN5A mutation analysis. On one hand these results question the major causality of the analyzed variants but on the other hand they might point in the direction of a polygenic inheritance of this disorder. To further investigate this hypothesis, we currently compare exomic SNP profiles, including the type, relative burden and pattern of variants, within a cardiac arrhythmias candidate gene set between control and BrS-patient samples.
Original languageEnglish
Title of host publicationThe EUROPEAN HUMAN GENETICS CONFERENCE 2016
Publication statusPublished - 21 May 2016
EventThe EUROPEAN HUMAN GENETICS CONFERENCE 2016 - Barcelona, Spain
Duration: 21 May 201624 May 2016

Conference

ConferenceThe EUROPEAN HUMAN GENETICS CONFERENCE 2016
CountrySpain
CityBarcelona
Period21/05/1624/05/16

Keywords

  • BRUGADA SYNDROME
  • exome
  • gene panel
  • MUTATIONS
  • segregation

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