Genotype-phenotype discrepancies in Brugada syndrome

Sonia Van Dooren, Pedro Brugada, Dorien Daneels, Uschi Peeters, Liszl Peirsman, Inge Timmermans, Gudrun Pappaert, Mary-Louise Bonduelle

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


Brugada syndrome (BrS) is one of common inheritable arrhythmogenic disorders in apparently structurally normal hearts, inherited as an autosomal dominant trait with incomplete penetrance and variable expression. Clinical diagnosis is based on documented ventricular arrhythmias and/or related symptoms, family history AND an appearance of the type 1 ST-segment ECG elevation of more than 2mm in more than one of the V1-V3 precordial leads either spontaneous or after sodium-blocker exposure (Brugada et al. 2009). Genetic diagnosis is currently still 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 20%. A panel of sporadic mutations in different sodium, potassium and calcium ion channel and accessory genes account in total for an additional 10% increase in diagnostic yield.
We performed SCN5A mutation analysis of all 27 translated exons and flanking intron-exon boundaries in 135 Brugada syndrome probands of our outclinic patient population. We identified 20 variants of which 17 described mutations and 3 novel potential disease causing variants by in silico prediction tools, resulting in a diagnostic yield of respectively 12,6% to 14,8% (3 variants included). Subsequent segregation analysis was performed in 8 large families of the identified SCN5A positive BrS probands to determine genotype-phenotype correlation. In total phenotypic data (baseline and ajmaline-induced ECG) of 44 patients were compared with genotypic data (SCN5A mutation analysis). A sensitivity of 76% and specificity of 79% was assessed and could be increased up to 85% and 92% respectively with exclusion of the undescribed SCN5A variants. 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.
These results urge for the need to revise the clinical diagnostic criteria for Brugada syndrome, especially since the ajmaline ECG data are of important added value for this low penetrant disorder in the discovery of novel major molecular genetic pathways in Brugada syndrome.
Original languageEnglish
Title of host publicationAbstract book of the 13th Annual Meeting of the Belgian Society of Human Genetics
Number of pages1
Publication statusPublished - 15 Mar 2013
Event13th Annual meeting of the Belgian Society of Human Genetics - EXPO, Brussels, Belgium
Duration: 15 Mar 201315 Mar 2013


Conference13th Annual meeting of the Belgian Society of Human Genetics


  • Brugada syndrome
  • SCN5A
  • cardiogenetics

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