Spectrum and prevalence of mutations involving BrS1- Through BrS12-susceptibility genes in a cohort of unrelated patients referred for brugada syndrome genetic testing: Implications for genetic testing

Lia Crotti, Cherisse A. Marcou, David J. Tester, Silvia Castelletti, John R. Giudicessi, Margherita Torchio, Argelia Medeiros-Domingo, Savastano Simone, Melissa L. Will, Federica Dagradi, Peter J. Schwartz, Michael John Ackerman

Research output: Contribution to journalArticle

130 Scopus citations


Objectives: The aim of this study was to provide the spectrum and prevalence of mutations in the 12 Brugada syndrome (BrS)-susceptibility genes discovered to date in a single large cohort of unrelated BrS patients. Background: BrS is a potentially lethal heritable arrhythmia syndrome diagnosed electrocardiographically by coved-type ST-segment elevation in the right precordial leads (V1 to V3; type 1 Brugada electrocardiographic [ECG] pattern) and the presence of a personal/family history of cardiac events. Methods: Using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing, comprehensive mutational analysis of BrS1- through BrS12-susceptibility genes was performed in 129 unrelated patients with possible/probable BrS (46 with clinically diagnosed BrS [ECG pattern plus personal/family history of a cardiac event] and 83 with a type 1 BrS ECG pattern only). Results: Overall, 27 patients (21%) had a putative pathogenic mutation, absent in 1,400 Caucasian reference alleles, including 21 patients with an SCN5A mutation, 2 with a CACNB2B mutation, and 1 each with a KCNJ8 mutation, a KCND3 mutation, an SCN1Bb mutation, and an HCN4 mutation. The overall mutation yield was 23% in the type 1 BrS ECG pattern-only patients versus 17% in the clinically diagnosed BrS patients and was significantly greater among young men <20 years of age with clinically diagnosed BrS and among patients who had a prolonged PQ interval. Conclusions: We identified putative pathogenic mutations in ∼20% of our BrS cohort, with BrS genes 2 through 12 accounting for <5%. Importantly, the yield was similar between patients with only a type 1 BrS ECG pattern and those with clinically established BrS. The yield approaches 40% for SCN5A-mediated BrS (BrS1) when the PQ interval exceeds 200 ms. Calcium channel-mediated BrS is extremely unlikely in the absence of a short QT interval.

Original languageEnglish (US)
Pages (from-to)1410-1418
Number of pages9
JournalJournal of the American College of Cardiology
Issue number15
StatePublished - Oct 9 2012



  • Brugada syndrome
  • cardiac arrest
  • genetic testing
  • ST-segment elevation
  • ventricular arrhythmias

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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