Abstract 21572: Spectrum and Prevalence of Mutations Involving the Known Brugada Syndrome-Susceptibility Genes in a Large Cohort of Unrelated Patients with Clinically Diagnosed Brugada Syndrome
Background: Brugada syndrome (BrS) is a heritable arrhythmia syndrome characterized by an ECG pattern of coved type ST-segment elevation in the right precordial leads (V1 through V3) and an increased risk for sudden death. To date, 8 genes have been implicated in the pathogenesis of BrS. However, except for the ∼20-25% yield contributed by SCN5A-mediated BrS (BrS1), the contribution of the other BrS-susceptibility genes has not been systematically analyzed in a large cohort of unrelated patients with BrS.
Methods: Using PCR, DHPLC, and direct DNA sequencing, comprehensive open reading frame/splice site mutational analysis of all 112 translated exons of SCN5A (BrS1), GPD1L (BrS2), CACNA1C (BrS3), CACNB2B (BrS4), SCN1B (BrS5), SCN3B (BrS6), KCNE3 (BrS7), and KCNJ8 (BrS8) was performed in 106 unrelated BrS patients (89 males, average age = 43 ±14 years, 96% Caucasian, 30% with spontaneous type 1 BrS ECG). DNA from 600 ostensibly healthy controls (500 Caucasians and 100 African Americans) was obtained from the Coriel Cell Repository and the European Collection of Cell Cultures (ECACC).
Results: Overall, 23/106 (21.7%) of BrS cases had a putative BrS1-8 mutation with the majority (83%) being BrS1-associated mutations in SCN5A. Nineteen patients (18%) hosted one of 18 unique BrS1-associated mutations including 12 missense mutations, 5 nonsense mutations, and 1 splice site mutation. Only, 4 (3 novel) unique mutations [1 in GPD1L (F215Y), 1 in CACNA1C (R2086Q) 1 in CACNB2B (E499D), and 1 in KCNJ8 (S422L)], absent in 600 controls, were identified in 4 (3.7%) patients.
Conclusion: Except for BrS1, the other BrS-susceptibility genes are indeed minor providing a putative pathogenic explanation for <4% of this BrS cohort. While previous reports have suggested that mutations in CACNA1C (BrS3) and CACNB2B (BrS4) alone may account for as much as 10% of BrS cases overall, we identified only a single CACNA1C-positive and a single CACNB2-positive case. Given the relative rarity of BrS2-8 genotypes, we suggest GPD1L-BrS rather than BrS2 as a more informative naming system for all minor BrS-susceptibility genes. Still, >70% of BrS remains genetically elusive.
- © 2010 by American Heart Association, Inc.