BACKGROUND: Brugada syndrome (BrS) is a common heritable channelopathy. 
Mutations in the SCN5A-encoded sodium channel (BrS1) culminate in the most 
common genotype.
OBJECTIVE: This study sought to perform a retrospective analysis of BrS 
databases from 9 centers that have each genotyped >100 unrelated cases of 
suspected BrS.
METHODS: Mutational analysis of all 27 translated exons in SCN5A was performed. 
Mutation frequency, type, and localization were compared among cases and 1,300 
ostensibly healthy volunteers including 649 white subjects and 651 nonwhite 
subjects (blacks, Asians, Hispanics, and others) that were genotyped previously.
RESULTS: A total of 2,111 unrelated patients (78% male, mean age 39 +/- 15 
years) were referred for BrS genetic testing. Rare mutations/variants were more 
common among BrS cases than control subjects (438/2,111, 21% vs. 11/649, 1.7% 
white subjects and 31/651, 4.8% nonwhite subjects, respectively, P <10(-53)). 
The yield of BrS1 genetic testing ranged from 11% to 28% (P = .0017). Overall, 
293 distinct mutations were identified in SCN5A: 193 missense, 32 nonsense, 38 
frameshift, 21 splice-site, and 9 in-frame deletions/insertions. The 4 most 
frequent BrS1-associated mutations were E1784K (14x), F861WfsX90 (11x), D356N 
(8x), and G1408R (7x). Most mutations localized to the transmembrane-spanning 
regions.
CONCLUSION: This international consortium of BrS genetic testing centers has 
added 200 new BrS1-associated mutations to the public domain. Overall, 21% of 
BrS probands have mutations in SCN5A compared to the 2% to 5% background rate of 
rare variants reported in healthy control subjects. Additional studies drawing 
on the data presented here may help further distinguish pathogenic mutations 
from similarly rare but otherwise innocuous ones found in cases.