An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing

作者：Kapplinger Jamie D; Tester David J; Alders Marielle; Benito Begona; Berthet Myriam; Brugada Josep; Brugada Pedro; Fressart Veronique; Guerchicoff Alejandra; Harris Kerr Carole; Kamakura Shiro; Kyndt Florence; Koopmann Tamara T; Miyamoto Yoshihiro; Pfeiffer Ryan; Pollevick Guido D; Probst Vincent; Zumhagen Sven; Vatta Matteo; Towbin Jeffrey A; Shimizu Wataru; Schulze Bahr Eric; Antzelevitch Charles; Sali**ury Benjamin A; Guicheney Pascale; Wilde Arthur A M

来源：Heart Rhythm, 2010, 7(1): 33-46.

DOI：10.1016/j.hrthm.2009.09.069

• Brugada syndrome
• Genetic testing
• Ion channels
• Sodium channel
• Sudden death

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.

• 出版日期2010-1