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.
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.
Authors: Barry London; Michael Michalec; Haider Mehdi; Xiaodong Zhu; Laurie Kerchner; Shamarendra Sanyal; Prakash C Viswanathan; Arnold E Pfahnl; Lijuan L Shang; Mohan Madhusudanan; Catherine J Baty; Stephen Lagana; Ryan Aleong; Rebecca Gutmann; Michael J Ackerman; Dennis M McNamara; Raul Weiss; Samuel C Dudley Journal: Circulation Date: 2007-10-29 Impact factor: 29.690
Authors: Michael J Ackerman; Igor Splawski; Jonathan C Makielski; David J Tester; Melissa L Will; Katherine W Timothy; Mark T Keating; Gregg Jones; Monica Chadha; Christopher R Burrow; J Claiborne Stephens; Chuanbo Xu; Richard Judson; Mark E Curran Journal: Heart Rhythm Date: 2004-11 Impact factor: 6.343
Authors: Hiroshi Watanabe; Tamara T Koopmann; Solena Le Scouarnec; Tao Yang; Christiana R Ingram; Jean-Jacques Schott; Sophie Demolombe; Vincent Probst; Frédéric Anselme; Denis Escande; Ans C P Wiesfeld; Arne Pfeufer; Stefan Kääb; H-Erich Wichmann; Can Hasdemir; Yoshifusa Aizawa; Arthur A M Wilde; Dan M Roden; Connie R Bezzina Journal: J Clin Invest Date: 2008-06 Impact factor: 14.808
Authors: Jamie D Kapplinger; John R Giudicessi; Dan Ye; David J Tester; Thomas E Callis; Carmen R Valdivia; Jonathan C Makielski; Arthur A Wilde; Michael J Ackerman Journal: Circ Cardiovasc Genet Date: 2015-04-22
Authors: Albert C Gaw; Byron Lee; Giselle Gervacio-Domingo; Charles Antzelevitch; Romeo Divinagracia; Felipe Jocano Journal: Philipp J Intern Med Date: 2011-07
Authors: 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 J Ackerman Journal: J Am Coll Cardiol Date: 2012-07-25 Impact factor: 24.094