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


CONCLUSIONS
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.
Kapplinger
Jamie D
JD
Department of Medicine, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota, USA.
Tester
David J
DJ
Alders
Marielle
M
Benito
Begoña
B
Berthet
Myriam
M
Brugada
Josep
J
Brugada
Pedro
P
Fressart
Véronique
V
Guerchicoff
Alejandra
A
Harris-Kerr
Carole
C
Kamakura
Shiro
S
Kyndt
Florence
F
Koopmann
Tamara T
TT
Miyamoto
Yoshihiro
Y
Pfeiffer
Ryan
R
Pollevick
Guido D
GD
Probst
Vincent
V
Zumhagen
Sven
S
Vatta
Matteo
M
Towbin
Jeffrey A
JA
Shimizu
Wataru
W
Schulze-Bahr
Eric
E
Antzelevitch
Charles
C
Salisbury
Benjamin A
BA
Guicheney
Pascale
P
Wilde
Arthur A M
AA
Brugada
Ramon
R
Schott
Jean-Jacques
JJ
Ackerman
Michael J
MJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D053840:Brugada Syndrome / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D030541:Databases, Genetic; D016757:Death, Sudden, Cardiac / Q000453:epidemiology; D005091:Exons / Q000235:genetics; D005260:Female; D005820:Genetic Testing; D005838:Genotype; D014943:Global Health; D006801:Humans; D007223:Infant; D038622:Internationality; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009124:Muscle Proteins / Q000235:genetics*; D020125:Mutation, Missense; D062554:NAV1.5 Voltage-Gated Sodium Channel; D012189:Retrospective Studies; D012307:Risk Factors; D015222:Sodium Channels / Q000235:genetics*; D055815:Young Adult
D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels