Spectrum and prevalence of cardiac sodium channel variants among black, white, Asian, and Hispanic individuals: implications for arrhythmogenic susceptibility and Brugada/long QT syndrome genetic testing.
OBJECTIVE
The purpose of this study was to determine the prevalence and spectrum of nonsynonymous polymorphisms (amino acid variants) in the cardiac sodium channel among healthy subjects.


BACKGROUND
Pathogenic mutations in the cardiac sodium channel gene, SCN5A, cause approximately 15 to 20% of Brugada syndrome (BrS1), 5 to 10% of long QT syndrome (LQT3), and 2 to 5% of sudden infant death syndrome.


METHODS
Using single-stranded conformation polymorphism, denaturing high-performance liquid chromatography, and/or direct DNA sequencing, mutational analysis of the protein-encoding exons of SCN5A was performed on 829 unrelated, anonymous healthy subjects: 319 black, 295 white, 112 Asian, and 103 Hispanic.


RESULTS
In addition to the four known common polymorphisms (R34C, H558R, S1103Y, and R1193Q), four relatively ethnic-specific polymorphisms were identified: R481W, S524Y, P1090L, and V1951L. Overall, 39 distinct missense variants (28 novel) were elucidated. Nineteen variants (49%) were found only in the black cohort. Only seven variants (18%) localized to transmembrane-spanning domains. Four variants (F1293S, R1512W, and V1951L cited previously as BrS1-causing mutations and S1787N previously published as a possible LQT3-causing mutation) were identified in this healthy cohort.


CONCLUSIONS
This study provides the first comprehensive determination of the prevalence and spectrum of cardiac sodium channel variants in healthy subjects from four distinct ethnic groups. This compendium of SCN5A variants is critical for proper interpretation of SCN5A genetic testing and provides an essential hit list of targets for future functional studies to determine whether or not any of these variants mediate genetic susceptibility for arrhythmias in the setting of either drugs or disease.
Ackerman
Michael J
MJ
Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. ackerman.michael@mayo.edu
Splawski
Igor
I
Makielski
Jonathan C
JC
Tester
David J
DJ
Will
Melissa L
ML
Timothy
Katherine W
KW
Keating
Mark T
MT
Jones
Gregg
G
Chadha
Monica
M
Burrow
Christopher R
CR
Stephens
J Claiborne
JC
Xu
Chuanbo
C
Judson
Richard
R
Curran
Mark E
ME
D002037:Bundle-Branch Block / Q000235:genetics; D002851:Chromatography, High Pressure Liquid; D004252:DNA Mutational Analysis; D005091:Exons; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics; D020125:Mutation, Missense; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018807:Polymorphism, Single-Stranded Conformational; D044469:Racial Groups / Q000235:genetics*; D015222:Sodium Channels / Q000235:genetics*; D013577:Syndrome; D014693:Ventricular Fibrillation / Q000235:genetics
D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels