TY - JOUR
T1 - Spectrum and prevalence of cardiac sodium channel variants among black, white, Asian, and Hispanic individuals
T2 - Implications for arrhythmogenic susceptibility and Brugada/long QT syndrome genetic testing
AU - Ackerman, Michael J.
AU - Splawski, Igor
AU - Makielski, Jonathan C.
AU - Tester, David J.
AU - Will, Melissa L.
AU - Timothy, Katherine W.
AU - Keating, Mark T.
AU - Jones, Gregg
AU - Chadha, Monica
AU - Burrow, Christopher R.
AU - Stephens, J. Claiborne
AU - Xu, Chuanbo
AU - Judson, Richard
AU - Curran, Mark E.
N1 - Funding Information:
M.J.A. was supported by a Mayo Foundation Clinic Research award, a Clinical Scientist Development Award from the Doris Duke Charitable Foundation, and a R01 grant from the National Institutes of Health (HD42569 to M.J.A., HL71092 to J.C.M.). M.T.K. and I.S. are supported by a Donald W. Reynolds Cardiovascular Clinical Research Center Grant. M.J.A. is a consultant for Genaissance Pharmaceuticals.
PY - 2004/11
Y1 - 2004/11
N2 - Objectives. 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 mu tations 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, dena turing 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 p olymorphisms (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 stud y 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.
AB - Objectives. 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 mu tations 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, dena turing 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 p olymorphisms (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 stud y 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.
KW - Arrhythmia
KW - Genetics
KW - Ion channels
KW - Long QT syndrome
KW - Sudden death
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U2 - 10.1016/j.hrthm.2004.07.013
DO - 10.1016/j.hrthm.2004.07.013
M3 - Article
C2 - 15851227
AN - SCOPUS:7744243863
SN - 1547-5271
VL - 1
SP - 600
EP - 607
JO - Heart rhythm
JF - Heart rhythm
IS - 5
ER -