Utilizing multiple in silico analyses to identify putative causal SCN5A variants in Brugada syndrome.
Brugada syndrome (BrS) is an inheritable sudden cardiac death disease mainly caused by SCN5A mutations. Traditional approaches can be costly and time-consuming if all candidate variants need to be validated through in vitro studies. Therefore, we developed a new approach by combining multiple in silico analyses to predict functional and structural changes of candidate SCN5A variants in BrS before conducting in vitro studies. Five SCN5A non-synonymous variants (1651G>A, 1776C>G, 1673A>G, 3269C>T and 3578G>A) were identified in 14 BrS patients using direct DNA sequencing. Several bioinformatics algorithms were applied and predicted that 1651G>A (A551T) and 1776C>G (N592K) were high-risk SCN5A variants (odds ratio 59.59 and 23.93). The results were validated by Mass spectrometry and in vitro electrophysiological assays. We concluded that integrating sequence-based information and secondary protein structures elements may help select highly potential variants in BrS before conducting time-consuming electrophysiological studies and two novel SCN5A mutations were validated.
1] Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan [2] Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Jyh-Ming Jimmy
JM
Juang
YongLin Biomedical Engineering Center, National Taiwan University, Taipei, Taiwan.
Tzu-Pin
TP
Lu
Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Liang-Chuan
LC
Lai
Department of Medicine, Krannert Institute of Cardiology and Division of Cardiology, Indiana University School of Medicine, Indianapolis, Indiana.
Chia-Hsiang
CH
Hsueh
Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
Yen-Bin
YB
Liu
Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
Chia-Ti
CT
Tsai
Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
Lian-Yu
LY
Lin
Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
Chih-Chieh
CC
Yu
Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
Juey-Jen
JJ
Hwang
Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
Fu-Tien
FT
Chiang
Department of Environmental and Occupational Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
Sherri Shih-Fan
SS
Yeh
Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Wen-Pin
WP
Chen
1] YongLin Biomedical Engineering Center, National Taiwan University, Taipei, Taiwan [2] Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan.
Eric Y
EY
Chuang
Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
Ling-Ping
LP
Lai
Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
Jiunn-Lee
JL
Lin
D000328:Adult; D053840:Brugada Syndrome / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000737:chemistry / Q000235:genetics*; D018408:Patch-Clamp Techniques; D017433:Protein Structure, Secondary
D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human