Utilizing multiple in silico analyses to identify putative causal SCN5A variants in brugada syndrome

Jyh Ming Jimmy Juang; Tzu Pin Lu; Liang Chuan Lai; Chia Hsiang Hsueh; Yen Bin Liu; Chia Ti Tsai; Lian Yu Lin; Chih Chieh Yu; Juey Jen Hwang; Fu Tien Chiang; Sherri Shih Fan Yeh; Wen Pin Chen; Eric Y. Chuang; Ling Ping Lai; Jiunn Lee Lin

doi:10.1038/srep03850

Utilizing multiple in silico analyses to identify putative causal SCN5A variants in brugada syndrome

Jyh Ming Jimmy Juang, Tzu Pin Lu, Liang Chuan Lai, Chia Hsiang Hsueh, Yen Bin Liu, Chia Ti Tsai, Lian Yu Lin, Chih Chieh Yu, Juey Jen Hwang, Fu Tien Chiang, Sherri Shih Fan Yeh, Wen Pin Chen, Eric Y. Chuang, Ling Ping Lai, Jiunn Lee Lin

Research output: Contribution to journal › Article › peer-review

21 Citations (Scopus)

Abstract

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 14â€...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.

Original language	English
Article number	3850
Journal	Scientific Reports
Volume	4
DOIs	https://doi.org/10.1038/srep03850
Publication status	Published - Jan 27 2014
Externally published	Yes

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Juang, J. M. J., Lu, T. P., Lai, L. C., Hsueh, C. H., Liu, Y. B., Tsai, C. T., Lin, L. Y., Yu, C. C., Hwang, J. J., Chiang, F. T., Yeh, S. S. F., Chen, W. P., Chuang, E. Y., Lai, L. P., & Lin, J. L. (2014). Utilizing multiple in silico analyses to identify putative causal SCN5A variants in brugada syndrome. Scientific Reports, 4, Article 3850. https://doi.org/10.1038/srep03850

@article{225e4fef52c84cb797a4694cfed63e33,

title = "Utilizing multiple in silico analyses to identify putative causal SCN5A variants in brugada syndrome",

abstract = "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{\^a}€...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.",

keywords = "Brugada syndrome, SCN5A protein, human, sodium channel Nav1.5",

author = "Juang, {Jyh Ming Jimmy} and Lu, {Tzu Pin} and Lai, {Liang Chuan} and Hsueh, {Chia Hsiang} and Liu, {Yen Bin} and Tsai, {Chia Ti} and Lin, {Lian Yu} and Yu, {Chih Chieh} and Hwang, {Juey Jen} and Chiang, {Fu Tien} and Yeh, {Sherri Shih Fan} and Chen, {Wen Pin} and Chuang, {Eric Y.} and Lai, {Ling Ping} and Lin, {Jiunn Lee}",

note = "Funding Information: We were sincerely grateful to many cardiologists for referring patients to our hospital, and to the staff of the Sixth Core Lab, Department of Medical Research, National Taiwan University Hospital for technical support and Melissa Stauffer, PhD, of Scientific Editing Solutions, for editing the manuscript. This work was supported partially through grants NTUH 98-N1266, NTUH100-N1775, VN100-08, NTUH101-N2010, NTUH101-S1780, VN101-04, NTUH 101-S1784, NTUH 102-M2224, NTUH.102-S2099, NTUH.102-S2035, UN102-019 and NSC 101-2314-B-002-168-MY2, NSC 101-2314-B-002-173-MY2.",

year = "2014",

month = jan,

day = "27",

doi = "10.1038/srep03850",

language = "English",

volume = "4",

journal = "Scientific Reports",

issn = "2045-2322",

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T1 - Utilizing multiple in silico analyses to identify putative causal SCN5A variants in brugada syndrome

AU - Juang, Jyh Ming Jimmy

AU - Lu, Tzu Pin

AU - Lai, Liang Chuan

AU - Hsueh, Chia Hsiang

AU - Liu, Yen Bin

AU - Tsai, Chia Ti

AU - Lin, Lian Yu

AU - Yu, Chih Chieh

AU - Hwang, Juey Jen

AU - Chiang, Fu Tien

AU - Yeh, Sherri Shih Fan

AU - Chen, Wen Pin

AU - Chuang, Eric Y.

AU - Lai, Ling Ping

AU - Lin, Jiunn Lee

N1 - Funding Information: We were sincerely grateful to many cardiologists for referring patients to our hospital, and to the staff of the Sixth Core Lab, Department of Medical Research, National Taiwan University Hospital for technical support and Melissa Stauffer, PhD, of Scientific Editing Solutions, for editing the manuscript. This work was supported partially through grants NTUH 98-N1266, NTUH100-N1775, VN100-08, NTUH101-N2010, NTUH101-S1780, VN101-04, NTUH 101-S1784, NTUH 102-M2224, NTUH.102-S2099, NTUH.102-S2035, UN102-019 and NSC 101-2314-B-002-168-MY2, NSC 101-2314-B-002-173-MY2.

PY - 2014/1/27

Y1 - 2014/1/27

N2 - 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 14â€...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.

AB - 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 14â€...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.

KW - Brugada syndrome

KW - SCN5A protein, human

KW - sodium channel Nav1.5

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DO - 10.1038/srep03850

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C2 - 24463578

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SN - 2045-2322

VL - 4

JO - Scientific Reports

JF - Scientific Reports

M1 - 3850

ER -

Utilizing multiple in silico analyses to identify putative causal SCN5A variants in brugada syndrome

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