Key result
In silico analyses link SCN5A variant A551T to ~60-fold greater Brugada syndrome risk.
Why the study?
Traditional approaches to validate candidate SCN5A variants in Brugada syndrome are costly and time-consuming, necessitating efficient predictive methods.
Case-Control (n=565)
Integrating sequence-based information and secondary protein structures can help identify high-risk SCN5A variants in Brugada syndrome prior to time-consuming in vitro studies.
Answers are grounded in this paper and cite their sources.
May support in silico prioritization of SCN5A variants in Brugada syndrome; leaves open clinical adoption pending further validation.
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.
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Juang et al. (2014) conducted a case-control in Brugada Syndrome (n=565). SCN5A variants (A551T and N592K) vs. Wild-type SCN5A / Healthy controls was evaluated on Association of SCN5A 1651G>A (A551T) variant with Brugada syndrome (OR 59.59, p=1.41E-04). In silico analyses identified SCN5A variants A551T and N592K as highly associated with Brugada syndrome (OR 59.59 and 23.93), which was subsequently validated by in vitro electrophysiological assays.
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