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Int. J. Mol. Sci. 2017, 18(8), 1668; doi:10.3390/ijms18081668

Mutations of Pre-mRNA Splicing Regulatory Elements: Are Predictions Moving Forward to Clinical Diagnostics?

1
Centre for Cardiovascular Surgery and Transplantation, Brno 65691, Czech Republic
2
International Centre for Genetic Engineering and Biotechnology, 34149 Trieste, Italy
3
Central European Institute of Technology, Masaryk University, Brno 62500, Czech Republic
*
Author to whom correspondence should be addressed.
Received: 27 June 2017 / Revised: 24 July 2017 / Accepted: 27 July 2017 / Published: 31 July 2017
(This article belongs to the Special Issue Pre-mRNA Splicing 2017)
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Abstract

For more than three decades, researchers have known that consensus splice sites alone are not sufficient regulatory elements to provide complex splicing regulation. Other regulators, so-called splicing regulatory elements (SREs) are needed. Most importantly, their sequence variants often underlie the development of various human disorders. However, due to their variable location and high degeneracy, these regulatory sequences are also very difficult to recognize and predict. Many different approaches aiming to identify SREs have been tried, often leading to the development of in silico prediction tools. While these tools were initially expected to be helpful to identify splicing-affecting mutations in genetic diagnostics, we are still quite far from meeting this goal. In fact, most of these tools are not able to accurately discern the SRE-affecting pathological variants from those not affecting splicing. Nonetheless, several recent evaluations have given appealing results (namely for EX-SKIP, ESRseq and Hexplorer predictors). In this review, we aim to summarize the history of the different approaches to SRE prediction, and provide additional validation of these tools based on patients’ clinical data. Finally, we evaluate their usefulness for diagnostic settings and discuss the challenges that have yet to be met. View Full-Text
Keywords: splicing regulatory elements; in silico predictions; pre-mRNA splicing; mutation; evaluation of prediction tools; variants of unknown significance; splicing aberration splicing regulatory elements; in silico predictions; pre-mRNA splicing; mutation; evaluation of prediction tools; variants of unknown significance; splicing aberration
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Grodecká, L.; Buratti, E.; Freiberger, T. Mutations of Pre-mRNA Splicing Regulatory Elements: Are Predictions Moving Forward to Clinical Diagnostics? Int. J. Mol. Sci. 2017, 18, 1668.

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