Alternative splicing is an important mechanism to regulate gene expression and to expand the repertoire of gene products in order to accommodate an increase in complexity of multicellular organisms. It needs to be precisely regulated, which is achieved via RNA structure, splicing factors, transcriptional regulation, and chromatin. Changes in any of these factors can lead to disease. These may include the core spliceosome, splicing enhancer/repressor sequences and their interacting proteins, the speed of transcription by RNA polymerase II, and histone modifications. While the basic principle of splicing is well understood, it is still very difficult to predict splicing outcome, due to the multiple levels of regulation. Current molecular diagnostics mainly uses Sanger sequencing of exons, or next-generation sequencing of gene panels or the whole exome. Functional analysis of potential splicing variants is scarce, and intronic variants are often not considered. This likely results in underestimation of the percentage of splicing variants. Understanding how sequence variants may affect splicing is not only crucial for confirmation of diagnosis and for genetic counseling, but also for the development of novel treatment options. These include small molecules, transsplicing, antisense oligonucleotides, and gene therapy. Here we review the current state of molecular mechanisms of splicing regulation and how deregulation can lead to human disease, diagnostics to detect splicing variants, and novel treatment options based on splicing correction.

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Keywords Alternative splicing, Genetic diagnostics, Human disease, Next-generation sequencing, Splicing therapy
Persistent URL dx.doi.org/10.1016/bs.ircmb.2017.07.008, hdl.handle.net/1765/101937
Series International Review of Cell and Molecular Biology
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Citation
Bergsma, A.J, van der Wal, E, Broeders, M. (Mike), van der Ploeg, A.T, & Pijnappel, W.W.M.P. (2017). Alternative Splicing in Genetic Diseases: Improved Diagnosis and Novel Treatment Options. International Review of Cell and Molecular Biology. doi:10.1016/bs.ircmb.2017.07.008