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Diagnostics of short tandem repeat expansion variants using massively parallel sequencing and componential tools

Short tandem repeats (STRs) are scattered throughout the human genome. Some STRs, like trinucleotide repeat expansion (TRE) variants, cause hereditable disorders. Unambiguous molecular diagnostics of TRE disorders is hampered by current technical limitations imposed by traditional PCR and DNA sequen...

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Autores principales: de Leeuw, Rick H., Garnier, Dominique, Kroon, Rosemarie M. J. M., Horlings, Corinne G. C., de Meijer, Emile, Buermans, Henk, van Engelen, Baziel G. M., de Knijff, Peter, Raz, Vered
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460572/
https://www.ncbi.nlm.nih.gov/pubmed/30455479
http://dx.doi.org/10.1038/s41431-018-0302-4
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author de Leeuw, Rick H.
Garnier, Dominique
Kroon, Rosemarie M. J. M.
Horlings, Corinne G. C.
de Meijer, Emile
Buermans, Henk
van Engelen, Baziel G. M.
de Knijff, Peter
Raz, Vered
author_facet de Leeuw, Rick H.
Garnier, Dominique
Kroon, Rosemarie M. J. M.
Horlings, Corinne G. C.
de Meijer, Emile
Buermans, Henk
van Engelen, Baziel G. M.
de Knijff, Peter
Raz, Vered
author_sort de Leeuw, Rick H.
collection PubMed
description Short tandem repeats (STRs) are scattered throughout the human genome. Some STRs, like trinucleotide repeat expansion (TRE) variants, cause hereditable disorders. Unambiguous molecular diagnostics of TRE disorders is hampered by current technical limitations imposed by traditional PCR and DNA sequencing methods. Here we report a novel pipeline for TRE variant diagnosis employing the massively parallel sequencing (MPS) combined with an opensource software package (FDSTools), which together are designed to distinguish true STR sequences from STR sequencing artifacts. We show that this approach can improve TRE diagnosis, such as Oculopharyngeal muscular dystrophy (OPMD). OPMD is caused by a trinucleotide expansion in the PABPN1 gene. A short GCN expansion, (GCN[10]), coding for a 10 alanine repeat is not pathogenic, but an alanine expansion is pathogenic. Applying this novel procedure in  a Dutch OPMD patient cohort, we found expansion variants from GCN[11] to GCN[16], with the GCN[16] as the most abundant variant. The repeat expansion length did not correlate with clinical features. However, symptom severity was found to correlate with age and with the initial affected muscles, suggesting that aging and muscle-specific factors can play a role in modulating OPMD.
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spelling pubmed-64605722019-06-25 Diagnostics of short tandem repeat expansion variants using massively parallel sequencing and componential tools de Leeuw, Rick H. Garnier, Dominique Kroon, Rosemarie M. J. M. Horlings, Corinne G. C. de Meijer, Emile Buermans, Henk van Engelen, Baziel G. M. de Knijff, Peter Raz, Vered Eur J Hum Genet Article Short tandem repeats (STRs) are scattered throughout the human genome. Some STRs, like trinucleotide repeat expansion (TRE) variants, cause hereditable disorders. Unambiguous molecular diagnostics of TRE disorders is hampered by current technical limitations imposed by traditional PCR and DNA sequencing methods. Here we report a novel pipeline for TRE variant diagnosis employing the massively parallel sequencing (MPS) combined with an opensource software package (FDSTools), which together are designed to distinguish true STR sequences from STR sequencing artifacts. We show that this approach can improve TRE diagnosis, such as Oculopharyngeal muscular dystrophy (OPMD). OPMD is caused by a trinucleotide expansion in the PABPN1 gene. A short GCN expansion, (GCN[10]), coding for a 10 alanine repeat is not pathogenic, but an alanine expansion is pathogenic. Applying this novel procedure in  a Dutch OPMD patient cohort, we found expansion variants from GCN[11] to GCN[16], with the GCN[16] as the most abundant variant. The repeat expansion length did not correlate with clinical features. However, symptom severity was found to correlate with age and with the initial affected muscles, suggesting that aging and muscle-specific factors can play a role in modulating OPMD. Springer International Publishing 2018-11-19 2019-03 /pmc/articles/PMC6460572/ /pubmed/30455479 http://dx.doi.org/10.1038/s41431-018-0302-4 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
de Leeuw, Rick H.
Garnier, Dominique
Kroon, Rosemarie M. J. M.
Horlings, Corinne G. C.
de Meijer, Emile
Buermans, Henk
van Engelen, Baziel G. M.
de Knijff, Peter
Raz, Vered
Diagnostics of short tandem repeat expansion variants using massively parallel sequencing and componential tools
title Diagnostics of short tandem repeat expansion variants using massively parallel sequencing and componential tools
title_full Diagnostics of short tandem repeat expansion variants using massively parallel sequencing and componential tools
title_fullStr Diagnostics of short tandem repeat expansion variants using massively parallel sequencing and componential tools
title_full_unstemmed Diagnostics of short tandem repeat expansion variants using massively parallel sequencing and componential tools
title_short Diagnostics of short tandem repeat expansion variants using massively parallel sequencing and componential tools
title_sort diagnostics of short tandem repeat expansion variants using massively parallel sequencing and componential tools
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460572/
https://www.ncbi.nlm.nih.gov/pubmed/30455479
http://dx.doi.org/10.1038/s41431-018-0302-4
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