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Whole exome sequencing and DNA methylation analysis in a clinical amyotrophic lateral sclerosis cohort
BACKGROUND: Gene discovery has provided remarkable biological insights into amyotrophic lateral sclerosis (ALS). One challenge for clinical application of genetic testing is critical evaluation of the significance of reported variants. METHODS: We use whole exome sequencing (WES) to develop a clinic...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5511806/ https://www.ncbi.nlm.nih.gov/pubmed/28717666 http://dx.doi.org/10.1002/mgg3.302 |
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author | Garton, Fleur C. Benyamin, Beben Zhao, Qiongyi Liu, Zhijun Gratten, Jacob Henders, Anjali K. Zhang, Zong‐Hong Edson, Janette Furlong, Sarah Morgan, Sarah Heggie, Susan Thorpe, Kathryn Pfluger, Casey Mather, Karen A. Sachdev, Perminder S. McRae, Allan F. Robinson, Matthew R. Shah, Sonia Visscher, Peter M. Mangelsdorf, Marie Henderson, Robert D. Wray, Naomi R. McCombe, Pamela A. |
author_facet | Garton, Fleur C. Benyamin, Beben Zhao, Qiongyi Liu, Zhijun Gratten, Jacob Henders, Anjali K. Zhang, Zong‐Hong Edson, Janette Furlong, Sarah Morgan, Sarah Heggie, Susan Thorpe, Kathryn Pfluger, Casey Mather, Karen A. Sachdev, Perminder S. McRae, Allan F. Robinson, Matthew R. Shah, Sonia Visscher, Peter M. Mangelsdorf, Marie Henderson, Robert D. Wray, Naomi R. McCombe, Pamela A. |
author_sort | Garton, Fleur C. |
collection | PubMed |
description | BACKGROUND: Gene discovery has provided remarkable biological insights into amyotrophic lateral sclerosis (ALS). One challenge for clinical application of genetic testing is critical evaluation of the significance of reported variants. METHODS: We use whole exome sequencing (WES) to develop a clinically relevant approach to identify a subset of ALS patients harboring likely pathogenic mutations. In parallel, we assess if DNA methylation can be used to screen for pathogenicity of novel variants since a methylation signature has been shown to associate with the pathogenic C9orf72 expansion, but has not been explored for other ALS mutations. Australian patients identified with ALS‐relevant variants were cross‐checked with population databases and case reports to critically assess whether they were “likely causal,” “uncertain significance,” or “unlikely causal.” RESULTS: Published ALS variants were identified in >10% of patients; however, in only 3% of patients (4/120) could these be confidently considered pathogenic (in SOD1 and TARDBP). We found no evidence for a differential DNA methylation signature in these mutation carriers. CONCLUSIONS: The use of WES in a typical ALS clinic demonstrates a critical approach to variant assessment with the capability to combine cohorts to enhance the largely unknown genetic basis of ALS. |
format | Online Article Text |
id | pubmed-5511806 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-55118062017-07-17 Whole exome sequencing and DNA methylation analysis in a clinical amyotrophic lateral sclerosis cohort Garton, Fleur C. Benyamin, Beben Zhao, Qiongyi Liu, Zhijun Gratten, Jacob Henders, Anjali K. Zhang, Zong‐Hong Edson, Janette Furlong, Sarah Morgan, Sarah Heggie, Susan Thorpe, Kathryn Pfluger, Casey Mather, Karen A. Sachdev, Perminder S. McRae, Allan F. Robinson, Matthew R. Shah, Sonia Visscher, Peter M. Mangelsdorf, Marie Henderson, Robert D. Wray, Naomi R. McCombe, Pamela A. Mol Genet Genomic Med Original Articles BACKGROUND: Gene discovery has provided remarkable biological insights into amyotrophic lateral sclerosis (ALS). One challenge for clinical application of genetic testing is critical evaluation of the significance of reported variants. METHODS: We use whole exome sequencing (WES) to develop a clinically relevant approach to identify a subset of ALS patients harboring likely pathogenic mutations. In parallel, we assess if DNA methylation can be used to screen for pathogenicity of novel variants since a methylation signature has been shown to associate with the pathogenic C9orf72 expansion, but has not been explored for other ALS mutations. Australian patients identified with ALS‐relevant variants were cross‐checked with population databases and case reports to critically assess whether they were “likely causal,” “uncertain significance,” or “unlikely causal.” RESULTS: Published ALS variants were identified in >10% of patients; however, in only 3% of patients (4/120) could these be confidently considered pathogenic (in SOD1 and TARDBP). We found no evidence for a differential DNA methylation signature in these mutation carriers. CONCLUSIONS: The use of WES in a typical ALS clinic demonstrates a critical approach to variant assessment with the capability to combine cohorts to enhance the largely unknown genetic basis of ALS. John Wiley and Sons Inc. 2017-06-12 /pmc/articles/PMC5511806/ /pubmed/28717666 http://dx.doi.org/10.1002/mgg3.302 Text en © 2017 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Articles Garton, Fleur C. Benyamin, Beben Zhao, Qiongyi Liu, Zhijun Gratten, Jacob Henders, Anjali K. Zhang, Zong‐Hong Edson, Janette Furlong, Sarah Morgan, Sarah Heggie, Susan Thorpe, Kathryn Pfluger, Casey Mather, Karen A. Sachdev, Perminder S. McRae, Allan F. Robinson, Matthew R. Shah, Sonia Visscher, Peter M. Mangelsdorf, Marie Henderson, Robert D. Wray, Naomi R. McCombe, Pamela A. Whole exome sequencing and DNA methylation analysis in a clinical amyotrophic lateral sclerosis cohort |
title | Whole exome sequencing and DNA methylation analysis in a clinical amyotrophic lateral sclerosis cohort |
title_full | Whole exome sequencing and DNA methylation analysis in a clinical amyotrophic lateral sclerosis cohort |
title_fullStr | Whole exome sequencing and DNA methylation analysis in a clinical amyotrophic lateral sclerosis cohort |
title_full_unstemmed | Whole exome sequencing and DNA methylation analysis in a clinical amyotrophic lateral sclerosis cohort |
title_short | Whole exome sequencing and DNA methylation analysis in a clinical amyotrophic lateral sclerosis cohort |
title_sort | whole exome sequencing and dna methylation analysis in a clinical amyotrophic lateral sclerosis cohort |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5511806/ https://www.ncbi.nlm.nih.gov/pubmed/28717666 http://dx.doi.org/10.1002/mgg3.302 |
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