Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2017
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
_version_ 1783250395209924608
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
work_keys_str_mv AT gartonfleurc wholeexomesequencinganddnamethylationanalysisinaclinicalamyotrophiclateralsclerosiscohort
AT benyaminbeben wholeexomesequencinganddnamethylationanalysisinaclinicalamyotrophiclateralsclerosiscohort
AT zhaoqiongyi wholeexomesequencinganddnamethylationanalysisinaclinicalamyotrophiclateralsclerosiscohort
AT liuzhijun wholeexomesequencinganddnamethylationanalysisinaclinicalamyotrophiclateralsclerosiscohort
AT grattenjacob wholeexomesequencinganddnamethylationanalysisinaclinicalamyotrophiclateralsclerosiscohort
AT hendersanjalik wholeexomesequencinganddnamethylationanalysisinaclinicalamyotrophiclateralsclerosiscohort
AT zhangzonghong wholeexomesequencinganddnamethylationanalysisinaclinicalamyotrophiclateralsclerosiscohort
AT edsonjanette wholeexomesequencinganddnamethylationanalysisinaclinicalamyotrophiclateralsclerosiscohort
AT furlongsarah wholeexomesequencinganddnamethylationanalysisinaclinicalamyotrophiclateralsclerosiscohort
AT morgansarah wholeexomesequencinganddnamethylationanalysisinaclinicalamyotrophiclateralsclerosiscohort
AT heggiesusan wholeexomesequencinganddnamethylationanalysisinaclinicalamyotrophiclateralsclerosiscohort
AT thorpekathryn wholeexomesequencinganddnamethylationanalysisinaclinicalamyotrophiclateralsclerosiscohort
AT pflugercasey wholeexomesequencinganddnamethylationanalysisinaclinicalamyotrophiclateralsclerosiscohort
AT matherkarena wholeexomesequencinganddnamethylationanalysisinaclinicalamyotrophiclateralsclerosiscohort
AT sachdevperminders wholeexomesequencinganddnamethylationanalysisinaclinicalamyotrophiclateralsclerosiscohort
AT mcraeallanf wholeexomesequencinganddnamethylationanalysisinaclinicalamyotrophiclateralsclerosiscohort
AT robinsonmatthewr wholeexomesequencinganddnamethylationanalysisinaclinicalamyotrophiclateralsclerosiscohort
AT shahsonia wholeexomesequencinganddnamethylationanalysisinaclinicalamyotrophiclateralsclerosiscohort
AT visscherpeterm wholeexomesequencinganddnamethylationanalysisinaclinicalamyotrophiclateralsclerosiscohort
AT mangelsdorfmarie wholeexomesequencinganddnamethylationanalysisinaclinicalamyotrophiclateralsclerosiscohort
AT hendersonrobertd wholeexomesequencinganddnamethylationanalysisinaclinicalamyotrophiclateralsclerosiscohort
AT wraynaomir wholeexomesequencinganddnamethylationanalysisinaclinicalamyotrophiclateralsclerosiscohort
AT mccombepamelaa wholeexomesequencinganddnamethylationanalysisinaclinicalamyotrophiclateralsclerosiscohort