---
_id: '7733'
abstract:
- lang: eng
text: "Sections\r\nPDFPDF\r\nTools\r\nShare\r\nAbstract\r\nBackground: 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.\r\nMethods: 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.”\r\nResults: 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.\r\nConclusions: 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."
article_processing_charge: No
article_type: original
author:
- first_name: Fleur C.
full_name: Garton, Fleur C.
last_name: Garton
- first_name: Beben
full_name: Benyamin, Beben
last_name: Benyamin
- first_name: Qiongyi
full_name: Zhao, Qiongyi
last_name: Zhao
- first_name: Zhijun
full_name: Liu, Zhijun
last_name: Liu
- first_name: Jacob
full_name: Gratten, Jacob
last_name: Gratten
- first_name: Anjali K.
full_name: Henders, Anjali K.
last_name: Henders
- first_name: Zong-Hong
full_name: Zhang, Zong-Hong
last_name: Zhang
- first_name: Janette
full_name: Edson, Janette
last_name: Edson
- first_name: Sarah
full_name: Furlong, Sarah
last_name: Furlong
- first_name: Sarah
full_name: Morgan, Sarah
last_name: Morgan
- first_name: Susan
full_name: Heggie, Susan
last_name: Heggie
- first_name: Kathryn
full_name: Thorpe, Kathryn
last_name: Thorpe
- first_name: Casey
full_name: Pfluger, Casey
last_name: Pfluger
- first_name: Karen A.
full_name: Mather, Karen A.
last_name: Mather
- first_name: Perminder S.
full_name: Sachdev, Perminder S.
last_name: Sachdev
- first_name: Allan F.
full_name: McRae, Allan F.
last_name: McRae
- first_name: Matthew Richard
full_name: Robinson, Matthew Richard
id: E5D42276-F5DA-11E9-8E24-6303E6697425
last_name: Robinson
orcid: 0000-0001-8982-8813
- first_name: Sonia
full_name: Shah, Sonia
last_name: Shah
- first_name: Peter M.
full_name: Visscher, Peter M.
last_name: Visscher
- first_name: Marie
full_name: Mangelsdorf, Marie
last_name: Mangelsdorf
- first_name: Robert D.
full_name: Henderson, Robert D.
last_name: Henderson
- first_name: Naomi R.
full_name: Wray, Naomi R.
last_name: Wray
- first_name: Pamela A.
full_name: McCombe, Pamela A.
last_name: McCombe
citation:
ama: Garton FC, Benyamin B, Zhao Q, et al. Whole exome sequencing and DNA methylation
analysis in a clinical amyotrophic lateral sclerosis cohort. Molecular Genetics
& Genomic Medicine. 2017;5(4):418-428. doi:10.1002/mgg3.302
apa: Garton, F. C., Benyamin, B., Zhao, Q., Liu, Z., Gratten, J., Henders, A. K.,
… McCombe, P. A. (2017). Whole exome sequencing and DNA methylation analysis in
a clinical amyotrophic lateral sclerosis cohort. Molecular Genetics & Genomic
Medicine. Wiley. https://doi.org/10.1002/mgg3.302
chicago: Garton, Fleur C., Beben Benyamin, Qiongyi Zhao, Zhijun Liu, Jacob Gratten,
Anjali K. Henders, Zong-Hong Zhang, et al. “Whole Exome Sequencing and DNA Methylation
Analysis in a Clinical Amyotrophic Lateral Sclerosis Cohort.” Molecular Genetics
& Genomic Medicine. Wiley, 2017. https://doi.org/10.1002/mgg3.302.
ieee: F. C. Garton et al., “Whole exome sequencing and DNA methylation analysis
in a clinical amyotrophic lateral sclerosis cohort,” Molecular Genetics &
Genomic Medicine, vol. 5, no. 4. Wiley, pp. 418–428, 2017.
ista: Garton FC, Benyamin B, Zhao Q, Liu Z, Gratten J, Henders AK, Zhang Z-H, Edson
J, Furlong S, Morgan S, Heggie S, Thorpe K, Pfluger C, Mather KA, Sachdev PS,
McRae AF, Robinson MR, Shah S, Visscher PM, Mangelsdorf M, Henderson RD, Wray
NR, McCombe PA. 2017. Whole exome sequencing and DNA methylation analysis in a
clinical amyotrophic lateral sclerosis cohort. Molecular Genetics & Genomic
Medicine. 5(4), 418–428.
mla: Garton, Fleur C., et al. “Whole Exome Sequencing and DNA Methylation Analysis
in a Clinical Amyotrophic Lateral Sclerosis Cohort.” Molecular Genetics &
Genomic Medicine, vol. 5, no. 4, Wiley, 2017, pp. 418–28, doi:10.1002/mgg3.302.
short: F.C. Garton, B. Benyamin, Q. Zhao, Z. Liu, J. Gratten, A.K. Henders, Z.-H.
Zhang, J. Edson, S. Furlong, S. Morgan, S. Heggie, K. Thorpe, C. Pfluger, K.A.
Mather, P.S. Sachdev, A.F. McRae, M.R. Robinson, S. Shah, P.M. Visscher, M. Mangelsdorf,
R.D. Henderson, N.R. Wray, P.A. McCombe, Molecular Genetics & Genomic Medicine
5 (2017) 418–428.
date_created: 2020-04-30T10:48:25Z
date_published: 2017-07-01T00:00:00Z
date_updated: 2021-01-12T08:15:10Z
day: '01'
doi: 10.1002/mgg3.302
extern: '1'
intvolume: ' 5'
issue: '4'
language:
- iso: eng
main_file_link:
- open_access: '1'
url: https://doi.org/10.1002/mgg3.302
month: '07'
oa: 1
oa_version: Published Version
page: 418-428
publication: Molecular Genetics & Genomic Medicine
publication_identifier:
issn:
- 2324-9269
publication_status: published
publisher: Wiley
quality_controlled: '1'
status: public
title: Whole exome sequencing and DNA methylation analysis in a clinical amyotrophic
lateral sclerosis cohort
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 5
year: '2017'
...