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. and McCombe, Pamela A. (2017) Whole exome sequencing and DNA methylation analysis in a clinical amyotrophic lateral sclerosis cohort. Molecular Genetics and Genomic Medicine, 5 4: 418-428. doi:10.1002/mgg3.302

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.
Title Whole exome sequencing and DNA methylation analysis in a clinical amyotrophic lateral sclerosis cohort
Journal name Molecular Genetics and Genomic Medicine   Check publisher's open access policy
ISSN 2324-9269
Publication date 2017-07-01
Year available 2017
Sub-type Article (original research)
DOI 10.1002/mgg3.302
Open Access Status DOI
Volume 5
Issue 4
Start page 418
End page 428
Total pages 11
Place of publication Chichester, West Sussex, United Kingdom
Publisher John Wiley & Sons
Language eng
Subject 1311 Genetics
2716 Genetics (clinical)
1312 Molecular Biology
Abstract Background
Formatted abstract
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.

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.
Keyword ALS
Clinical genetics
Motor neuron disease
Next-generation sequencing
Whole exome sequencing
Hexanucleotide Repeat
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID 1440
Institutional Status UQ

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