Whole exome sequencing and DNA methylation analysis in a clinical amyotrophic lateral sclerosis cohort

Fleur C. Garton, Beben Benyamin, Qiongyi Zhao, Zhijun Liu, Jacob Gratten, Anjali K Henders, Zong-Hong Zhang, Janette Edson, Sarah Furlong, Sarah Morgan, Susan Heggie, Kathryn Thorpe, Casey Pfluger, Karen A. Mather, Perminder S. Sachdev, Allan F. McRae, Matthew R. Robinson, Sonia Shah, Peter M. Visscher, Marie MangelsdorfRobert D. Henderson, Naomi R. Wray, Pamela A. McCombe

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)418-428
Number of pages11
JournalMolecular Genetics and Genomic Medicine
Issue number4
Publication statusPublished - Jul 2017
Externally publishedYes

Bibliographical note

Copyright the Author(s) 2017. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.


  • ALS
  • clinical genetics
  • motor neuron disease
  • next-generation sequencing
  • whole exome sequencing


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