@article{7733,
  abstract     = {Sections
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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.”
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.},
  author       = {Garton, Fleur C. and Benyamin, Beben and Zhao, Qiongyi and Liu, Zhijun and Gratten, Jacob and Henders, Anjali K. and Zhang, Zong-Hong and Edson, Janette and Furlong, Sarah and Morgan, Sarah and Heggie, Susan and Thorpe, Kathryn and Pfluger, Casey and Mather, Karen A. and Sachdev, Perminder S. and McRae, Allan F. and Robinson, Matthew Richard and Shah, Sonia and Visscher, Peter M. and Mangelsdorf, Marie and Henderson, Robert D. and Wray, Naomi R. and McCombe, Pamela A.},
  issn         = {2324-9269},
  journal      = {Molecular Genetics & Genomic Medicine},
  number       = {4},
  pages        = {418--428},
  publisher    = {Wiley},
  title        = {{Whole exome sequencing and DNA methylation analysis in a clinical amyotrophic lateral sclerosis cohort}},
  doi          = {10.1002/mgg3.302},
  volume       = {5},
  year         = {2017},
}