Whole exome sequencing and DNA methylation analysis in a clinical amyotrophic lateral sclerosis cohort.
AuthorGarton, FC; Benyamin, B; Zhao, Q; Liu, Z; Gratten, J; Henders, AK; Zhang, Z-H; Edson, J; Furlong, S; Morgan, S; ...
Source TitleMolecular Genetics and Genomic Medicine
University of Melbourne Author/sGarton, Fleur
Document TypeJournal Article
CitationsGarton, F. C., Benyamin, B., Zhao, Q., Liu, Z., Gratten, J., Henders, A. K., Zhang, Z. -H., Edson, J., Furlong, S., Morgan, S., Heggie, S., Thorpe, K., Pfluger, C., Mather, K. A., Sachdev, P. S., McRae, A. F., Robinson, M. R., Shah, S., Visscher, P. M. ,... McCombe, P. A. (2017). Whole exome sequencing and DNA methylation analysis in a clinical amyotrophic lateral sclerosis cohort.. Mol Genet Genomic Med, 5 (4), pp.418-428. https://doi.org/10.1002/mgg3.302.
Access StatusOpen Access
Open Access at PMChttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC5511806
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.
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