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

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. [ABSTRACT FROM AUTHOR]