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.