To describe the frequency of pathogenic mutations and variants of unknown significance (VUS) in a Midwest population cohort of amyotrophic lateral sclerosis (ALS), and compare to gene-negative patients.

While certain gene mutations have been associated with ALS phenotypes; overall, the relationship of mutation to phenotype is variable. In addition, it is not known whether certain mutations are more prevalent in certain regions of the United States. Recently sponsored genetic testing programs have made large-scale screening of newly diagnosed patients possible. Here we report the frequency of mutations and VUS in a large Midwestern ALS clinic.

We obtained IRB approval to conduct a retrospective chart review of patients newly diagnosed with ALS with genetic testing using sponsored panels of ALS genes (Invitae or Prevention Genetics).  Patients were included if diagnosed within the last 5 years and any ALS gene panel was ordered. Clinical data was obtained including region of onset, slope of progression of ALS Function Rating Scale (ALSFRS), laboratory and electrodiagnostic data, time from diagnosis to event, symptoms duration, change in weight, and time to diagnosis.

We report on the first 10 patients (out of an estimated n=200). 40% of patients were gene positive (either had a pathogenic mutation or VUS). A pathogenic C9orf72 variant was identified in 20% of patients and VUS in 20% (SOD1 and MAPT genes). The remainder (60%) were gene negative (no mutation). The demographics for gene positive versus negative patients is 75% male (versus 50%), mean age of 68.8 years (versus 58.3 years), and mean time to diagnosis of 9.3 months (versus 18.2 months). Data on the full cohort will be presented at the AAN meeting.

We present data on patients evaluated in a Midwest ALS clinic that may provide additional insight into ALS gene load frequency, phenotype and disease trajectory in our region.