Value of systematic genetic screening of patients with amyotrophic lateral sclerosis

The clinical utility of routine genetic sequencing in amyotrophic lateral sclerosis is uncertain. Our aim was to determine whether routine targeted sequencing of 44 ALS-relevant genes would have a significant impact on clinical care and disease subclassification. We performed targeted sequencing of a 44 gene panel in a prospective case series of 100 consecutive ALS patients recruited sequentially from the Sheffield Motor Neuron Disorders Clinic, United Kingdom. All participants were diagnosed with ALS by a specialist Consultant Neurologist. 7/100 patients had familial ALS, but the majority were apparently sporadic cases. 21% of ALS patients carried a confirmed pathogenic or likely-pathogenic mutation, of whom 93% had no family history of ALS. 15% met the inclusion criteria for a current ALS genetic-therapy trial. 5/21 patients with a pathogenic mutation had an additional variant of uncertain significance (VUS). An additional 21% of ALS patients carried a VUS in an ALS-associated gene. Overall, 13% of patients carried more than one genetic variant (pathogenic or VUS). ALS patients carrying two variants developed disease at a significantly earlier age compared to patients with a single variant (median age of onset = 56 versus 60 years, p=0.0074). In conclusion, routine screening for ALS-associated pathogenic mutations in a specialised ALS referral clinic will impact clinical care in 21% of cases. An additional 21% of patients have variants in the ALS gene panel currently of unconfirmed significance after removing non-specific or predicted benign variants. Overall, variants within known ALS-linked genes are of potential clinical importance in 42% of patients