• Stephanie R Shepheard, Matthew D Parker, Johnathan Cooper-Knock, Nick S Verber, Lee Tuddenham, Paul Heath, Nick Beauchamp, Elsie Place, Elizabeth S A Sollars, Martin R Turner, Andrea Malaspina, Pietro Fratta, Channa Hewamadduma, Thomas M Jenkins, Christopher J McDermott, Dennis Wang, Janine Kirby, Pamela J Shaw, Project MINE Consortium, and Project MinE.
• Sheffield Institute for Translational Neuroscience, The University of Sheffield, Sheffield, UK.
• J. Neurol. Neurosurg. Psychiatr. 2021 May 1; 92 (5): 510518510-518.

ObjectiveThe clinical utility of routine genetic sequencing in amyotrophic lateral sclerosis (ALS) is uncertain. Our aim was to determine whether routine targeted sequencing of 44 ALS-relevant genes would have a significant impact on disease subclassification and clinical care.MethodsWe performed targeted sequencing of a 44-gene panel in a prospective case series of 100 patients with ALS recruited consecutively from the Sheffield Motor Neuron Disorders Clinic, UK. All participants were diagnosed with ALS by a specialist Consultant Neurologist. 7/100 patients had familial ALS, but the majority were apparently sporadic cases.Results21% of patients with ALS 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 patients with ALS carried a VUS in an ALS-associated gene. Overall, 13% of patients carried more than one genetic variant (pathogenic or VUS). Patients with ALS carrying two variants developed disease at a significantly earlier age compared with patients with a single variant (median age of onset=56 vs 60 years, p=0.0074).ConclusionsRoutine 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.© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

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