TY - JOUR T1 - Value of systematic genetic screening of patients with amyotrophic lateral sclerosis JF - Journal of Neurology, Neurosurgery & Psychiatry JO - J Neurol Neurosurg Psychiatry SP - 510 LP - 518 DO - 10.1136/jnnp-2020-325014 VL - 92 IS - 5 AU - Stephanie R Shepheard AU - Matthew D Parker AU - Johnathan Cooper-Knock AU - Nick S Verber AU - Lee Tuddenham AU - Paul Heath AU - Nick Beauchamp AU - Elsie Place AU - Elizabeth S A Sollars AU - Martin R Turner AU - Andrea Malaspina AU - Pietro Fratta AU - Channa Hewamadduma AU - Thomas M Jenkins AU - Christopher J McDermott AU - Dennis Wang AU - Janine Kirby AU - Pamela J Shaw A2 - , Y1 - 2021/05/01 UR - http://jnnp.bmj.com/content/92/5/510.abstract N2 - Objective The 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.Methods We 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.Results 21% 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).Conclusions 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.Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as online supplemental information. Data are stored in the AMBRoSIA consortium repository. Anonymised raw data can be made available on reasonable request. ER -