PT  - JOURNAL ARTICLE
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
ED  - ,
TI  - Value of systematic genetic screening of patients with amyotrophic lateral sclerosis
AID  - 10.1136/jnnp-2020-325014
DP  - 2021 Feb 13
TA  - Journal of Neurology, Neurosurgery & Psychiatry
PG  - jnnp-2020-325014
4099  - http://jnnp.bmj.com/content/early/2021/02/15/jnnp-2020-325014.short
4100  - http://jnnp.bmj.com/content/early/2021/02/15/jnnp-2020-325014.full
AB  - 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.