Value of systematic genetic screening of patients with amyotrophic lateral sclerosis.
J Neurol Neurosurg Psychiatry
; 92(5): 510-518, 2021 05.
Article
in En
| MEDLINE
| ID: mdl-33589474
ABSTRACT
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Genetic Testing
/
Amyotrophic Lateral Sclerosis
/
Mutation
Type of study:
Diagnostic_studies
/
Prognostic_studies
/
Screening_studies
Limits:
Adult
/
Aged
/
Aged80
/
Female
/
Humans
/
Male
/
Middle aged
Language:
En
Journal:
J Neurol Neurosurg Psychiatry
Year:
2021
Type:
Article
Affiliation country:
United kingdom