| Summary: | 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.
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