Screening for ALS Mutations Can Positively Impact Clinical Care


Overall, variants within known ALS-linked genes are of potential clinical importance for 42% of patients, according to the study authors.

Stephanie Shepheard, PhD

Stephanie Shepheard, PhD

Results from a prospective case series of patients with amyotrophic lateral sclerosis (ALS) showed that screening for known ALS genes lead to clinically actionable results in 21% of patients, and a variant of uncertain significance (VUS) may be discovered with potential clinical implications was identified in a further 21% of patients.

Lead author Stephanie Shepheard, PhD, postdoctoral researcher, Sheffield Institute for Translational Neuroscience, and colleagues performed targeting sequencing of a 44-gene panel in 100 patients with ALS recruited consecutively from the Sheffield Motor Neuron Disorders Clinic.

In 21 patients (21%), Shepheard and colleagues identified 22 clinically reportable pathogenic and likely pathogenic variants. Seven of the 21 patients reported a family history of ALS in a first-degree relative, but 14 patients with a clinically reportable pathogenic mutation had apparently sporadic disease.

"Although this study took place in a large tertiary referral ALS center and requires further validation in other settings, our data suggest that all patients with ALS should, with careful counseling, be offered genetic testing, especially in light of new personalized medicine treatments in development,” Shepheard et al wrote.

READ MORE: Sonja W. Scholz, MD, PhD, on Advancing Genomics Against Complex, Polygenic Neurodegenerative Disorders

Among the 21 patients identified with clinically genetic changes, 15 had C90RF72 or SOD1 mutations that would potentially be eligible for recruitment into an ongoing genetic-therapy trial. The most frequently identified pathogenic mutation was in C90RF72 in 10 patients, 3 of which had reported a family history of ALS. Five patients (5%) reported with the SOD1 mutation, 4 of whom had a family history of ALS.

Patients were also evaluated through the ClinVar database to determine if the variant had been previously assessed. The investigators found that 34 variants in 26 patients with ALS were reported in ClinVar as of uncertain significance, or absent from ClinVar and met the criteria for predicted pathogenic variants. Notably, 5 of 26 patients with a VUS had an additional pathogenic variant.

The number of clinically reportable variants and VUS were combined to assign a “mutation-load” to 42 patients with ALS. To determine whether mutation load was clinically relevant, investigators excluded those with absent information and compared age of onset between patients with 1 or 2 variants.

Those carrying 2 variants (n = 13) compared with 1 variant developed disease at a significantly earlier age (median age of onset, 56 years vs 60 years; log-rank test P = .0074). The authors noted, however, that it is not possible to assess any potential effect on disease duration because 67% of this cohort is still living.

In total, 20 of the 44 genes screened in the panel had no mutations identified in any member of the cohort. This was in part because genetic changes were individually rare, which was consistently shown throughout the data.

The research into the genetic aspects of ALS and how they relate to the care of patients has been ongoing for some time. Recently, NeurologyLive spoke with James Berry, MD, MPH, director, ALS Care Center, Massachusetts General Hospital, about the greatest unmet needs within ALS care, as well as why genetics play a major factor in improving clinical trials and treatment outcomes. He touched on what had been previously observed in terms of disease progression among different genetic variants and the complexities of clinical trials using patients with multiple different variants.

Shepheard SR, Parker MD, Cooper-Knock J, et al. Value of systemic genetic screening of patients with amyotrophic lateral sclerosis. J Neurol Neursurg Psychiatry. Published online February 14, 2021. doi: 10.1136/jnnp-2020-325014
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