Incidence of pathogenic, likely pathogenic, and uncertain ALS variants in a clinic cohort

Abstract

ObjectiveTo determine the incidence of amyotrophic lateral sclerosis (ALS) genetic variants in a clinic-based population.MethodsA prospective cohort of patients with definite or probable ALS was offered genetic testing using a testing algorithm based on family history and age at onset.ResultsThe incidence of pathogenic (P) or likely pathogenic (LP) variants was 56.0% in familial ALS (fALS); 11.8% in patients with ALS with a family history of dementia, and 6.8% in sporadic ALS (p < 0.001). C9orf72 expansions accounted for the majority (79%) of P or LP variants in fALS cases. Variants of uncertain significance were identified in 20.0% of fALS cases overall and in 35.7% of C9orf72-negative cases. P or LP variants were detected in 18.5% of early-onset cases (onset age <50 years); the incidence of P or LP variants was not significantly different between family history types in this group.ConclusionsOur data suggest that the incidence of P and LP variants in genes other than C9orf72 is lower than expected in Midwestern fALS cases compared with research cohorts and highlights the challenge of variant interpretation in ALS. An accurate understanding of the incidence of pathogenic variants in clinic-based ALS populations is necessary to prioritize targets for therapeutic intervention and inform clinical trial design.

High-Throughput Genetic Testing in ALS: The Challenging Path of Variant Classification Considering the ACMG Guidelines

“…Comparing our results with those presented in previous reports [ 5 , 6 ], we can confirm that the majority of pathogenic variants identified are C9orf72 repeat expansions (39/59, 66%), followed by SOD1 (10/59, 17%) and TARDBP (8/59, 14%) variants.…”

“…By applying these criteria, variants should be classified in five different categories: “Pathogenic”, “likely pathogenic”, “uncertain significance”, “likely benign”, and “benign”. Recently, researchers used the ACMG standards to interpret variants found in ALS patients [ 4 , 5 , 6 ]. In this study, we discuss the application of ACMG guidelines to ALS, combining data reported in literature with results obtained from a large ALS cohort, screened with gene panel sequencing over a four-year period.…”

Amyotrophic Lateral Sclerosis Genetic Access Program

“…To optimize program funding for the identification of genetic cases, our testing approach relied on family history criteria and a targeted, 5 gene sequencing panel for familial cases. The diagnostic yield in familial cases, 45.8% (138/301), is somewhat lower than that of other recently reported clinic-based ALS testing programs, which ranged from 56.0% in a US 12 to 66.7% in an Italian cohort. 13 Although larger panels were used in these cohorts, the higher diagnostic yields in those reports are not attributable to a greater number of genes tested because nearly all P and LP variants were identified in the same 6 genes tested in our program.…”

C9orf72 and the Care of the Patient With ALS or FTD

“…However, many circumstances may obscure a clear pattern of dominant transmission in families with the C9orf72 HRE, 37 and data from ALS clinic cohorts suggest that only about half of those who carry the HRE have a family history of ALS. 38,39 Family history information may be used to provide HRE risk assessment for affected persons who are considering HRE testing. See testing to determine whether they will develop ALS or FTD, but we currently cannot predict whether a healthy HRE carrier will develop ALS, FTD, both, or neither.…”

“…The incidence of pathogenic or likely pathogenic variants in SOD1 and in genes other than C9orf72 in clinic-based ALS cases in the United States may be lower than that reported in research cohorts. 39 Accordingly, research and industry should prioritize the C9orf72 HRE as a target for therapy. Carriers of the HRE are present in every ALS and FTD clinic, and with consistent testing practices, they will be increasingly identified.…”