Abstract
Objective To report the frequency of amyotrophic lateral sclerosis (ALS) genetic variants in a nationwide cohort of clinic-based patients with ALS with a family history of ALS (fALS), dementia (dALS), or both ALS and dementia (fALS/dALS).
Methods A multicenter, prospective cohort of 573 patients with fALS, dALS, or fALS/dALS, underwent genetic testing in the ALS Genetic Access Program (ALS GAP), a clinical program for clinics of the Northeast ALS Consortium. Patients with dALS underwent C9orf72 hexanucleotide repeat expansion (HRE) testing; those with fALS or fALS/dALS underwent C9orf72 HRE testing, followed by sequencing of SOD1, FUS, TARDBP, TBK1, and VCP.
Results A pathogenic (P) or likely pathogenic (LP) variant was identified in 171/573 (30%) of program participants. About half of patients with fALS or fALS/dALS (138/301, 45.8%) had either a C9orf72 HRE or a P or LP variant identified in SOD1, FUS, TARDBP, TBK1, or VCP. The use of a targeted, 5-gene sequencing panel resulted in far fewer uncertain test outcomes in familial cases compared with larger panels used in other in clinic-based cohorts. Among dALS cases 11.8% (32/270) were found to have the C9orf72 HRE. Patients of non-Caucasian geoancestry were less likely to test positive for the C9orf72 HRE, but were more likely to test positive on panel testing, compared with those of Caucasian ancestry.
Conclusions The ALS GAP program provided a genetic diagnosis to ∼1 in 3 participants and may serve as a model for clinical genetic testing in ALS.
Glossary
- ACMG=
- American College of Medical Genetics;
- ALS=
- amyotrophic lateral sclerosis;
- dALS=
- patients with a family history of dementia;
- fALS=
- patients with a family history of ALS;
- fALS/dALS=
- patients with a family history of both ALS and dementia;
- FDR=
- first-degree relative;
- FTD=
- frontotemporal dementia;
- GAP=
- Genetic Access Program;
- HRE=
- hexanucleotide repeat expansion;
- LP=
- likely pathogenic;
- OR=
- odds ratio;
- P=
- pathogenic;
- SDR=
- second-degree relative;
- TDR=
- third-degree relative;
- VUS=
- variant of uncertain significance
Footnotes
Go to Neurology.org/NG for full disclosures. Funding information is provided at the end of the article.
The Article Processing Charge was funded by the authors.
- Received February 10, 2021.
- Accepted in final form May 20, 2021.
- Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
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