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Abstract
Objective: To estimate the genetic risk conferred by known amyotrophic lateral sclerosis (ALS)–associated genes to the pathogenesis of sporadic ALS (SALS) using variant allele frequencies combined with predicted variant pathogenicity.
Methods: Whole exome sequencing and repeat expansion PCR of C9orf72 and ATXN2 were performed on 87 patients of European ancestry with SALS seen at the University of Utah. DNA variants that change the protein coding sequence of 31 ALS-associated genes were annotated to determine which were rare and deleterious as predicted by MetaSVM. The percentage of patients with SALS with a rare and deleterious variant or repeat expansion in an ALS-associated gene was calculated. An odds ratio analysis was performed comparing the burden of ALS-associated genes in patients with SALS vs 324 normal controls.
Results: Nineteen rare nonsynonymous variants in an ALS-associated gene, 2 of which were found in 2 different individuals, were identified in 21 patients with SALS. Further, 5 deleterious C9orf72 and 2 ATXN2 repeat expansions were identified. A total of 17.2% of patients with SALS had a rare and deleterious variant or repeat expansion in an ALS-associated gene. The genetic burden of ALS-associated genes in patients with SALS as predicted by MetaSVM was significantly higher than in normal controls.
Conclusions: Previous analyses have identified SALS-predisposing variants only in terms of their rarity in normal control populations. By incorporating variant pathogenicity as well as variant frequency, we demonstrated that the genetic risk contributed by these genes for SALS is substantially lower than previous estimates.
GLOSSARY
- ALS=
- amyotrophic lateral sclerosis;
- ALSoD=
- Amyotrophic Lateral Sclerosis Online Database;
- dbNSFP=
- database for nonsynonymous single nucleotide polymorphism functional predictions;
- dbSNP=
- Single Nucleotide Polymorphism database;
- ExAC=
- Exome Aggregation Consortium;
- FALS=
- familial amyotrophic lateral sclerosis;
- FTD=
- frontotemporal dementia;
- HGMD=
- Human Gene Mutation Database;
- MAF=
- minor allele frequency;
- OR=
- odds ratio;
- PCA=
- principal components analysis;
- SALS=
- sporadic amyotrophic lateral sclerosis;
- SNV=
- single nucleotide variant;
- SSC=
- Simons Simplex Collection;
- VQSR=
- variant quality score recalibration
Footnotes
↵* These authors contributed equally to this work.
↵† Co–senior authors.
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Supplemental data at Neurology.org
Editorial, page 220
- Received December 8, 2016.
- Accepted in final form March 17, 2017.
- © 2017 American Academy of Neurology
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