Amyotrophic lateral sclerosis onset is influenced by the burden of rare variants in known amyotrophic lateral sclerosis genes
- 7 November 2014
- journal article
- research article
- Published by Wiley in Annals of Neurology
- Vol. 77 (1), 100-113
- https://doi.org/10.1002/ana.24306
Abstract
Objective To define the genetic landscape of amyotrophic lateral sclerosis (ALS) and assess the contribution of possible oligogenic inheritance, we aimed to comprehensively sequence 17 known ALS genes in 391 ALS patients from the United States. Methods Targeted pooled‐sample sequencing was used to identify variants in 17 ALS genes. Fragment size analysis was used to define ATXN2 and C9ORF72 expansion sizes. Genotype–phenotype correlations were made with individual variants and total burden of variants. Rare variant associations for risk of ALS were investigated at both the single variant and gene level. Results A total of 64.3% of familial and 27.8% of sporadic subjects carried potentially pathogenic novel or rare coding variants identified by sequencing or an expanded repeat in C9ORF72 or ATXN2; 3.8% of subjects had variants in >1 ALS gene, and these individuals had disease onset 10 years earlier (p = 0.0046) than subjects with variants in a single gene. The number of potentially pathogenic coding variants did not influence disease duration or site of onset. Interpretation Rare and potentially pathogenic variants in known ALS genes are present in >25% of apparently sporadic and 64% of familial patients, significantly higher than previous reports using less comprehensive sequencing approaches. A significant number of subjects carried variants in >1 gene, which influenced the age of symptom onset and supports oligogenic inheritance as relevant to disease pathogenesis. ANN NEUROL 2015;77:100–113Keywords
Funding Information
- National Institute of Neurological Disorders and Stroke (K08-NS075094)
- National Institute of Neurological Disorders and Stroke (R01-NS069669)
- National Heart, Lung, and Blood Institute (T32-HL83822)
- National Center for Research Resources (UL1 RR024992)
- National Center for Research Resources (UL1 TR000448)
- National Cancer Institute (P30 CA91842)
This publication has 38 references indexed in Scilit:
- Extensive genetics of ALSNeurology, 2012
- An integrated map of genetic variation from 1,092 human genomesNature, 2012
- Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosisNature, 2012
- Classification of familial amyotrophic lateral sclerosis by family history: effects on frequency of genes mutationJournal of Neurology, Neurosurgery & Psychiatry, 2012
- Contribution of major amyotrophic lateral sclerosis genes to the etiology of sporadic diseaseNeurology, 2012
- Evidence for an oligogenic basis of amyotrophic lateral sclerosisHuman Molecular Genetics, 2012
- Screening of the SOD1, FUS, TARDBP, ANG, and OPTN mutations in Korean patients with familial and sporadic ALSNeurobiology of Aging, 2012
- Genetics of familial and sporadic amyotrophic lateral sclerosisBiochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2006
- El escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosisJournal of the Neurological Sciences, 1994
- Epidemiologic Investigations of Amyotrophic Lateral SclerosisNeurology, 1955