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Abstract
Objective: To detect genetic variants underlying familial and sporadic amyotrophic lateral sclerosis (ALS).
Methods: We analyzed 2 founder Jewish populations of Moroccan and Ashkenazi origins and ethnic matched controls. Exome sequencing of 2 sisters with ALS from Morocco was followed by genotyping the identified causative null mutation in 379 unrelated patients with ALS and 1,000 controls. The shared risk haplotype was characterized using whole-genome single nucleotide polymorphism array.
Results: We identified 5 unrelated patients with ALS homozygous for the null 691_692insAG mutation in the optineurin gene (OPTN), accounting for 5.8% of ALS of Moroccan origin and 0.3% of Ashkenazi. We also identified a high frequency of heterozygous carriers among patients with ALS, 8.7% and 2.9%, respectively, compared to 0.75% and 1.0% in controls. The risk of carriers for ALS was significantly increased, with odds ratio of 13.46 and 2.97 in Moroccan and Ashkenazi Jews, respectively. We determined that 691_692insAG is a founder mutation in the tested populations with a minimal risk haplotype of 58.5 Kb, encompassing the entire OPTN gene.
Conclusions: Our data show that OPTN 691_692insAG mutation is a founder mutation in Moroccan and Ashkenazi Jews. This mutation causes autosomal recessive ALS and significantly increases the risk to develop the disease in heterozygous carriers, suggesting both a recessive mode of inheritance and a dominant with incomplete penetrance. These data emphasize the important role of OPTN in ALS pathogenesis, and demonstrate the complex genetics of ALS, as the same mutation leads to different phenotypes and appears in 2 patterns of inheritance.
GLOSSARY
- AAO=
- age at onset;
- AJ=
- Ashkenazi Jewish;
- ALS=
- amyotrophic lateral sclerosis;
- AR=
- autosomal recessive;
- CI=
- confidence interval;
- fALS=
- familial amyotrophic lateral sclerosis;
- FTD=
- frontotemporal dementia;
- IBD=
- identical by descent;
- MJ=
- Moroccan Jewish;
- OR=
- odds ratio;
- PCA=
- principal component analysis;
- sALS=
- sporadic amyotrophic lateral sclerosis;
- SNP=
- single nucleotide polymorphism
Footnotes
↵* These authors contributed equally to this work.
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
- Received July 6, 2015.
- Accepted in final form October 9, 2015.
- © 2016 American Academy of Neurology
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