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Neurol Genet. 2020 Feb 27;6(2):e406. doi: 10.1212/NXG.0000000000000406. eCollection 2020 Apr.

Association of a structural variant within the SQSTM1 gene with amyotrophic lateral sclerosis.

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University of Western Australia (J.P., R.S.A., L.L.F., F.T., L.J., F.L.M., P.A.A.), Centre for Neuromuscular and Neurological Disorders, Crawley; Perron Institute for Neurological and Translational Science (J.P., R.S.A., L.L.F., F.T., L.J., I.P., F.L.M., P.A.A.), Nedlands; University of Notre Dame Australia (R.S.A.), School of Health Sciences; University of Notre Dame Australia (R.S.A.), Institute for Health Research, Fremantle; Murdoch University (L.L.F., I.P., P.A.A.), Centre for Molecular Medicine and Innovative Therapeutics; Murdoch University, Institute for Immunology and Infectious Diseases (I.J.), Western Australia, Australia; Department of Neurology (R.B.), Duke University School of Medicine, Durham, NC; Zinfandel Pharmaceuticals (A.M.S.), Inc.; Duke University (R.B.), ALS Clinic, Durham, NC; and Departments of Neurology, Pathology and Cell and Molecular Biology (T.S., N.S.), Northwestern University Feinberg School of Medicine, the Les Turner ALS Center and the Northwestern University Interdepartmental Neuroscience Program, Chicago, IL.



As structural variations may underpin susceptibility to complex neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), the objective of this study was to investigate a structural variant (SV) within sequestosome 1 (SQSTM1).


A candidate insertion/deletion variant within intron 5 of the SQSTM1 gene was identified using a previously established SV evaluation algorithm and chosen according to its subsequent theoretical effect on gene expression. The variant was systematically assessed through PCR, polyacrylamide gel fractionation, Sanger sequencing, and reverse transcriptase PCR.


A reliable and robust assay confirmed the polymorphic nature of this variant and that the variant may influence SQSTM1 transcript levels. In a North American cohort of patients with familial ALS (fALS) and sporadic ALS (sALS) (n = 403) and age-matched healthy controls (n = 562), we subsequently showed that the SQSTM1 variant is associated with fALS (p = 0.0036), particularly in familial superoxide dismutase 1 mutation positive patients (p = 0.0005), but not with patients with sALS (p = 0.97).


This disease association highlights the importance and implications of further investigation into SVs that may provide new targets for cohort stratification and therapeutic development.

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