Disease-modifying effects of an SCAF4 structural variant in a predominantly SOD1 ALS cohort

Pytte, Julia, Flynn, Loren L, Anderton, Ryan S, Mastaglia, Frank L, Theunissen, Frances, James, Ian, Pfaff, Abigail, Koks, Sulev ORCID: 0000-0001-6087-6643, Saunders, Ann M, Bedlack, Richard
et al (show 6 more authors) (2020) Disease-modifying effects of an SCAF4 structural variant in a predominantly SOD1 ALS cohort. NEUROLOGY-GENETICS, 6 (4). e470-.

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<h4>Objective</h4>To test the hypothesis that rs573116164 will have disease-modifying effects in patients with superoxide dismutase 1 (<i>SOD1</i>) familial amyotrophic lateral sclerosis (fALS), we characterized rs573116164 within a cohort of 190 patients with fALS and 560 healthy age-matched controls to assess the variant for association with various measures of disease.<h4>Methods</h4>Using a previously described bioinformatics evaluation algorithm, a polymorphic short structural variant associated with <i>SOD1</i> was identified according to its theoretical effect on gene expression. An 12-18 poly-T repeat (rs573116164) within the 3' untranslated region of serine and arginine rich proteins-related carboxy terminal domain associated factor 4 (<i>SCAF4</i>), a gene that is adjacent to <i>SOD1</i>, was assessed for disease association and influence on survival and age at onset in an fALS cohort using PCR, Sanger sequencing, and capillary separation techniques for allele detection.<h4>Results</h4>In a North American cohort of predominantly <i>SOD1</i> fALS patients (n =190) and age-matched healthy controls (n = 560), we showed that carriage of an 18T <i>SCAF4</i> allele was associated with disease within this cohort (odds ratio [OR] 6.6; 95% confidence interval [CI] 3.9-11.2; <i>p</i> = 4.0e-11), but also within non-<i>SOD1</i> cases (n = 27; OR 5.3; 95% CI 1.9-14.5; <i>p</i> = 0.0014). This finding suggests genetically <i>SOD1</i>-independent effects of SCAF4 on fALS susceptibility. Furthermore, carriage of an 18T allele was associated with a 26-month reduction in survival time (95% CI 6.6-40.8; <i>p</i> = 0.014), but did not affect age at onset of disease.<h4>Conclusions</h4>The findings in this fALS cohort suggest that rs573116164 could have <i>SOD1</i>-independent and broader relevance in ALS, warranting further investigation in other fALS and sporadic ALS cohorts, as well as studies of functional effects of the 18T variant on gene expression.

Item Type: Article
Depositing User: Symplectic Admin
Date Deposited: 16 Sep 2020 08:54
Last Modified: 18 Jan 2023 23:33
DOI: 10.1212/NXG.0000000000000470
Open Access URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC73574...
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URI: https://livrepository.liverpool.ac.uk/id/eprint/3101376