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

To test the hypothesis that rs573116164 will have disease-modifying effects in patients with superoxide dismutase 1 ( ) 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. Using a previously described bioinformatics evaluation algorithm, a polymorphic short structural variant associated with 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 ( ), a gene that is adjacent to , 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. In a North American cohort of predominantly fALS patients (n =190) and age-matched healthy controls (n = 560), we showed that carriage of an 18T allele was associated with disease within this cohort (odds ratio [OR] 6.6; 95% confidence interval [CI] 3.9-11.2; = 4.0e-11), but also within non- cases (n = 27; OR 5.3; 95% CI 1.9-14.5; = 0.0014). This finding suggests genetically -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; = 0.014), but did not affect age at onset of disease. The findings in this fALS cohort suggest that rs573116164 could have -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.