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Objective  To test the hypothesis that rs573116164 will have disease-modifying effects in patients with superoxide dismutase 1 ( SOD1 ) 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.    Methods  Using a previously described bioinformatics evaluation algorithm, a polymorphic short structural variant associated with  SOD1  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 ( SCAF4 ), a gene that is adjacent to  SOD1 , 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.    Results  In a North American cohort of predominantly  SOD1  fALS patients (n =190) and age-matched healthy controls (n = 560), we showed that carriage of an 18T  SCAF4  allele was associated with disease within this cohort (odds ratio [OR] 6.6; 95% confidence interval [CI] 3.9–11.2;  p  = 4.0e-11), but also within non- SOD1  cases (n = 27; OR 5.3; 95% CI 1.9–14.5;  p  = 0.0014). This finding suggests genetically  SOD1 -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;  p  = 0.014), but did not affect age at onset of disease.    Conclusions  The findings in this fALS cohort suggest that rs573116164 could have  SOD1 -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.

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