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Objective  There is a critical need to establish genetic markers that explain the complex phenotypes and pathogenicity of ALS. This study identified a polymorphism in the Stathmin-2 gene and investigated its association with sporadic ALS (sALS) disease risk, age-of onset and survival duration.    Methods  The candidate CA repeat was systematically analyzed using PCR, Sanger sequencing and high throughput capillary separation for genotyping. Stathmin-2 expression was investigated using RT-PCR in patient olfactory neurosphere-derived (ONS) cells and RNA sequencing in laser-captured spinal motor neurons.    Results  In a case-control analysis of a combined North American sALS cohort ( n  = 321) and population control group ( n  = 332), long/long CA genotypes were significantly associated with disease risk ( p  = 0.042), and most strongly when one allele was a 24 CA repeat ( p  = 0.0023). In addition, longer CA allele length was associated with earlier age-of-onset ( p  = 0.039), and shorter survival duration in bulbar-onset cases ( p  = 0.006). In an Australian longitudinal sALS cohort ( n  = 67), ALS functional rating scale scores were significantly lower in carriers of the long/long genotype ( p  = 0.034). Stathmin-2 mRNA expression was reduced in sporadic patient ONS cells. Additionally, sALS patients and controls exhibited variable expression of Stathmin-2 mRNA according to CA genotype in laser-captured spinal motor neurons.    Conclusions  We report a novel non-coding CA repeat in Stathmin-2 which is associated with sALS disease risk and has disease modifying effects. The potential value of this variant as a disease marker and tool for cohort enrichment in clinical trials warrants further investigation.

Novel STMN2 Variant Linked to Amyotrophic Lateral Sclerosis Risk and Clinical Phenotype