C9orf72 Intermediate Alleles in Patients with Amyotrophic Lateral Sclerosis, Systemic Lupus Erythematosus, and Rheumatoid Arthritis.

The commonest genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a large hexanucleotide expansion within the non-coding region of the C9orf72 gene. The pathogenic mechanisms of the mutation seem toxic gain of functions, while haploinsufficiency alone appears insufficient to cause neurodegeneration. C9orf72 mice rather develop features of autoimmunity. Immune-mediated dysfunctions are involved in the pathogenesis of ALS and FTD and high prevalence of autoimmune disease has recently been observed in C9orf72 expansion-positive patients. Since intermediate repeat expansions result in decreased transcription of the gene, we explored the hypothesis that C9orf72 intermediate alleles could be a genetic risk for autoimmune conditions. We genotyped 69 systemic lupus erythematosus (SLE) and 77 rheumatoid arthritis (RA) patients, with 68 expansion-negative ALS patients, as control. A cut-off of ≥ 9 and ≤ 30 hexanucleotide units was chosen to define intermediate-length expansions. In the SLE and SLE + RA cohorts, both the number of patients with intermediate expansions and the overall number of intermediate alleles were significantly higher than in controls (23.2% vs. 7.4%, p = 0.020; 13.8% vs. 3.7%, p = 0.006, and 19.9% vs. 7.4%, p = 0.033, 11% vs. 3.7%, p = 0.021, respectively) and discernible although non-significant differences were found for the RA only cohort. Three SLE patients had intermediate-length expansions on both alleles, two of them harboring sequence variations within the hexanucleotide downstream region. However, no peculiar clinical features associated with the intermediate expansion were identified. Our results suggest that C9orf72 intermediate alleles could be associated with systemic autoimmune diseases, indicating a role of C9orf72 in immunity regulation.