Intermediate C9orf72 repeat numbers are not ALS risk factors

Abstract : Introduction: Amyotrophic lateral sclerosis (ALS) is one of the most severe motor neuron (MN) disorders in adults. The C9orf72 repeat expansion is the most common genetic cause of the disease. Initial findings have set the pathogenic cut-off to 30 repeat. However, intermediate repeat numbers between 16 and 30 have also been proposed to be associated with ALS risk. As most studies rely on ALS patients, we performed a case-control study in a French cohort to understand the involvement of intermediate repeats on the ALS risk. Methods: In a cohort of 412 C9orf72-negative sporadic ALS patients and 327 healthy controls, the C9orf72 repeat number was assessed by Repeat-Primed PCR. Results: The most frequent alleles were two, five and eight repeats both in ALS and control groups. The highest repeat number was 22 in controls and 26 in patients. The allelic distribution was not significantly different between both groups. Conclusions: These findings show a lack of association between C9orf72 intermediate repeat numbers and the risk of developing ALS. These data suggest that repeat numbers below 30 are not an ALS risk factor in the French population and confirms the definition of the C9orf72 pathogenic cut-off.