Genetic characterisation of ATXN2 in Australian amyotrophic lateral sclerosis

• Intermediate ATXN2 expansions of 30-33 repeats increase ALS risk in Australia • Familial cases drove this association between ALS and intermediate ATXN2 expansions • ATXN2 expansions of 32-33 repeats were associated with shortened disease duration • ALS intermediate expansions contained between one and three CAA interruptions • Four extremely rare protein-altering variants in ATXN2 were identified in ALS cases Large expansions of a trinucleotide repeat encoding a polyglutamine tract in ATXN2 are a known cause of spinocerebellar ataxia 2, and intermediate length expansions in this gene have been reported as a risk factor and phenotypic modifier for amyotrophic lateral sclerosis (ALS). Here we present a comprehensive analysis of the genetic contribution of ATXN2 to ALS within an Australian cohort of 821 ALS cases. We performed association for both disease status and ALS clinical phenotypes, with careful consideration of repeat size and composition, and the presence of additional genetic variants within ATXN2 . The largest expansion detected among cases was 33 repeat units, and 32 in controls, while the most common repeat size was 22. Intermediate expansions of 30-33 repeats were significantly more common in ALS cases (1.95%) than controls (0.42%, p=0.02543), and we found this association to be primarily driven by familial rather than sporadic ALS cases (frequency of 4.30% vs 1.65% and p=0.00790 vs 0.05799). All intermediate expansions in ALS cases harboured at least one CAA synonymous interruption. No association was found between intermediate expansions and site or age of disease onset, or disease duration. However, larger intermediate repeat sizes of 32-33 repeats were associated with a shorter disease duration (median=27.35 months) when compared with cases who harboured an ATXN2 repeat size in the normal range (median=35.47 months, p=1.89 × 10 -6 ). These findings indicate that intermediately expanded ATXN2 repeats may play an important gene modifier role in Australian ALS cohorts.