Statistical analysis of rare genetic variants in the first exon of the ataxin-2 gene in patients with neurodegenerative diseases

The ataxin-2 gene (ATXN2) encodes a ribonucleic acid (RNA) binding protein involved in messenger RNA translation and regulation. Large polyglutamine (CAG) expansions or repeat regions in ATXN2 are causative of the neurodegenerative disease spinocerebellar ataxia type 2 (SCA2) and intermediate expansions are considered to be a risk factor for the neurodegenerative disease amyotrophic lateral sclerosis (ALS). However, most variants in the repeat regions of ATXN2 remain unreported because they are difficult to capture with traditional short-read sequencing. We analyze rare genetic variants found in short-read sequencing of exon 1, a polyglutamine repeat region of the ATXN2 gene. The variants were identified during diagnostic exome sequencing of patients for neurodegenerative disease. After adjusting for potentially confounding variables such as age, biological sex, and the enrichment kit used in the sequencing, we find the variants to be associated with neurodegenerative disease, suggesting their involvement in disease pathology. Our preliminary results with short-read sequencing suggest that re-investigation of the ATXN2 gene with long-read sequencing technologies that allow a better resolution of repeat regions shows promise for new insights into neurodegeneration.