Detection of ATXN2 Expansions in an Exome Dataset: An Underdiagnosed Cause of Parkinsonism

Abstract

Background: CAG-repeat expansions in Ataxin 2 (ATXN2) are known to cause spinocerebellar ataxia type 2 (SCA2), but CAA interrupted expansions may also result in autosomal dominant Parkinson's disease (AD PD). However, because of technical limitations, such expansions are not explored in whole exome sequencing (WES) data.

Objectives: To identify ATXN2 expansions using WES data from PD cases.

Methods: We explored WES data from a cohort of 477 index cases with PD using ExpansionHunter (Illumina DRAGEN Bio-IT Platform, San Diego, CA). Putative expansions were confirmed by combining polymerase chain reaction and fragment length analysis followed by sub-cloning and sequencing methods.

Results: Using ExpansionHunter, we identified three patients from two families with AD PD carrying either ATXN2 22/39 or 22/37 repeats, both interrupted by four CAA repeats.

Conclusion: These findings demonstrate the usefulness of WES to detect pathogenic CAG repeat expansions, which were found in 1.7% of AD PD in the ATXN2 gene in our exome dataset.

Keywords: ATXN2 gene; CAA interruption; Parkinson's disease; repeat expansions; whole exome sequencing.

FIG. 1

Estimated ATXN2 repeat size using ExpansionHunter according to the enrichment kits used. The solid line delineates the mean ATXN2 CAG‐repeat size to 22, estimated from Caucasian populations; the dashed line indicates the pathological threshold up to 32.

FIG. 2

Pedigrees of families A and B with autosomal dominant Parkinson's disease (AD PD) and expanded CAG‐repeat alleles in ATXN2. A: Pedigrees of families A and B. Square = male; circles = female; black symbol = affected; white symbol = unaffected; slashed symbol = deceased. Asterisks indicate individuals with genetic testing and arrow, the proband. AO, age at onset. B: Length and structure of the expanded CAG/CAA repeats in ATXN2 for the three carriers. Open circles = CAG; filled circles = CAA interruptions.