A Novel Duplication Inatxn2as Modifier For Spinocerebellar Ataxia 3 (Sca3) Andc9orf72-Als

Background The ataxin-2 (ATXN2) gene contains a cytosine-adenine-guanine repeat sequence ranging from 13 to 31 repeats, but when surpassing certain thresholds causes neurodegeneration. Genetic alterations inATXN2other than pathological cytosine adenine guanine (CAG) repeats are unknown. Methods/Results We have identified a 9-base pair duplication in the 2-geneATXN2sense/antisense region. The duplication was found in a Swedish family with spinocerebellar ataxia 3 with parkinsonism, conferring a deviated age at onset unexplained by the concomitant presence ofATXN2intermediate alleles. Similarly,C9ORF72amyotrophic lateral sclerosis cases bearing the same duplication had earlier age at onset than those withC9ORF72andATXN2intermediate alleles. No effect was evident in Parkinson's disease (PD) cases without known PD gene mutations. Conclusions We describe the first genetic alteration other than the known intermediate-range CAG repeats inATXN2. This 9-base pair duplication may act as an additional hit among carriers of pathological nucleotide expansions inATXN3andC9ORF72withATXN2intermediate. (c) 2020 The Authors.Movement Disorderspublished by Wiley Periodicals LLC. on behalf of International Parkinson and Movement Disorder Society.