Spinocerebellar ataxia type 2 has multiple ancestral origins

Abstract

Spinocerebellar ataxia type 2 (SCA2) is an adult onset, dominant neurodegenerative disorder due to expansions of a CAG repeat tract at the ATXN2 gene. A few studies on ancestral haplotypes were performed so far, and the allele C at rs695871 was always found in SCA2 carriers. We aimed to describe SCA2 ancestral haplotypes constructed based on the SNPs rs9300319, rs3809274, rs695871, rs1236900 and rs593226, using the STRs D12S1329, D12S1333, D12S1672 and D12S1332 to determine their genetic variation. Seventy-seven SCA2 families were recruited from Brazil, Peru, and Uruguay; 162 chromosomes from the Brazilian general population and the chromosomes with normal repeats from 101 SCA2 carriers were used as 263 controls. Eleven ancestral haplotypes were found in SCA2 families. The most frequent ones were A-G-C-C-C (46.7% of families), G-C-C-C-C (24.6%) and A-C-C-C-C (10.3%), with assigned risks of being associated with disease of {delta} = 0.326, 0.197 and 0, respectively. Their mean (sd) CAGexp were 41.68 (3.55), 40.42 (4.11) and 45.67 (9.70) (p = 0.055), while the mean (sd) CAG lengths at normal alleles were 23.85 (3.59), 22.97 (3.93) and 30.81 (4.27) (p < 0.001), respectively. The other SCA2 haplotypes were rare: among them, a G-C-G-A-T was found, evidencing a G allele in rs695871. In summary, our work identified eleven distinct SCA2 haplotypes in Brazilian, Uruguayan, and Peruvian families, including an unexpected SCA2 haplotype with a G allele at rs695871. These results suggest that SCA2 has multiple origins in these populations.