Spinocerebellar Ataxia Type 2 Has Multiple Ancestral Origins

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 δ = 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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by Fundo de Incentivo a Pesquisa do Hospital de Clinicas de Porto Alegre (FIPE-HCPA), grants number GPPG 2006-0384, 2019-0169 and 2019-0254; and DNABank Neurogenetics-INCH Lima-Peru trough grant number ASAP/GP2 - MJFF-023323. LSS, MLSP and LBJ were supported by CNPq. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the Institutional Ethics Committee (Comissao de Etica em Pesquisa do Hospital de Clinicas de Porto Alegre) by the numbers CAAE 0324.1.001.000-06 and 02857818.6.0000.5327 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors