SCA10 expansions occur in the Brazilian general population, but rearrangement happens between expansion and rs41524547

Extract

We read with interest the paper ‘Extended haplotype with rs41524547-G defines the ancestral origin of SCA10’, by MacFarland et al, that appeared in 2024 in Human Molecular Genetics [1]. SCA10 is an autosomal dominant cerebellar ataxia, due to the expansion of a non-coding polymorphic pentanucleotide repeat in intron 9 of ATXN10 [2]. As MacFarland et al described, all SCA10 cases to date came from the American continents plus two Chinese Han and one Japanese families, suggesting that the ancestral origin was probably related to the period associated with the entry of Homo Sapiens into the Americas. To better confirm this hypothesis, there was a need to construct a more informative haplotype than the C (rs5764850)- expansion(n)-G (rs72556348)-G (rs72556349)-C (rs72556350) formerly detected in all SCA10 families [3]. For this purpose, McFarland et al chose to study the C/G/T polymorphism at rs41524547 in the genomic region flanking ATXN10.

The G allele of this SNP (rs41524547-G) corresponds to less than 5% in Asian and American populations, and was never found in populations in the rest of the world [1]. McFarland et al performed a deductive sequence of association studies. First, they analyzed rs41524547 in 123 SCA10 subjects and found the minor allele rs41524547-G in all of them. Then, they tested the size of the ATTCT alleles in 54 DNA samples with rs41524547-G from a repository of samples from the HapMap Project—i.e. from the general population. As expected, these rs41524547-G DNA samples were from East Asia and Latin America. And surprisingly, 14 (25.9%) had ATTCT expansions:10 Peruvians, 2 Colombians, one Mexican, and one undetermined individual. Next, the authors examined a larger sample of 2163 control individuals—1313 originating from Asian and 850 from American populations. The rs41524547-G was found in 123 subjects, 26 of them with American ancestries. Four out of 123 (3.25%) presented ATTCT expansions: three originated from the area surrounding Mexico City, and the last one, from Fujian, China. Of note, these three Mexicans with ATTCT expansions corresponded to 11% of 26 American subjects carrying rs41524547-G. Alleles considered non-pathogenic but intermediate (between 33 and 279 repeats) were recently detected in 8.7% of 871 healthy Peruvian individuals; half of them carried rs41524547-G [4]. These results demonstrated that there might be inadvertent carriers of ATTCT expansions in populations living around the Pacific Ocean, and especially in populations of the American continents, a finding that matches the incomplete penetrance characteristic of the SCA10 expansion. The authors concluded that rs41524547-G was the most robust at-risk SNP allele for SCA10, was useful for screening of SCA10 expansions in population studies, and provides strong evidence for a single, prehistoric origin of SCA10 expansions [1].