A Complete Association of an intronic SNP rs6798742 with Origin of Spinocerebellar Ataxia Type 7‐CAG Expansion Loci in the Indian and Mexican Population

Summary Spinocerebellar ataxiatype 7 (SCA7) is a rare neurogeneticdisorder caused by highly unstable CAG repeat expansion mutation in coding region of SCA7. We aimed to understand the effect of diverse ATXN7 cis-element in correlation with CAG expansion mutation of SCA7. We initially performed an analysis to identify the haplotype background of CAG expanded allelesusing eight bi- allelicsingle nucleotide polymorphisms (SNPs) flanking an ATXN7-CAG expansion in 32 individuals from nine unrelated Indian SCA7 families and 88 healthy controls. Subsequent validation of the findings was performed in 89 ATXN7-CAG mutation carriers and in 119 unrelated healthy controls of Mexican ancestry. The haplotype analyses showed a shared haplotype background and C alleleof SNP rs6798742 (approximately 6 kb from the 3′-end of CAG repeats) is in complete association with expanded, premutation, intermediate, and the majority of large normal (≥12) CAG allele. The C allele(ancestral/ chimp allele) association was validated in SCA7 subjects and healthy controls from Mexico, suggesting its substantial association with CAG expanded and expansion-prone chromosomes. Analysisof rs6798742 and other neighboring functional SNPs within 6 kb in experimental datasets (Encyclopedia of DNA Elements; ENCODE) shows functional marks that could affect transcription as well as histone methylation. An allelicassociation of the CAG region to an intronic SNP in two different ethnic and geographical populations suggests a -cis factor-dependent mechanism in ATXN7 CAG-region expansion.