Location score and haplotype analyses of the locus for autosomal recessivespastic ataxia of Charlevoix-Saguenay, in chromosome region 13q11

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a cli nically homogeneous form of early-onset familial spastic ataxia with promin ent myelinated retinal nerve fibers. More than 300 patients have been ident ified, and most of their families originated in the Charlevoix-Saguenay reg ion of northeastern Quebec, where the carrier prevalence has been estimated to be 1/22. Consistent with the hypothesis of a founder effect, we observe d excess shared homozygosity at 13q11, among patients in a genomewide scan of 12 families. Analysis of 19 pedigrees demonstrated very tight linkage be tween the ARSACS locus and an intragenic polymorphism of the gamma-sarcogly can (SGCG) gene, but genomic DNA sequence analysis of all eight exons of SC CG revealed no disease-causing mutation. On the basis of haplotypes compose d of seven marker loci that spanned 11.1 cM, the most likely position of th e ARSACS locus was 0.42 cM distal to the SCCG polymorphism. Two groups of A RSACS-associated haplotypes were identified: a large group that carries a c ommon SGCG allele and a small group that carries a rare SGCG allele. The ha plotype groups do not appear to be closely related. Therefore, although chr omosomes within each haplotype group may harbor a single ARSACS mutation id entical by descent, the two mutations could have independent origins.