Somatic instability of the androgen receptor CAG repeat in a normal female

The polyglutamine repeat disorders represent a family of degenerative neurological diseases which are characterized by expansions of tandemly repeated CAG repeats. Investigations have demonstrated that in Huntington disease, dentatorubral pallidoluysian atrophy, and the spinocerebellar ataxias type 1, 2, and 3, the polyglutamine expansions show both meiotic and mitotic instability. However, previous studies have suggested that the polyglutamine motif within exon 1 of the androgen receptor gene (AR) which expands in cases of spinobulbar muscular atrophy differs in that it is apparently mitotically stable. During linkage analysis in a family with FG syndrome, a rare condition mapped to Xq12-q22.1, we detected the presence of an unusually small AR allele segregating within the pedigree. Sequencing, cytogenetic analysis, and PCR of flanking markers indicate that this allele arose by a somatic contraction of seven CAG repeats in the proband's mother, representing the first report of mitotic instability of an AR CAG repeat of normal size.