AUTISM AND MULTIPLE EXOSTOSES ASSOCIATED WITH AN X-8 TRANSLOCATION OCCURRING WITHIN THE GRPR GENE AND 3' TO THE SDC2 GENE

An X;8 translocation was identified in a 27-year-old female patient ma nifesting multiple exostoses and autism accompanied by mental retardat ion and epilepsy. Through molecular analysis using yeast artificial ch romosomes (YACs) and cosmid clones, the translocation breakpoint was i solated and confirmed to be reciprocal within a 5'-GGCA-3' sequence fo und on both X and 8 chromosomes without gain or loss of a single nucle otide. The translocation breakpoint on the X chromosome occurred in th e first intron of the gastrin-releasing peptide receptor (GPPR) gene a nd that on chromosome 8 occurred similar to 30 kb distal to the 3' end of the Syndecan-2 gene (SDC2), also known as human heparan sulfate pr oteoglycan or fibroglycan. The GRPR gene was shown to escape X-inactiv ation. A dosage effect of the GRPR and a position effect of the SDC2 g ene may, however, contribute the phenotype observed in this patient si nce the orientation of these genes with respect to the translocation w as incompatible with the formation of a fusion gene. Investigation of mutations in these two genes in unrelated patients with either autism or multiple exostoses as well as linkage and association studies is ne eded to validate them as candidate genes.