Positional cloning of an X;8 translocation (p22.13;q22.1) associated with multiple exostoses and autism
Autism is characterized by qualitative impairments in communication and reciprocal social interaction. About 3 in 10,000 in the general population suffer from this neurodevelopmental disorder. The majority of patients also manifest mental retardation and about 20-45% epilepsy. Multiple exostoses is the commonest form of all skeletal dysplasias, affecting 1 in 50,000 live births. The condition, characterized by cartilaginous protuberances at the ends of the diaphyses, affects the extremities causing skeletal deformities and short stature. Autism and multiple exostoses are considered to be inherited disorders, but the underlying biochemical defects of the disorders are unknown. Both of these conditions allow for survival but considerably diminish the quality of life. An X;8 translocation was identified in a female patient, ML, with autism and multiple exostoses. Her phenotypic manifestations are likely due to the chromosomal abnormality. A positional candidate cloning strategy was used to investigate the genes involved in the translocation. The translocation breakpoint was first isolated in Yeast Artificial Chromosomes (YACs), then in cosmid and plasmid clones. The translocation was reciprocal within a 5'-GGCA-3' sequence found on both X and 8 chromosomes without gain or loss of a single nucleotide. The translocation breakpoint on the X chromosome occurred in the first intron of the gastrin releasing peptide receptor (GRPR) gene and on chromosome 8 approximately 30 kb distal to the 3' end of the Syndecan-2 gene (SDC2), also known as human heparan sulfate proteoglycan or fibroglycan. Although the GRPR gene was shown to escape X-inactivation and the coding region of the SDC2 gene was not disrupted, a dosage effect of the GRPR gene and a position effect of the SDC2 gene may, however, have contributed to the phenotype observed in this patient. The orientation of these genes with respect to the translocation was incompatible with the formation of a fusion gene. The GRPR and SDC2 genes may provide insight into the biochemical nature of autism and multiple exostoses. Investigation of mutations in these two genes in unrelated patients with either autism or multiple exostoses as well as linkage and association studies are needed to validate them as candidate genes.