published_or_final_version / Zoology / Doctoral / Doctor of Philosophy

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The present study employed the Rust Inventory of Schizotypal Cognitions (RISC) to identify an experimental group of schizotypics (as well as an appropriate control group). It was hypothesized that these individuals would show patterns on a battery of neuropsychological tests (e.g., Category Test, Tactual Performance Test, and Trails B from the Halstead-Reitan Neuropsychological Battery; Expressive Speech, Memory, and Intellectual Processes Scales from the Luria-Nebraska Neuropsychological Batter; and the Rey Complex Figure Test) similar to those exhibited by actual schizophrenics. Findings indicated that schizotypes do show a pattern of deficits on neuropsychological tests similar to those observed in diagnosed schizophrenics. These results lend validity to the RISC as an instrument for use in selecting those at-risk for schizophrenia. They also illustrate a possible neuropsychological vulnerability marker for schizophrenia. / Department of Psychological Science

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.

Approximately 4% of English-speaking children are affected by Specific Language Impairment (SLI); a disorder in the development of language skills despite adequate opportunity and normal intelligence. Several studies have indicated the importance of genetic factors in SLI; a positive family history confers an increased risk of development, and monozygotic concordance consistently exceeds that of dizygotic twins. However, like many behavioural traits, SLI is assumed to be genetically complex with several loci contributing to the overall risk. This thesis aims to clarify the genetic mechanisms underlying Specific Language Impairment by the exploitation of recent advances in technological, genetic and statistical techniques. This goal is achieved, for the main part, through the completion of the first-ever, systematic genome-wide screen for loci involved in the disorder. A collection of 98 families was drawn from both epidemiological and clinical populations, all with probands who display severe deficits in language skills. Genome-wide linkage analyses were completed for three language-related measures and identified two regions which may harbour susceptibility gene variants for SLI, one on chromosome 16 and a second on chromosome 19. Both of these loci yielded maximum LOD scores of 3.55 and exceeded the threshold for suggestive linkage under all types of analysis performed. Fine mapping of the chromosome 19 locus with a high-density map of microsatellite markers provided further support for the role of this region in SLI but failed to narrow the area of linkage. The second section of the thesis therefore explores alternative genetic strategies that may facilitate the localisation of susceptibility variants from the genomic regions identified. Mutation screening and association analyses were performed for two candidate genes within a subset of 48 families affected by SLI. The first ⎼ numblike (NBL), or numb-related (NUMB-R) (MIM 604018) ⎼ was selected from the region of linkage on chromosome 19q and the second ⎼ Forkhead-bOX domain P2 (FOXP2) (MIM 605317) ⎼ has recently been shown to be mutated in a family with a severe speech and language disorder. Finally, I describe the mapping of a translocation breakpoint within a child affected by a severe language impairment and orofacial dyspraxia. This breakpoint lies on chromosome 2q and coincides with a putative region of linkage in both language impairment and autism. In the long-term it is hoped that techniques similar to those described here will allow the identification of the gene variants which underlie SLI allowing to the development of better diagnosis and treatment for those children with language impairments.