CANDIDATE GENE STUDIES IN PATIENTS WITH AUTISM SPECTRUM DISORDER

Autism Spectrum Disorder is a grouping of disorders that range from the diagnosis of Asperger Syndrome to Autistic Disorder (formally known as autism). Attention Deficit Disorders and Pervasive Developmental Disorder-Not Otherwise Specified are also a part of this spectrum of disorders. Autism Spectrum Disorder affects one out of every 110 children and has a male to female ratio of 4:1. This has led to the need to identify genes that may be causative for this disorder. Several genome-wide scans have been conducted and have identified locations in the human genome that may contain causative genes for Autism Spectrum Disorder. One such area was found to be located at chromosome 7q and included the MET gene. Campbell et al. (2006) identified the rs1858830 C variant in the MET gene and a study found it to be associated with ASD. Screening of the rs1858830 C variant in the MET gene was conducted in a unique population comprised of individuals diagnosed with Autistic Disorder and controls. Results indicated that this variant was associated with Autistic Disorder. The high male to female ratio of individuals affected with Autism Spectrum Disorder raises the possibility that genes on the X chromosome may be involved in these disorders. Alterations in NLGN4X , which is involved in neuronal synapse formation and located at Xq22.2, have previously been identified that are associated with Autism Spectrum Disorder. We screened a cohort of individuals diagnosed with Autistic Disorder for any alterations in NLGN4X. We identified two alterations in NLGN4X within this cohort. Further studies were conducted to observe cell morphology after transfection with the altered NLGN4X proteins in PC12 cells, a rat pheochromocytoma cell line. Fluorescence microscopy determined that neuronal cells expressing the two altered forms of NLGN4X had altered cell morphology. Cellular localization studies also identified a difference between the location of the altered NLGN4X proteins within the cell and the location of wild type NLGN4X. To further identify causative genes for Autism Spectrum Disorder, the translocation breakpoint region at chromosome 2q21 of a patient with a chromosomal translocation t(2;16) and autistic like characteristics was partially mapped. The breakpoint at chromosome 2q was narrowed to a region of only 80kb in size and one candidate Autism Spectrum Disorder gene within this region was identified. The understanding and identification of Autism Spectrum Disorder causative genes is very important given the large number of individuals that are affected. The wide range of phenotypes associated with this disorder implies the involvement of many genes that lead to different phenotypes. The studies within this dissertation determined that Autistic Disorder is associated with an alteration in the MET gene, identified two alterations, one being de novo, in NLGN4X that are associated with Autistic Disorder, and provided cellular studies of the NLGN4X alterations in a neuronal cell line. Additionally, this research revealed candidate genes located at chromosome 2q21 that may be associated with Autism Spectrum Disorder