Autistic Disorder (AD) is a neurodevelopmental abnormality characterized by significant disturbances in social, communicative, and behavioral functioning. Epidemiologic data has implicated a strong genetic component in AD. Recently, The International Molecular Genetic Study of Autism Consortium reported the results of their genomic screen. Significant results were obtained for markers in the region 7q31-35, with a peak maximum lod score (MLS) of 3.55. Sibpair analysis of our AD data set with markers spanning this region resulted in 5 markers with evidence for linkage (p is greater than or equal to 0.05). Our most significant result was for D7S2527 (p=0.002). Additional support in our data comes from a multiplex AD family (Duke 7543) with a cytogenetic abnormality (Inv (7) (q22q31.2) overlapping the region of potential linkage. Finally, preliminary data suggests an increased recombination rate in this region in AD families when compared to non-AD families. Thus, we hypothesize that there is a gene for AD located in this region. We also hypothesize that AD will be marked y abnormalities in the expression of this gene and/or the association of specific mutations or haplotypes. We propose developing markers from genomic contigs to genetically fine map the D locus within 7q31-35 using our AD families. Our mapping studies will include both linkage and association studies using the Transmission Disequilibrium Test (TDT). Furthermore, we will define the inversion breakpoint in family 7543 and analyze this area for abnormalities. We will use estimated identity by descent (IBD) sharing from markers in the breakpoint region to identify those families that most likely segregate a chromosome 7 susceptibility gene. These families will be thoroughly examined for methylation and cytogenetic abnormalities. AD candidate genes will be isolated, physically mapped, sequenced, directly examined for mutations and genotyped. Candidate gene transcription and expression will be quantitated in AD and control tissues. Using this multi-pronged approach will allow us to ultimately identify the chromosome 7AD gene, representing a substantial step in solving the complex riddle of AD.
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