A major goal of human genetics is to identify and discern how genetic variation contributes to variation in human disease risk. Human geneticists have made remarkable progress identifying disease gene variants with large phenotypic effects, but finding the genetic causes of common, complex disorders like autism, has proven more difficult. While family-based linkage studies have identified regions of the genome harboring putative autism susceptibility alleles, the apparent great genetic heterogeneity of the disorder has prevented the identification of disease causing variants.
We aim to reduce this heterogeneity by performing high-throughput, highly accurate microarray-based resequencing of 2 270kb X chromosomes regions among 314 male affected sibpairs from the Autism Genetic Resource Exchange (ACRE) sample collection. The first region contains the FMR1 gene. Fragile X syndrome is caused by a trinucleotide repeat sequence at FMR1 and approximately 20% of patients with this disorder exhibit symptoms consistent with the DSM IV diagnosis of autism. Our goal is to identify others mutations leading to a diagnosis of autism. The second region contains candidate genes in the vicinity of marker DXS1047 that shows suggestive linkage in the AGRE sample. Rare alleles will be confirmed within pedigrees while common alleles will be genotyped across the entire AGRE sample collection. Rapid resequencing can identify disease gene variants, reduce heterogeneity in mapping studies, and provide insight into autism enabling a greater concordance between the patient genotype and autism phenotype. We believe that the approach we propose will eventually be required to dissect human genomic regions harboring susceptibility alleles to common complex diseases like autism, whether these regions are discovered through family-based linkage studies or whole genome association studies in a case-control design. The genetic causes of autism, a common pervasive developmental disorder (FDD), remain largely undiscovered. We propose using DMA chips to resequence genes that may harbor mutations that cause autism. Identifying the genetic basis of autism could enable more rapid diagnostic testing and provide insight into the root causes and eventually pave the way for better treatments of this increasingly common disorder.
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