Session 3: Molecular Genetics of Autism
Thomas H. Wassink, M.D.
University of Iowa
The WNT family of genes influences the development of numerous organs and systems, including the central nervous system. WNT2 is located in the region of chromosome 7q31-33 linked to autism and is adjacent to a chromosomal breakpoint in an individual with autism. A mouse knockout of Dvl1, a member of a gene family essential for the function of the WNT pathway, exhibits a behavioral phenotype characterized primarily by diminished social interaction. We, therefore, screened WNT2 as an autism candidate gene. We identified two families containing non-conservative coding sequence variants that segregated with autism in those families. We also identified linkage disequilibrium (LD) between a WNT2 3'UTR SNP and our sample of autism affected sibling pair (ASP) families and trios. The LD arose almost exclusively from a subgroup of our ASP families defined by the presence of severe language abnormalities, and was also found to be associated with the evidence for linkage to 7q from our previously published genome-wide linkage screen. Furthermore, expression analysis demonstrated WNT2 expression in the human thalamus. To follow up these preliminary findings, we have assessed the functional relevance of the WNT2 sequence variants in cell-based transfection assays. We have identified and genotyped more SNPs in and around WNT2 in order to further characterize the LD of WNT2 with autism. We have also screened a number of genes related to WNT function, such as Frizzled-1 and Frizzled-9, as autism candidate genes. No coding sequence changes unique to autism have yet been found in these genes, though a number of polymorphisms useful for testing for LD have been identified.
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