Evidence supporting WNT2 as an autism susceptibility gene

We examined WNT2 as a candidate disease gene for autism for the following r easons. First, the WNT family of genes influences the development of numero us organs and systems, including the central nervous system. Second, WNT2 i s located in the region of chromosome 7q31-33 linked to autism and is adjac ent to a chromosomal breakpoint in an individual with autism. Third, a mous e knockout of Dvl1, a member of a gene family essential for the function of the WNT pathway, exhibits a behavioral phenotype characterized primarily b y diminished social interaction. We screened the WNT2 coding sequence for m utations in a large number of autistic probands and found two families cont aining nonconservative 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) famil ies and trios. The LD arose almost exclusively from a subgroup of our ASP f amilies defined by the presence of severe language abnormalities and was al so found to be associated with the evidence for linkage to 7q from our prev iously published genomewide linkage screen. Furthermore, expression analysi s demonstrated WNT2 expression in the human thalamus, Based on these findin gs, we hypothesize that rare mutations occur in the WNT2 gene that signific antly increase susceptibility to autism even when present in single copies, while a more common WNT2 allele (or alleles) not yet identified may exist that contributes to the disorder to a lesser degree (C) 2001 Wiley-Liss, In c.