Identifying Autism Susceptibility Genes

stantial (36%–90%), whereas in dizygotic (DZ) pairs the rate is similar to the rate of autism among siblings of De Crespigny Park London, SE5 8AF affected children. Twin studies also suggest that the genetic predisposition extends to related, but milder, communication and/or social deficits. In the largest study (Bailey et al., 1995), 92% of MZ pairs were concor-Roosevelt Drive Oxford, OX3 7BN dant for a broader spectrum of social/cognitive abnor-malities—the most severely affected cotwins showing United Kingdom ‡ Department of Biology other PDDs; this was in marked contrast to the 10% concordance rate in DZ pairs. A similar range and pat-University of Bologna via Selmi 3 tern of difficulties is observed among a minority of relatives in family studies (Bailey et al., 1998). 40126 Bologna Italy The genetic mechanisms predisposing to autism and related milder phenotypes are not known, but neither the level of familial risk nor the very different concordance rates in MZ and DZ twin pairs is compatible with Introduction a simple monogenic model. It is possible that Mendelian, The current interest in identifying susceptibility loci for monogenic inheritance is implicated in a minority of indi-autism reflects the degree to which molecular genetic viduals, but the majority of cases seem likely to arise findings seem likely to transform our understanding of on the basis of multiple susceptibility genes; otherwise the underlying pathology, improve diagnosis and ge-known as polygenic or oligogenic inheritance. In such netic counseling, and eventually lead to new strategies genetically complex disorders, functional variants in of prevention and treatment for this handicapping dis-susceptibility genes have only a weak or moderate ef-ease. Autism represents the prototypical pervasive defect: they confer an increased risk of developing the velopmental disorder (PDD): a group of neurodevel-disorder but each locus is insufficient alone to cause the opmental conditions characterized by impaired social full clinical phenotype. There may also be heterogeneity interaction and communication, accompanied by un-with susceptibility attributable to several, possibly over-usually restricted and stereotyped patterns of behaviors lapping, sets of interacting genes. Models using family and interests and an onset in the first 3 years of life (for and twin data for autism and related phenotypes have review, see Bailey et al., 1996). The diagnostic features been generated suggesting that between two and ten of autism are outlined in Table 1. The clinical presenta-loci may be implicated (Pickles et al., 1995), a model tion can vary considerably between affected individuals …