Autism is influenced by complex, yet strong genetic factors. The strongest evidence for genetic factors comes from twin studies that show a high concordance for autism in monozygotic twins and relatively small concordance in dizygotic twins. The strong decrease in risk from monozygotic twins to dizygotic twins and siblings suggests that two or more genes interact to contribute to autism susceptibility. Statistical modeling of the genetics of autism suggests that two to five susceptibility genes are acting in concert. The recurrence risk for siblings (4.5%) is 45-90 times greater than the population risk (0.05-0.1%), providing further evidence for a complex and strong genetic contribution. In addition to an increased risk of autism for relatives, relatives have been found to have an increased frequency of lesser variants of autism including social, language, and cognitive difficulties. Autism has been associated with several single gene disorders, particularly tuberous sclerosis. Several chromosomal abnormalities have been identified in autism, including the fragile X syndrome, Down's syndrome, and Turner's syndrome. More recently, duplications of the Prader-Willi/Angelman syndrome region of proximal 15q have been reported in patients with autism. The parent of origin of such proximal 15q duplications may influence the risk for autism. Because of the similarity of the phenotype of 15q11-13 duplications in typical autism, linkage analysis has been conducted in autism, and linkage and linkage disequilibrium have been reported for markers on 15q11-13. Several genome-wide screens are under way, with the first full report suggesting a potential susceptibility locus on 7q. Heterogeneity and the multiplicative nature of autism susceptibility genes increase the number of families needed to demonstrate and replicate linkage. Conversely, when susceptibility genes are identified, there will be several potential targets for conventional pharmacotherapy, which often modifies gene expression, as well as direct gene therapy.
1998 Wiley-Liss, Inc.