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Autism is a heterogeneous syndrome defined by impairments in three core domains: social interaction, language and range of interests. Recent work has led to the identification of several autism susceptibility genes and an increased appreciation of the contribution of de novo and inherited copy number variation. Promising strategies are also being applied to identify common genetic risk variants. Systems biology approaches, including array-based expression profiling, are poised to provide additional insights into this group of disorders, in which heterogeneity, both genetic and phenotypic, is emerging as a dominant theme.Autistic disorder is the most severe end of a group of neurodevelopmental disorders referred to as autism spectrum disorders (ASDs), which share the common feature of dysfunctional reciprocal social interaction. A meta-analysis of ASD prevalence rates suggests that approximately 37 in 10,000 individuals are affected 1 . ASDs encompass several clinically defined conditions (see BOX 1 and the Diagnostic and Statistical Manual of Mental Disorders), pervasive developmental disorder -not otherwise specified and autistic disorder are the most common, whereas Asperger syndrome appears less frequently. Boys are at increased risk for the ASDs, an effect that becomes even more pronounced in so-called high-functioning cases.A chronological overview of research in the ASDs underscores the short history of genetic work in this area as well as the diversity of the methods used. Before the 1970s, autism was not widely appreciated to have a strong biological basis. Instead, various psychodynamic interpretations, including the role of a cold or aloof style of mothering, were invoked as potential causes. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript co-occurrence of chromosomal disorders and rare syndromes with the ASDs were noted 2 . Subsequent twin and family studies provided additional support for a complex genetic aetiology, but these were limited by the lack of uniform diagnostic criteria. The development of validated diagnostic and assessment tools in the early 1990s, most notably the Autism Diagnostic Interview -Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS), addressed these concerns and these tools have proven crucial to the advancement of international research into the ASDs. This work, in concert with important technical advances, made it possible to carry out the first candidate gene association studies and resequencing efforts in the late 1990s. Whole-genome linkage studies followed, and were used to identify additional loci of potential interest. Although the application of genome-wide techniques to assess copy number variation (CNV) has only just begun 3-5 , these studies have already identified a large number of potentially important novel candidate loci.Thus, in contrast to the complete absence of any biological understanding of the ASDs as recently as 30 years ago, we now know that defined mutations, genetic syndromes and de novo CNV acco...

SUMMARY Although many genes predisposing to autism spectrum disorders (ASD) have been identified, the biological mechanism(s) remain unclear. Mouse models based on human disease-causing mutations provide the potential for understanding gene function and novel treatment development. Here we characterize a mouse knockout of the Cntnap2 gene, which is strongly associated with ASD and allied neurodevelopmental disorders. Cntnap2−/− mice show deficits in the three core ASD behavioral domains, as well as hyperactivity and epileptic seizures, as has been reported in humans with CNTNAP2 mutations. Neuropathological and physiological analyses of these mice before the onset of seizures reveal neuronal migration abnormalities, reduced number of interneurons and abnormal neuronal network activity. In addition, treatment with the FDA approved drug risperidone, ameliorates the targeted repetitive behaviors in the mutant mice. These data demonstrate a functional role for CNTNAP2 in brain development and provide a new tool for mechanistic and therapeutic research in ASD.

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