Autistic Spectrum Disorders (ASD) are characterized by delay in or absence of language acquisition, deficits in social interactions and repetitive behaviors. ASD are largely genetic in origin, and occur either sporadically (simplex) or in a familial (multiplex) pattern, are far more commonly in males (4:1 ratio over females), and have an overall incidence of ~1 in 150 births. Identification of genes responsible for ASD has been complicated by many factors, such as the small number of autistic pedigrees-which may reflect the sporadic incidence-as well as the lack of consistent clinical data among existing samples, particularly with respect to the less severe (and more phenotypically heterogeneous) portion of the autistic spectrum. This project is intended to address the genetic basis of ASD through a high-throughput, candidate-gene sequencing approach. The proposed approach is designed to complement existing comparative genomic hybridization (CGH) analyses. The combination of identifying novel ASD candidate genes through the ongoing CGH study and detailing the mutational spectra of 100 known/predicted and novel ASD candidate genes through this work will reveal a major fraction of the genetic variation underlying ASD. For these experiments, the Simons Simplex Collection (SSC) will be utilized as the sample population. The SSC is the largest high- quality set of ASD families assembled so far, and it is specifically designed to compensate for the shortcomings of existing ASD family populations by ensuring comprehensive and consistent clinical analyses. More importantly, it is a collection of simplex families, and as a result the proportion of cases of autism due to spontaneous mutation-as opposed to inheritance-is maximized. A likely outcome of this work will be significant advances in molecular screening of ASD among young children. This impact would be felt in many ways: more precise diagnosis with respect to clinical subtypes of ASD;assessment of ASD severity based on genetic markers;and treatment more specifically tailored to the needs of affected individuals. Given the heterogeneity of ASD and current lack of markers, this study stands to provide significant progress in deconvoluting the complex phenotypes associated with autism. This work will also provide new avenues for future studies, from new mouse models to elucidation of genetic pathways required for language acquisition, social interactions and behavior.
This study will yield significant insight into the molecular basis of autistic spectrum disorders, which are largely genetic in origin, highly prevalent among all populations, and difficult to diagnose and classify. This work will lead to advances in molecular screening of ASD among young children, which will in turn result in improved diagnoses and more precisely targeted treatment regimes.
| Iossifov, Ivan; Ronemus, Michael; Levy, Dan et al. (2012) De novo gene disruptions in children on the autistic spectrum. Neuron 74:285-99 |
