Neuropsychopathological Study of Autism: From Clinical, Neurocognitive, to Genetic Studies and Animal Models

The specific aims of the study aree:

1. To collect complete environmental, developmental, clinical, neuropsychological, and genetic data of 350 probands with autism (800 in total, 450 from [96HD008]) and their families;
2. To re-sequence promoter region, all the exons, and the 3'UTR region of the DLGAP2, CLN8, ARHGEF10, FBXO25, and GABRB3 genes (one gene per year);
3. To conduct fine-mapping and replication studies for selected candidate genes from GWA study[96HD008];
4. To validate social impairment and speech delay as intermediate phenotypes and the executive functions as effective cognitive endophenotypes by first demonstrating the differences in these measures among probands, their unaffected siblings and neurotypicals, followed by different genetic risks (e.g., neurexin, neuroligin, CNTNAP2, SHANK3, MET, PTEN, WNT2, FOXP2, DLGAP2, CLN8, ARHGEF10, FBXO25, and GABRB3);
5. To validate the structural and functional connectivity as effective imaging endophenotypes by demonstrating the differences between probands with autism, their siblings, and matched neurotypicals; and
6. To characterize the phenotypes of and to explore the possible function of other autism-related genes found by using GWAS, and to explore the possible drug targets for the treatment for Dlgap2, Fbxo25, and Arhgef10 mutant mice.

The investigators will recruit 350 probands with clinical diagnosis of autism confirmed by the ADI-R and ADOS, and their families. The probands and their siblings will also be assessed for other psychiatric disorders (K-SADS-E); autistic symptom dimensions (SRS, SCQ, CAST, ABC), other behavioral symptoms (CBCL, SNAP-IV), and perinatal/environmental risk factors. The direct tests include intelligence (CPM/SPM, WISC-III, WPPSI-R) and neuropsychological tests (CPT, WCST, CANTAB). The parents will be assessed for DSM-IV psychiatric disorders (ASRI-4) and autistic features (AQ, SRS). The investigators will collect blood samples from all the subjects. Probands with previous CNVs findings (n = 20) and high-functioning autism (n=30) will receive the MRI assessments (Diffusion Spectrum Imaging, resting-state fMRI) as compared to 50 age-, sex-, and handedness-matched neurotypicals.

The investigators will (1) characterize the behavioral, structural, electrophysiological and biochemical phenotypes of Dlgap2, and Arhgef10 mice at 4 weeks, 8 weeks, 12 weeks and 16 weeks of ages; (2) explore the possible function of other autism-related genes found by GWAS analysis; and (3) explore the possible drug targets for the treatment of autism from KO mice. While the potential target is recognized, existing compounds of this target can be tested.

The investigators anticipate to establishing a representative cohort of 800 patients with autism and their families from this study and [96HD008] with comprehensive clinical and genetic data. This well-characterized cohort will contribute to validation of intermediate phenotypes and cognitive and imaging endophenotypes for autism in this study, and will be used to search for rare variants by CNVs analysis and common variants by GWAS analysis in future study, and will pave the way to have 2-3 lines of well-characterized transgenic animal models of autism (e.g., Dlgap2). In addition, a wealth of data from this cohort will benefit to current and future investigation on autism and will be the basis for future international collaboration. The investigators also anticipated to publication of 20 SCI papers (4 per year) and presentation of our work in peer-reviewed scientific conferences by more than 40 posters or oral communications.