The goal of this application is to initiate genetic studies of a cohort of well characterized autistic patients already enrolled in a program project, titled """"""""Orbitofrontal-limbic dysfunction in autism"""""""". Autism is a neurodevelopmental disorder with considerable heterogeneity among affected children. This heterogeneity is due, to a large extent, to many known and unknown genetic factors. Therefore the neurobehavioral development and dysfunction in autism must be understood within a genetic context. Consequently this application will focus on recalling autistic patients and their families so a thorough medical genetics evaluation can be performed. Medical histories and physical examinations will enable the diagnosis of known and novel genetic syndromes. Specifically the frequency of macrocephaly, a physical finding associated with autism, will be assessed and correlated with cognitive functioning and genetic testing. Routine genetic studies will be performed, including G-banded karyotypes at the 550-600 band resolution, fragile X syndrome molecular testing, and plasma amino and urine organic acid analyses. Array Comparative Genomic Hybridization (CGH) will be performed on all mentally retarded and/or dysmorphic patients to screen for subtle, unrecognized genomic deletions or duplications. Metabolic studies will include the novel assessment of creatine metabolism. To further genetic studies, lymphoblastoid cell lines from patients and DNA from patients and parents will be banked. Patient DNA will be used to screen for novel mutations in the tuberous sclerosis complex genes TSC1 and TSC2. The specific role of these genes in autism is still unclear. Results from these studies will further delineate autistic phenotypes, allow the correlation of specific genetic lesions with data from other aspects of the program project, and provide a foundation for larger genetic studies of autism.
