This grant will support the Rare Diseases Clinical Research Center (RDCRC), which focuses on three autism-related clinical disorders: Angelman syndrome (AS), Rett syndrome (RTT), and Prader-Willi syndrome (PWS). The near-term potential for meaningful therapy for all 3 of these disorders is strong. The specific aims for AS are: 1) to conduct longitudinal assessments on individuals with Angelman syndrome according to genotype, 2) establish genotype-phenotype correlations based on molecular defect type, and 3) to examine the efficacy of existing therapies including developmental interventions with respect to the genotype-phenotype. The specific aims for Rett syndrome will be: 1) to establish phenotype/genotype correlations over a broad spectrum of Rett phenotypes, 2) to perform longitudinal studies on an extensive population of individuals with Rett, and 3) to extend the survival study on a broad spectrum of Rett individuals. The specific aims for PWS are: 1) to conduct longitudinal studies according to genotype, 2) to perform natural history studies on non-Prader-Willi syndrome individuals with early-onset morbid obesity (EMO) and compare them with Prader-Willi syndrome, and 3) to develop parameters and tool for clinical trials. In addition, a pilot project spanning the three disorders will examine the characteristics and patterns of sleep disorders, well-known accompaniments of each. An extensive training program is also proposed for stimulating the entry of new investigators into clinical research on rare diseases.