Genome-wide association studies have indicated that main effects of common polymorphisms or rare variants are unlikely to lead to improved ability to predict disease risk and therapeutic response. Epistasis (gene-gene interaction) and pleiotropy (diverse effects of the same gene) are known to play major roles in the genetic architecture of complex traits in model organisms, but have not yet been explored in human biology. This project aims to overcome this challenge by studying autism traits in congenital disorders of the Ras-MAPK signaling pathway. Ras-MAPK diseases are genetic disorders with known mutations that include effects on craniofacial, cardiac, cutaneous, musculoskeletal and ocular development, as well as carrying increased risk of cancer and varying expression of neurocognitive impairment. Preliminary data show that these disorders are strongly associated with autism and that common polymorphisms in the same genes are associated with idiopathic familial autism. Autism-related traits will be measured in subjects with Ras-MAPK disorders followed by genome-wide mapping for interactors with the known Ras-MAPK genes. Then induced pluripotent stem cell models from fibroblasts of patients with these disorders will be established in order to investigate expression and functional assays utilizing cells differentiated into varying fates. This project could further understanding of how genetic variants mediate disease risk and improve diagnosis, prognosis, prevention and treatment options for autism.