Developmental Synaptopathies Associated with TSC, PTEN &SHANK3 Mutations
Autism spectrum disorder and intellectual disability (ASD/ID) are severeneurodevelopmental conditions with early childhood onset. ASD symptoms, first described over sixtyyears ago, persist throughout life and produce significant impairments in social, communicative,cognitive and behavioral functioning. ASD/ID is a major public health problem that disrupts families andleads to significant disability, resulting in a total annual societal cost of caring for and treating ASD/IDindividuals over their lifetimes of ~$35-50 billion. The long-range goal of this RDCRC Program ismechanistic analysis of three genetic disorders with high penetrance of ASD/ID to shed light onmolecular pathways and therapeutic targets relevant to ASD/ID. The disorders are Tuberous SclerosisComplex (TSC1 and TSC2 genes), PTEN ASD/ID syndrome and Phelan-McDermid syndrome (PMS;SHANK3 gene). The short-term goal is to better characterize the neurodevelopmental phenotype ofthese three groups of patients longitudinally and to identify biomarkers that predict risk for diseaseseverity and response to treatment. These biomarkers may also provide a way to subcategorize thepatients with ASD/ID based on their similarity to well-characterized behavioral syndromes associatedwith TSC1/2, PTEN and SHANK3 loss. By focusing not on a single gene, but on a comparative analysisof multiple genes across a converging pathway, this RDCRC Program represents a crucial step forwardin the treatment of ASD/ID. In addition, the knowledge and infrastructure established by the currentproposal, especially collaborative interdisciplinary training in genetics and neurodevelopment, willultimately allow further study of the efficacy of pathway-specific, mechanism-based therapies in thesegenetic subsets of ASD/ID and ultimately in “idiopathic” ASD/ID.