PROJECT SUMMARY Recent work suggests that up to 2% of individuals with autism spectrum disorder (ASD) and intellectual disability (ID) have deletions or point mutations in the SHANK3 gene, resulting in Phelan-McDermid syndrome (PMS), and approximately 85% of people with PMS meet criteria for ASD. SHANK3 codes for a master scaffolding protein that forms a key framework in the postsynaptic density of glutamatergic (excitatory) synapses and plays a critical role in synaptic function. SHANK3 and glutamate pathways are implicated in multiple forms of ASD and this convergence implies shared biochemical pathways with potentially overlapping therapeutic targets. Thus, targeting SHANK3 deficiency in PMS as a specific genetic cause of ASD allows us to inform treatment in broader idiopathic ASD (iASD). Our ongoing studies provide in-depth phenotyping of PMS, pointing toward a specific clinical and electrophysiological (EEG) profile. However, the efficacy of potential EEG biomarkers as a measure of treatment response remains to be determined. Preliminary data using visual evoked potentials (VEPs) to examine cortical excitatory postsynaptic potentials demonstrate promising links to disease mechanisms in PMS and iASD. Biomarkers and novel clinical measures for evaluating response to intervention have also been piloted successfully at our site in cohorts of patients with PMS and iASD. We have identified a unique VEP profile of excitatory deficits in PMS (markedly reduced P60-N75 amplitude) that is also present in a subset of children with iASD. Here, we propose to extend this work to a larger sample in PMS and to parallel excitatory processes in the auditory domain, in order to stratify individuals with iASD and select those we predict will show response to IGF-1. We will enroll 150 children (60 PMS; 90 iASD; age 5-12 years), specifically recruiting intellectually disabled and minimally verbal children given the prominence of this profile in PMS and the critical need to address this group in broader ASD research. Our short-term goal is to show that select electrophysiological markers in PMS are relevant to iASD and predictive of treatment response. Our long-term goal is to optimize treatment selection in iASD by establishing biological signature(s) derived from PMS that are: a) useful for predicting treatment responders, and b) responsive to intervention. The expected outcome of this study is to establish the feasibility of electrophysiological biomarkers for use in clinical trials in PMS and iASD and to define a biological profile that will mark a subset of patients with iASD likely to show neural and clinical response to IGF-1.

PROJECT NARRATIVE This research is relevant to public health and to the NIH mission because the proposed study will take a genetics-first approach to personalized medicine by establishing electrophysiological biomarkers of Phelan-McDermid syndrome (PMS), a single gene form of autism spectrum disorder (ASD). The project will use these biomarkers to identify an overlapping subset of children with idiopathic ASD and evaluate the feasibility of our biomarkers in a clinical trial with Insulin-Like Growth Factor-1 (IGF-1). Upon successful completion of the proposed research, we expect to clarify an underlying neural mechanism in PMS common to subsets of iASD and to validate methods to predict treatment response for future clinical trials.