Clinical trial readiness for targeting neuropsychiatric manifestations in SHANK3 and SYNGAP1 pathogenic variants

Boston Children'S Hospital, Boston MA

Investigators

Linked publications & trials

Abstract

Increased use of genome-wide arrays and sequencing efforts have identified several single gene causes of autism spectrum disorder (ASD) and intellectual disability (ID), including SHANK3, known as Phelan- McDermid syndrome (PMS), and SYNGAP1-related intellectual disability (SYNGAP1-ID). Disruptions in SHANK3 and SYNGAP1 pathways are also common to multiple monogenic forms of ID and ASD, such as tuberous sclerosis complex (TSC), and PTEN Hamartoma Tumor Syndrome (PHTS). Importantly, this convergence may inform subgroups amenable to treatment with similar compounds. Following a translational approach using model systems, specific deficits in synaptic function and plasticity have been documented in PMS and SYNGAP1-ID and provide potential targets for intervention. The proposed project represents a unique effort between clinical and basic science resources at seven geographically distributed sites with recognized expertise in PMS, SYNGAP1-ID, and ASD/ID. This project is undertaken in the context of a broader program using a mechanistic approach to four rare genetic disorders with high penetrance of ASD/ID and aims to shed light on molecular pathways and targets relevant to ASD/ID: TSC, PHTS, SYNGAP1-ID, and PMS. The current proposal seeks to extend our multi-site infrastructure to characterize an additional 250 patients across the lifespan. The goal is to characterize the neurobehavioral phenotype of these four groups of patients longitudinally and to identify biomarkers. The use of neurophysiological measures to study genetically defined subtypes of ASD/ID is a novel approach with promising preliminary data. Combining EEG paradigms across sensory domains and with associated clinical measures, including sleep, in a genetic cause of ASD/ID will allow us to determine the relationship between neurophysiological biomarkers and clinical outcomes in PMS and SYNGAP1-ID, and to identify the most sensitive and reliable measures of neurophysiology and target symptoms for clinical trials. Our results will be critical to advance treatments and establish target engagement and sensitivity to clinical improvement in trials. Specific aims are to: 1) comprehensively characterize the phenotype and natural history of PMS and SYNGAP1-ID using a broad assessment battery with a focus on communication, sensory reactivity, and sleep; 2) identify biomarkers using electrophysiology; 3) develop a comprehensive understanding of neuropsychiatric symptom profiles to inform future clinical trials. At the conclusion of this project, we expect to fully characterize the neurobehavioral phenotype and to track the natural history of PMS and SYNGAP1-ID. Knowledge gained from this project will identify key electrophysiological biomarkers and assessment practices to provide a foundation for therapeutics development. Because the SHANK3 and SYNGAP1 pathways are highly relevant to other forms of ASD/ID, knowledge gained from the proposed research will also improve our understanding of the neurobiology of ASD/ID and may aid in developing treatments of these conditions more broadly.