Developmental Synaptopathies Associated with TSC, PTEN, SHANK3 and SynGAP1 Pathogenic Variants

Boston Children'S Hospital, Boston MA

Investigators

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Abstract

Advances in genetics have illustrated that many neurodevelopmental disorders such as autism spectrum disorder (ASD) and intellectual disability (ID) include a spectrum of rare disorders, and that pathogenic variants in hundreds of genes may result in susceptibility to ASD/ID. This heterogeneity presents significant challenges, but at the same time unique opportunities for research in the field of ASD/ID. Many of the genes implicated in ASD/ID appear to converge on a few common pathways, suggesting that there may be a common dysfunction at the cellular or systems level. Deeper understanding of the shared pathophysiology of these diseases may serve as gateways for understanding mechanisms of other causes of ASD/ID and for shared treatment possibilities. The Developmental Synaptopathies Consortium (DSC) was formed and funded in 2014 to perform mechanistic analysis of three genetic disorders with high penetrance of ASD/ID and investigate molecular pathways and mechanism-based therapeutic targets relevant to ASD/ID. We propose to continue our focus on genetic syndromes with abnormal synapse structure or function and that are associated with high penetrance for ASD/ID: TSC1/2 (Tuberous Sclerosis Complex or TSC), PTEN (PTEN Hamartoma Tumor Syndrome or PHTS) and SHANK3 (Phelan McDermid Syndrome or PMS) pathogenic variants. Over the last ten years, DSC has developed potential biomarkers and clinical outcome assessments for clinical trials, initiated clinical treatment trials in TSC and PHTS, developed longitudinal natural history data used to achieve FDA-approval for a first-in-human gene therapy trial for PMS, created consensus guidelines for the assessment and treatment of these conditions and trained and mentored several junior investigators who are now taking leadership positions in the field. Here we will add another genetic condition, SYNGAP1-related intellectual disability (SYNGAP1-ID), to test the generalizability of our approach and infrastructure. In the next grant cycle, DSC proposes four specific aims: (1) comprehensively characterize the phenotypes of individuals with these rare diseases across the lifespan, including cognition, communication, sleep, sensory deficits and neuropsychiatric symptoms while developing neurophysiological biomarkers to accelerate clinical trial readiness; (2) support pilot projects using strategic priorities of each disorder in collaboration with the patient advocacy groups; (3) continue to cultivate a pipeline of highly skilled new investigators within a collaborative and translational framework, emphasizing clinical trialist training and community engagement; (4) build on our current Administrative Core by expanding the leadership structure, continuing successful oversight of the activities of the DSC, disseminate DSC information to physicians, researchers, patient families and the lay public and planning future sustainability of this Consortium beyond RDCRN funding.