# Developmental Synaptopathies Associated with TSC, PTEN and SHANK3 Mutations

> **NIH NIH U54** · BOSTON CHILDREN'S HOSPITAL · 2021 · $1,414,252

## Abstract

Advances in genetics have illustrated that autism spectrum disorder (ASD) and intellectual disability (ID) include
a spectrum of rare disorders, and that mutations in hundreds of genes may result in susceptibility to ASD/ID.
This heterogeneity represents 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 in order to perform mechanistic analysis of three genetic disorders with high
penetrance of ASD/ID, and shed light on molecular pathways and mechanism-based therapeutic targets relevant
to ASD/ID. We propose to continue our focus on three 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) mutations. Specific aims for TSC are: 1) Characterize the phenotype of ASD and ID in a large cohort of
pediatric and adult patients with TSC in a prospective, multi-center longitudinal design; 2) Identify
electrophysiological biomarkers of synaptic function and connectivity associated with ASD and ID in TSC; and
3) Evaluate the suitability of the TAND Checklist as TSC-specific research tool for assessing clinically-meaningful
outcomes in future ASD and ID clinical trials. Specific aims for PHTS are: 1) Determine cross-sectional and
longitudinal neurobehavioral and medical differences between PTEN-ASD and other groups in an expanded age
range; 2) Identify EEG and molecular biomarkers specific to PTEN-ASD and those shared with other groups;
and 3) Validate TAND and develop a comprehensive, multi-level, longitudinal model of PTEN-ASD using data
from Aims 1 and 2 and TAND scores, in order to inform future clinical trials and the development of consensus
care guidelines. Specific aims for PMS are: 1) Comprehensively characterize PMS across the lifespan and track
the natural history; 2) Validate electrophysiological biomarkers of PMS; and 3) Develop a comprehensive clinical
model of PMS to inform assessment and future clinical trials. As detailed in the Resources sections, this
Consortium involves experienced physician-researchers from premier academic institutions with strong
institutional and patient advocacy group support, along with impressive mentors for training of future physician-
researchers and genetic counselors focused on translational research in neurodevelopmental disorders. We will
continue to work closely with the patient advocacy groups to engage and inform the families affect...

## Key facts

- **NIH application ID:** 10242077
- **Project number:** 5U54NS092090-08
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** MUSTAFA SAHIN
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,414,252
- **Award type:** 5
- **Project period:** 2014-09-20 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242077

## Citation

> US National Institutes of Health, RePORTER application 10242077, Developmental Synaptopathies Associated with TSC, PTEN and SHANK3 Mutations (5U54NS092090-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10242077. Licensed CC0.

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