Leveraging predictive models to design high-throughput assays to resolve variants of uncertain significance (VUS) in SYNGAP1

Awardee: Gemma Carvill

Institution: Northwestern University

Grant Amount: $61,222.00

Funding Period: February 1, 2024 - January 31, 2025

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Summary:

SYNGAP1-related disorder is caused by pathogenic (disease-causing) loss of function variants, and while most variants described to date are truncations, there are also at least 50 pathogenic missense variants that have been described. However, missense variants are more likely to be classified as uncertain significance i.e. of unknown impact on protein function, we call these VUS. This is because of the difficulties with predicting whether these variants impact SYNGAP1 function using current tools. Here we will use a computational approach to determine what characteristics of missense variants are more likely to impact SYNGAP1 function. We will then design and test a method/assay based on this characteristic to identify pathogenic missense variants. This method will be able to screen hundreds of missense variants at a time. We will make this data available in an accessible manner to the patient community.

Editing the epigenome: Curing SYNGAP1 heterozygosity

Awardee: Elizabeth Heller

Institution: University of Pennsylvania

Grant Amount: $65,705.00

Funding Period: February 1, 2023 - January 31, 2024

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Summary:

SynGAP1 syndrome occurs when a child is born with only one functional copy of the SynGAP1 gene. One approach to correct and cure this syndrome is to further activate the functional copy of the SynGAP1 gene, in order to compensate for the mutated copy. A major benefit of this approach is that it is independent of the specific mutation on the dysfunctional copy, and therefore can be utilized by all children with SynGAP1 syndrome. In order to develop a therapy that activates the functional copy of the SynGAP1 gene, we will first uncover the cellular mechanisms that govern SynGAP1 gene activation. Next we will develop tools to artificially activate SynGAP1 in the brain. Our goal is to design an intervention that is functional at all stages of development, for all SynGAP1 children.