SYNGAP1 Syndrome and the Brain Gene Registry

Abstract

Background: The human brain relies on complex synaptic communication regulated by key genes such as SYNGAP1. SYNGAP1 encodes the GTPase-Activating Protein (SYNGAP), a critical synaptic plasticity and neuronal excitability regulator. Impaired SYNGAP1 function leads to neurodevelopmental disorders (NDDs) characterized by intellectual disability (ID), epilepsy, and behavioral abnormalities. These variants disrupt Ras signaling, altering AMPA receptor transport and synaptic plasticity and contributing to cognitive and motor difficulties. Despite advancements, challenges remain in defining genotype-phenotype correlations and distinguishing SYNGAP1-related disorders from other NDDs, which could improve underdiagnosis and misdiagnosis. Brain Gene Registry: The Brain Gene Registry (BGR) was established as a collaborative initiative, consolidating genomic and phenotypic data across multiple research centers. This database allows for extensive analyses, facilitating improved diagnostic accuracy, earlier interventions, and targeted therapeutic strategies. The BGR enhances our understanding of rare genetic conditions and is critical for advancing research on SYNGAP1-related disorders.

Conclusions: While no FDA-approved treatments exist for SYNGAP1-related disorders, several therapeutic approaches are being investigated. These include taurine supplementation, ketogenic diets, and molecular strategies such as antisense oligonucleotide therapy to restore SYNGAP1 expression. Behavioral and rehabilitative interventions remain key for managing developmental and cognitive symptoms. Advancing research through initiatives like the BGR is crucial for refining genotype-phenotype associations and developing precision medicine approaches. A comprehensive understanding of SYNGAP1-related disorders will improve clinical outcomes and patient care, underscoring the need for continued interdisciplinary collaboration in neurodevelopmental genetics.

Keywords: SYNGAP1; brain gene registry; intellectual disability; neurodevelopmental disorder.

Figure 1

Schematic of synaptic signaling regulation pathway, linking CaMKII activity to phosphorylation of SYNGAP1 and its regulation of downstream effects [1]. SYNGAP1 heterozygotes (symbolized as #) are unable to effectively inhibit Ras activation, resulting in increased AMPAR exocytosis to the post-synaptic membrane [1]. It is unclear how Syngap1 (pSYNGAP1) regulates Cdc42 and Rac1, as represented by the dotted orange lines [1]. Image from Jeyabalan & Clement (2016) [1].

Figure 2

Structure and workflow of the Brain Gene Registry (BGR) and comparison of data completeness between the BGR and ClinVar, showing the proportion of unique variants captured by the BGR versus ClinVar [9]. The information collected by the RNAP is listed under “#RNAP Domains”, and the information included in the EHR is listed under “*EHR Domains”. EHR, electronic health record; LP/P, likely pathogenic/pathogenic; NDD, neurodevelopmental disorder; RNAP, rapid neurobehavioral assessment protocol; VUS, variant of uncertain significance [9]. Image from Chopra et al. (2024) [9].