SYNGAP1: The Gene and Syndrome

SYNGAP1 is a RAS-GTPase Activating Protein (GAP) that is a major risk gene for nonsyndromic intellectual disability, autism spectrum disorder, and epileptic encephalopathy. Unlike other RASopathies, SYNGAP1 is not associated with the typical cardiac, skin, or craniofacial features. Although pathogenic variants in SYNGAP1 are rare, they are a common cause of neurodevelopmental disabilities due to the gene’s intolerance to loss of function mutations. SYNGAP1 exists in multiple isoforms and has differential patterns of expression and subcellular localization. The isoforms are expressed at various levels throughout the lifespan, regulate neuronal development, synaptic plasticity, and independently regulate the maturation of excitatory neurons. It is posited that isoform-specific regulation of the small GTPases may account for the pleiotropy seen in SYNGAP1-related disorders.