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SYNGAP1 encodes a synaptic Ras/Rap GTPase-activating protein critical for excitatory synapse development. Heterozygous loss-of-function (LoF) or damaging missense variants lead to haploinsufficiency and an autosomal dominant neurodevelopmental disorder characterized by intellectual disability, autism, and a specific form of generalized epilepsy, including myoclonic-astatic seizures. Mouse models and cellular assays corroborate that reduction of SYNGAP1 disrupts synaptic plasticity and promotes hyperexcitability, mirroring the human seizure phenotype.
Multiple cohort studies have identified de novo SYNGAP1 variants in patients with myoclonic-astatic epilepsy (MAE) and related early childhood-onset generalized epilepsies. Four probands harbored pathogenic SYNGAP1 variants in a 61-patient series of early generalized epilepsies ([PMID:31401500]), and three additional LoF or damaging missense variants were found among 85 MAE patients ([PMID:32469098]). No familial segregation beyond these sporadic de novo events has been reported. Based on seven unrelated probands with concordant phenotypes and functional concordance, we assign a ClinGen clinical validity of Moderate.
Inheritance is autosomal dominant via haploinsufficiency. In total, seven unrelated patients with MAE or overlapping generalized epilepsy syndromes harbor de novo LoF (nonsense, frameshift, splice) or damaging missense variants. A representative variant is c.1685C>T (p.Pro562Leu) ([PMID:23161826]), shown to abrogate SYNGAP1 function in cortical neuron assays. No recurrent population-specific or founder alleles have been described. Reported variants cluster in the GTPase-activating domain and C-terminal region, consistent with disruption of key synaptic regulatory motifs.
SYNGAP1 haploinsufficiency perturbs Ras/MAPK signaling and synaptic homeostasis. Biolistic transfection assays in organotypic cultures demonstrate that LoF and p.Pro562Leu constructs fail to suppress activity-dependent pERK accumulation, unlike wild-type ([PMID:23161826]). Chronic MEK inhibition with PD-0325901 normalizes basal synaptic transmission in Syngap1+/- hippocampal slices ([PMID:29940508]). Knock-in mouse models carrying patient-derived frameshift (L813RfsTer22) or cryptic splice (c.3583-9G>A) variants exhibit ~50% SYNGAP1 reduction, deficits in LTP, hyperactivity, impaired working memory, and spontaneous seizures ([PMID:37669379]). These studies provide Moderate functional evidence of pathogenicity.
Collectively, data support haploinsufficiency as the primary mechanism. No studies have refuted the association of SYNGAP1 LoF with MAE; alternative phenotypes (autism, intellectual disability) overlap but do not contradict seizure association.
Genetic screening of SYNGAP1 should be included in diagnostic panels for MAE and early childhood-onset generalized epilepsies. Functional data suggest potential for targeted modulation of Ras/MAPK pathways in therapeutic development. Additional large-scale segregation studies would strengthen evidence but currently exceed available cohort sizes.
Key Take-home: De novo SYNGAP1 haploinsufficiency is a moderate-evidence cause of myoclonic-astatic epilepsy with actionable implications for diagnosis and pathway-directed research.
Gene–Disease AssociationModerateSeven probands with de novo LoF or missense variants in SYNGAP1 across two independent cohorts Genetic EvidenceModerateSeven probands with de novo variants (4 in early childhood-onset generalized epilepsy; 3 in MAE) Functional EvidenceModerateHeterozygous Syngap1 knockout and knock-in mice recapitulate seizures and cognitive deficits; rescue by MEK inhibition and functional assays concordant |