SYNGAP1 – SYNGAP1-related Developmental and Epileptic Encephalopathy

SYNGAP1 encodes a neuron-specific Ras GTPase-activating protein localized at excitatory synapses. Heterozygous loss-of-function variants in SYNGAP1 cause SYNGAP1-related developmental and epileptic encephalopathy, characterized by global developmental delay, intellectual disability, and early-onset, often pharmacoresistant seizures.

Inheritance is autosomal dominant, with most pathogenic alleles arising de novo. A 9-year-old male presented with developmental delay, intellectual disability, behavioral issues, and eyelid myoclonia-associated epilepsy refractory to multiple antiseizure medications; genetic testing identified the de novo frameshift variant c.1267del (p.Tyr423MetfsTer17) (PMID:39611106). Literature review reveals over 75 unrelated patients harboring de novo truncating or missense variants, including recurrent hotspot mutations, with complete absence in large control cohorts (PMID:23161826).

Segregation data are limited by the predominance of sporadic cases; only rare instances of parental mosaicism have been reported. Affected relatives are not observed in classical familial inheritance beyond de novo occurrences.

The variant spectrum is dominated by protein-truncating alleles (nonsense, frameshift, canonical splice), with a minority of pathogenic missense changes (e.g., p.Trp362Arg, p.Pro562Leu) proven disruptive in cellular assays (PMID:23161826). Intronic splice-site variants such as c.664-2A>G demonstrate aberrant exon skipping and loss of function via minigene analysis (PMID:37928246).

Mechanistically, SYNGAP1 haploinsufficiency dysregulates Ras-ERK signaling, leading to enhanced basal synaptic transmission and impaired plasticity. Biolistic transfection assays show wild-type but not mutant SYNGAP1 restores activity-dependent ERK phosphorylation (PMID:23161826). In Syngap1+/- mouse models, chronic MEK inhibition normalizes basal synaptic responses in hippocampal slices (PMID:29940508). Knock-in mice carrying human frameshift or cryptic splice variants recapitulate cognitive deficits, hyperactivity, and seizures, confirming dosage sensitivity (PMID:37669379). Alternative-splicing rescue using oligonucleotides elevates SYNGAP1 protein and alleviates LTP and excitability deficits in mouse and human neurons (PMID:36917980).

Collectively, abundant genetic and functional evidence establishes a definitive role for SYNGAP1 haploinsufficiency in developmental and epileptic encephalopathy. Clinical testing for SYNGAP1 variants is recommended in patients with unexplained neurodevelopmental delay and refractory epilepsy. Functional rescue strategies targeting splicing or Ras-MEK-ERK signaling hold promise for personalized therapies.

References

• SAGE Open Medical Case Reports • 2024 • Unveiling a de novo SYNGAP1 variant: Clinical progression and management challenges in a case of developmental and epileptic encephalopathy - A case report. PMID:39611106
• Human Mutation • 2013 • Mutations in SYNGAP1 cause intellectual disability, autism, and a specific form of epilepsy by inducing haploinsufficiency. PMID:23161826
• Pharmacological Reports: PR • 2018 • Chronic treatment with a MEK inhibitor reverses enhanced excitatory field potentials in Syngap1+/- mice. PMID:29940508
• Proceedings of the National Academy of Sciences of the United States of America • 2023 • Mouse models of SYNGAP1-related intellectual disability. PMID:37669379
• Neuron • 2023 • Upregulation of SYNGAP1 expression in mice and human neurons by redirecting alternative splicing. PMID:36917980
• Frontiers in Genetics • 2023 • Identification and functional characterization of de novo variant in the SYNGAP1 gene causing intellectual disability. PMID:37928246

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