SYNGAP1 – Autosomal Dominant Mental Retardation 5

SYNGAP1 encodes a synaptic Ras GTPase-activating protein localized to the postsynaptic density of excitatory neurons. Heterozygous loss-of-function variants in SYNGAP1 cause Autosomal Dominant Mental Retardation 5, manifesting as global intellectual disability (ID), autism spectrum disorder (ASD), and often epilepsy (PMID:23161826). The phenotype is fully penetrant with consistent developmental delay and variable behavioral features.

Genetic evidence is robust and consistent with an autosomal dominant, de novo mechanism. Initial studies reported six de novo truncating and two deleterious missense variants in eight unrelated probands (PMID:23161826). Large-scale sequencing in 95 sporadic nonsyndromic ID cases revealed 11 de novo potentially deleterious variants, including nonsense, frameshift, and splice-site changes (PMID:21376300). Single-patient case series have since added over ten independent de novo cases (PMID:29381230, PMID:37467311), bringing the total to >50 LoF alleles across populations. Segregation analyses show de novo occurrence in nearly all cases, with one mosaic transmission event (PMID:23161826). Representative variant: c.283dup (p.His95ProfsTer5).

Functional assays demonstrate a haploinsufficiency mechanism. Wild-type SYNGAP1 reduces activity-dependent phosphorylated ERK levels in cortical organotypic cultures, whereas missense mutants (p.Trp362Arg, p.Pro562Leu) and truncating alleles fail to do so, indicating loss of function (PMID:23161826). Clinical transcriptome sequencing confirmed cryptic splice-site activation for intronic variants, resulting in frameshifts and premature stops (PMID:30800045). In vitro studies further show decreased protein stability and altered Ras/ERK signaling for multiple patient-derived variants.

Animal models recapitulate key human phenotypes. Syngap1+/- mice exhibit elevated basal synaptic responses, impaired long-term potentiation, hyperactivity, and seizure susceptibility. Chronic MEK inhibition with PD-0325901 normalizes basal transmission but not LTP (PMID:29940508). CRISPR-Cas9 knock-in mice carrying a frameshift (L813RfsTer22) or cryptic splice acceptor variant (c.3583-9G>A) show ~50% reduction in Syngap1 protein and deficits in synaptic plasticity and working memory (PMID:37669379). Splice-switching oligonucleotides reprogram unproductive A3SS-NMD isoforms to functional transcripts and alleviate synaptic deficits in mouse and human neurons (PMID:36917980).

No strong conflicting evidence has been reported to dispute the SYNGAP1–MRD5 association. All genetic and experimental data are concordant across independent cohorts and model systems.

Collectively, the breadth of de novo LoF variants, consistent segregation, and concordant functional and animal model data over >10 years establish SYNGAP1 as a definitive gene for MRD5 via haploinsufficiency. Genetic testing of SYNGAP1 is critical for accurate diagnosis, prognosis, and guiding therapeutic development.

References

• American journal of human genetics • 2011 • Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability. PMID:21376300
• Human mutation • 2013 • Mutations in SYNGAP1 cause intellectual disability, autism, and a specific form of epilepsy by inducing haploinsufficiency. PMID:23161826
• Congenital anomalies • 2018 • Novel SYNGAP1 variant in a patient with intellectual disability and distinctive dysmorphisms. PMID:29381230
• Laboratory medicine • 2024 • Molecular and phenotypical findings of a novel de novo SYNGAP1 gene variant in an 11-year-old Iranian boy with intellectual disability. PMID:37467311
• 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

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