Several studies have found rare variants in the SYNGAP1 gene to be associated with autism as well as intellectual disability and epilepsy (PMIDs 19196676, 20531469, 21237447, 23020937). Multiple LoF variants (either predicted in silico or demonstrated experimentally) in SYNGAP1 have been identified in patients with ASD and intellectual disability with or without epilepsy (PMIDs 23020937, 23161826, 23708187, 26989088, 27525107, 28554332, 28708303). De novo LoF variants in SYNGAP1 has also been identified in a simplex ASD case from the Simons Simplex Collection (PMID 24267886) and in ASD probands from the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified SYNGAP1 as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Additional de novo LoF variants in SYNGAP1 were identified in an ASD proband from a cohort of 200 Canadian ASD trio families in PMID 27525107 and in an ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in PMID 27824329. A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified SYNGAP1 as a gene reaching exome-wide significance (P < 2.5E-06).
Molecular Function
A major component of the postsynaptic density (PSD)associated with NMDA receptors
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
De novo SYNGAP1 mutations in nonsyndromic intellectual disability and autism.
Learning and reaction times in mouse touchscreen tests are differentially impacted by mutations in genes encoding postsynaptic interacting proteins SYNGAP1, NLGN3, DLGAP1, DLGAP2 and SHANK2
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Deletion of first common methionine along with adjacent exon encoding portion of C2 domain.
Allele Type: Targeted (Knock Out)
Strain of Origin: Not specified
Genetic Background: C57BL/6
ES Cell Line: Not specified
Mutant ES Cell Line: Not Specified
Model Source: Not Specified
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Targeted knock-out of Syngap1 gene.
Allele Type: Targeted (Knock Out)
Strain of Origin: Not Specified
Genetic Background: C57BL/6
ES Cell Line: Not Specified
Mutant ES Cell Line: Not Specified
Model Source: Not Specified
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Deletion of first common methionine along with adjacent exon encoding portion of C2 domain.
Allele Type: Targeted (Knock Out)
Strain of Origin: Not specified
Genetic Background: 129sv/ev x c57/B6J
ES Cell Line: Not specified
Mutant ES Cell Line: Not Specified
Model Source: Not Specified
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Deletion of first common methionine along with adjacent exon encoding portion of C2 domain.
Allele Type: Targeted (Knock Out)
Strain of Origin: Not specified
Genetic Background: 129sv/ev x c57/B6J
ES Cell Line: Not specified
Mutant ES Cell Line: Not Specified
Model Source: Not Specified
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Conditional deletion of exons 4 - 9 of the Syngap1 gene, which encode the PH, C2, and GAP domains, with intrahippocampal microinjections of AAV- Cre at 8-10 weeks of age
Allele Type: Conditional loss-of-function
Strain of Origin: Not specified
Genetic Background: C57BL/6
ES Cell Line: Not specified
Mutant ES Cell Line: Not Specified
Model Source: Not Specified
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Conditional heterozygous deletion of exons 5-6 of the Syngap1 gene, temporally using unilateral injection of AAV8-cre into the hippocampus of neonate floxed mice (het)
Allele Type: Conditional loss-of-function
Strain of Origin: 129S2/SvPas
Genetic Background: 129S2/SvPas * 129S6/SvEvTac* C57Vl/6* C57Bl/6 NCr
ES Cell Line: Not Reported
Mutant ES Cell Line: Not Reported
Model Source: Not Reported
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Conditional heterozygous deletion of exons 5-6 of the Syngap1 gene, temporally using unilateral injection of AAV8-cre into the hippocampus of adult floxed mice (het)
Allele Type: Conditional loss-of-function
Strain of Origin: 129S2/SvPas
Genetic Background: 129S2/SvPas * 129S6/SvEvTac* C57Vl/6* C57Bl/6 NCr
ES Cell Line: Not Reported
Mutant ES Cell Line: Not Reported
Model Source: Not Reported
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Based on the conventional mouse knock out line ( Kim et al., 2003). A knockin targeting construct was prepared that contained an artificial exon immediately downstream of exon 5 of the mouse gene. This artificial exon contained the neomycin resistance gene, series of stop codons and flanking LoxP sites. This cassette would be expected to prevent the expression of full length Syngap protein, essentially mimicking the KO line, expression coul dbe restored in the presence of Cre expression through excision of the Neo stop cassette.
Allele Type: Targeted (knockin)
Strain of Origin: 129S2/SvPas
Genetic Background: 129S2/SvPas * C57BL/6 * CBA
ES Cell Line: Not Reported
Mutant ES Cell Line: Not Reported
Model Source: Not Reported
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Exons encoding C2 and GAP domains of the protein were replaced with a vector containing an IRES-lacZ-pA and MC1-neo cassette.
Allele Type: Targeted (knockout)
Strain of Origin: 129P2/OlaHsd
Genetic Background: 129P2/OlaHsd*MF1
ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Hemizygous (Fmr1), heterozygous (Syngap1)
Mutation:
Syngap1 het mice were mated with FMR1-/+ females to get FMR1-/y:Syngap1+/- mice.
Allele Type: Knockout
Strain of Origin: 129P2/OlaHsd*C57BL/6JOla
Genetic Background: ES Cell Line: Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Conditional deletion of exons 6-7 of the Syngap1 gene using Emx1-Cre, in neurons and glia of the neocortex, hippocampus and pallium, E10.5 onwards
Allele Type: Conditional loss-of-function
Strain of Origin: Genetic Background: C57BL6*B129sv/ev
ES Cell Line: Not Reported
Mutant ES Cell Line: Not Reported
Model Source: Not Reported
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Conditional deletion of exons 6-7 of the Syngap1 gene using Cux2-CreERT2, in upper lamina neurons (layer 4) in the neocortex forming the corticocortical or callosal projection neurons
Allele Type: Conditional loss-of-function
Strain of Origin: Genetic Background: C57BL6*B129sv/ev
ES Cell Line: Not Reported
Mutant ES Cell Line: Not Reported
Model Source: Not Reported
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Conditional deletion of exons 6-7 of the Syngap1 gene using Rbp4-Cre, in layer 5 glutamatergic neurons of the neocortex (pyramidal tract neurons (and corticostriatal)), piriform cortex and dentate granule cells of the hippocampus
Allele Type: Conditional loss-of-function
Strain of Origin: Genetic Background: C57BL6*B129sv/ev
ES Cell Line: Not Reported
Mutant ES Cell Line: Not Reported
Model Source: Not Reported
Model Type:
Genetic LOF
Model Genotype:
Heterozygous
Mutation:
Exons encoding c2 and gap domains of the protein were replaced with a vector containing an ires-lacz-pa and mc1-neo cassette. (existing construct as in m_syngap1_8_ko_ht on a new background)
Allele Type: Knockout
Strain of Origin: 129P2/OlaHsd
Genetic Background: C57BL/6J
ES Cell Line: E14TG2a (ES Cell)
Mutant ES Cell Line: E14TG2a (ES Cell)
Model Source: University of Edinburgh
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
A de novo frameshift mutation that leads to a premature stop codon (SYNGAP1-L813RfsX22) was selected. Guide RNA, Cas9, and homology-directed repair DNA (HDR-DNA) oligos were injected into fertilized eggs to introduce the mutations
Allele Type: NDD Mutation
Strain of Origin: Genetic Background: C57/B6J and 129/ SvEv
ES Cell Line: Mutant ES Cell Line: Model Source: Johns Hopkins University
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
A de novo SYNGAP1 mutation associated with SRID that is within an intron and creates a cryptic splice site and a premature stop codon was selected. Guide RNA, Cas9, and homology-directed repair DNA (HDR-DNA) oligos were injected into fertilized eggs to introduce the mutations.
Allele Type: NDD Mutation
Strain of Origin: Genetic Background: C57/B6J and 129/ SvEv
ES Cell Line: Mutant ES Cell Line: Model Source: Johns Hopkins University
Description: Syngap1 het mutants with heads fixed show increase in spontaneous whisking behavior compared with controls.
Exp Paradigm: Reporter line thy1-gcamp6s4.3 (jackson laboratories, #024275) was used.
Description: Decreased number of cb-positive interneurons in ca1 and ca3 hippocampal subfields
Exp Paradigm: Stereological evaluation of immunohistochemical analysis using calbindin in hippocampus
Description: Syngap1 het mutants show decrease in dendritic length in l4 stellate neurons and in l2/3 pyramidal neurons in the somatosensory cortex compared with controls.
Exp Paradigm: NA
Description: Syngap1 het mutants show decrease in the size of l4 stellate neurons and in l2/3 pyramidal neurons in the somatosensory cortex compared with controls.
Exp Paradigm: NA
Description: Syngap1 het mutant mice show decrease in spine density in l4 stellate neurons and in l2/3 pyramidal neurons in the somatosensory cortex compared with controls.
Exp Paradigm: NA
Dendritic architecture: dendritic tree complexity3
Decreased
Description: Syngap1 het mutants show decrease in the complexity of dendritic arbors in l4 stellate neurons and in l2/3 pyramidal neurons in the somatosensory cortex compared with controls.
Exp Paradigm: NA
Description: Syngap1 het mutant mice show reduced activity in neurons of layers l2/3 of the somatosensory cortex compared with controls. syngap1 het mutants show neuronal activity of lower amplitude and frequency compared with controls. syngap1 het mutants with botox injection induced whisker paralysis show no change in event amplitude or frequency compared with syngap1 mutants, 1 week after botox injection, indicating whisker movement and/or touch resulted in less activity in mutants than in controls. cluster analysis showed botox reduced neuronal activity within wild type, but not het, somatosensory cortex circuits.
Exp Paradigm: Reporter line thy1-gcamp6s4.3 (jackson laboratories, #024275) was used.
Description: Syngap1 het mutants with whisker paralysis show reduction in response probability of the whisker-responsive neurons compared with controls, in response to passive whisker bending.
Exp Paradigm: NA
Description: Syngap1 het mutants show reduced amplitude of synaptic currents in l2/l3 somatosensory cortex neurons evoked by electrical stimulation of l4, compared with controls.
Exp Paradigm: NA
Description: Decreased long term potentiation induced by theta burst stimulation (tbs)
Exp Paradigm: Whole cell recordings of ltp induced by theta burst stimulation in ca1 region of hippocampus
Description: Syngap1 het mutants show decreased intrinsic excitability in l2/3 neurons of the somatosensory cortex compared with controls.
Exp Paradigm: NA
Description: Syngap1 het mice crossed with thy1-gcamp6 mice show reduced amplitude of somatosensory cortex responses to whisker deflections compared with controls, in a stimulus-dependent manner.
Exp Paradigm: Reporter line thy1-gcamp6s4.3 (jackson laboratories, #024275) was used.
Description: Syngap1 heterozygous mice show reduction in the amplitude of cortical intrinsic optical signals elicited by c2 and beta whisker deflections compared with controls.
Exp Paradigm: Whisker paralysis was induced by botox injection.
Description: Syngap1 het mutants with gcamp6s expression in excitatory and inhibitory neurons show reduction in neuronal activation in response to passive whisker stimulation in excitatory and inhibitory neurons compared with controls, particularly in those excitatory neurons most responsive to whisker stimulation.
Exp Paradigm: Syngap1 het mice are crossed with gad2-t2a-nls-mcherry mice and injected them with an aav vector that drives gcamp6s expression in inhibitory and excitatory neurons.
Description: Syngap1 het mutants show reduced response of l2/l3 neurons in the somatosensory cortex in response to whisker curvature compared with controls, measured by the fraction of responding neurons, event amplitude and frequency. syngap1 het mutants show a smaller number of responsive neurons in response to a mild stimulus compared with controls. syngap1 het mutants show a smaller number of responsive neurons, reduced amplitude and frequency in response to a strong stimulus compared with controls. syngap1 het mice with whisker paralysis induced using botox show decrease in cellular sensory responsiveness in response to passive whisker deflections compared with controls.
Exp Paradigm: NA
Description: Decreased spatial working memory demonstrated by no improvement with training
Exp Paradigm: Radial arm maze test for spatial working memory
Description: Syngap1 het mutants show no preference for novel objects with familiar textures whereas controls spent more time with objects of novel textures, indicating mutants did not discriminate between similar objects that differed only in texture.
Exp Paradigm: NA
Description: Decreased spatial reference memory demonstrated by no improvement across training in radial arm maze
Exp Paradigm: Radial arm maze test for spatial reference memory
Description: Abnormal spatial reference memory highlighted by impairment in transfer test of water maze test
Exp Paradigm: Water maze spatial reference memory test
Description: Syngap1 het mutants show no increase in performance over trials whereas wildtype mice learnt to discriminate between whisker stimulation and no stimulation measured by an increase in number of licks of water in the presence of whisker cues, in a stimulus-strength dependent manner.
Exp Paradigm: Water-deprived mice learn to perceptually report passive deflections of their whiskers by licking a water dispensing port during a short answer period
Description: Increased stereotypies with elevated stereotypic counts in 30 min trials over 5 consecutive days
Exp Paradigm: Stereotyped movements recordings in open field test
Description: Increased stereotypies with elevated stereotypic counts in 30 min trials over 5 consecutive days administration of mk-801 injections
Exp Paradigm: Stereotyped movements recordings in open field test after administration of mk-801 injections
Description: Decreased prepulse inhibition of acoutic stimulus after administration of clozapine
Exp Paradigm: Prepulse inhibition of acoustic startle reflex after administration of clozapine
Description: Increased social isolation indicated by more time spent in center of chamber vs. novel conspecific
Exp Paradigm: Three chambered test for social isolation by habituating mice to observation chamber and then interact with novel conspecific
Description: Decreased social recognition memory indicated by inability to distinguish between familiar and novel conspecifics
Exp Paradigm: Three chambered test
Description: Abnormal anxiety levels indicated by more time spent in open arm and less time in closed arm
Exp Paradigm: Elevated plus maze test of anxiety
Description: Abnormal anxiety levels indicated by higher number of ventures into center of field during few minutes of test session
Exp Paradigm: Thigmotaxis in open field test
Description: Decreased spatial working memory indicated by decreased nonmatching performance significantly below training criterion level and not different from random chance
Exp Paradigm: Eight-arm radial maze
Cued or contextual fear conditioning: memory of cue1
Decreased
Description: Decreased cued freezing behavior indicated by dramatic elevation in activity to testing tone
Exp Paradigm: Contextual plus cued fear conditioning
Description: Decreased spontaenous excitatory post-synaptic currents amplitude with increased frequency and decrease in intervent intervals
Exp Paradigm: Whole-cell patch-clamp recordings of ca1 neurons in hippocampal slices
Description: Increased activity levels in the open field was seen in ki mice,rescued by tmx in adulthod to induce cre activity. this behavior is similar to the same ( younger) ki mice without rescue ( or hets/haploinsufficient for syngap1).
Exp Paradigm: NA
Description: Time spent by the ki mice, rescued by tmx in adulthod to induce cre activity, is increased in the open arms of the elevated plus maze showing decreased anxiety. this behavior is similar to the same ( younger) ki mice without rescue ( or hets/haploinsufficient for syngap1)
Exp Paradigm: NA
Description: Spontaneous alternation was absent in ki mice,rescued by tmx in adulthod to induce cre activity. this behavior is similar to the same ( younger) ki mice without rescue ( or hets/haploinsufficient for syngap1)
Exp Paradigm: NA
Description: Some features of the spine morphology calculated using the compartmentalization factor are increased in syngap1 het mice, as the volume and neck length of spines appears to be more relative to the area of the neck
Exp Paradigm: Compartmentalization factor was calculated
Description: Syngap1 het mice have a significant increase in the magnitidue of mglur dependent ltd in the hippocampus compared to wild typ littermate controls
Exp Paradigm: NA
Description: Syngap1 het: fmr1 null male double ko mice have a significant increase in the magnitidue of mglur dependent ltd in the hippocampus compared to wild type littermate controls and authors note the increase in magnitude is more than what is seen in the individual mutations (syngap1 het or fmr1-/y)
Exp Paradigm: NA
Description: Increase in the number of trials from first presentation to 80% correct criterion; increased in the number of correction trials to reach criterion
Description: Syngap1 mutant mice exhibited a decreased number of spontaneous alternations and an increased number of repetitive arm visits compared to wildtype controls.
Description: Syngap1 mutant mice exhibited a significant increase in phosphorylated ERK over total ERK compared to wildtype controls.
Exp Paradigm: phospho-ERK
Description: Syngap1 mutant mice exhibited a decreased number of spontaneous alternations and an increased number of repetitive arm visits compared to wildtype controls.
Description: Syngap1 mutant mice exhibited a significant increase in phosphorylated ERK over total ERK compared to wildtype controls.
Exp Paradigm: phospho-ERK
Description: Differential expression analysis revealed significant changes in gene expression, with 21 upregulated and 33 downregulated genes. Gene set enrichment analysis of these genes revealed strong enrichment of genes involved in the Wnt signaling pathway, phagocytosis, regulation of neuronal synaptic plasticity, and neuron projection morphogenesis.
Description: Syngap1 mutant mice exhibited a significant reduction of Syngap1 protein in the whole brain compared to wildtype controls. Additionally, protein expression of Syngap1 alpha-1 and alpha-2 C-terminal isoforms was reduced by approximately 50%.
