SYNGAP1 gene: MedlinePlus Genetics (2024)

SYNGAP1-related intellectual disability

At least 40 mutations in the SYNGAP1 gene have been found to cause SYNGAP1-related intellectual disability. In addition to mild-to-moderate intellectual disability, this condition commonly features other neurological problems, including recurrent seizures (epilepsy) and autism spectrum disorder, which affects communication and social interaction.

Gene mutations involved in SYNGAP1-related intellectual disability prevent the production of functional SynGAP protein from one copy of the gene, reducing the protein's activity in cells. Studies show that a reduction of SynGAP activity can have multiple effects in nerve cells, including pushing synapses to develop (mature) too early. The changes triggered by a reduction of SynGAP activity disrupt the synaptic adaptations in the brain that underlie learning and memory, leading to cognitive impairment and other neurological problems characteristic of SYNGAP1-related intellectual disability.

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Autism spectrum disorder

At least five SYNGAP1 gene mutations have been identified in people with autism spectrum disorder (ASD), a condition that appears early in childhood development, varies in severity, and is characterized by impaired social skills, communication problems, and repetitive behaviors. These mutations result in a SynGAP protein with impaired function or prevent the production of the protein. Changes in synaptic adaptation in individuals with these mutations may underlie the behavioral abnormalities characteristic of ASD. It is not known why some people with SYNGAP1 gene mutations develop ASD while others have the additional features of SYNCAP1-related intellectual disability (described above).

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Tests Listed in the Genetic Testing Registry

• Tests of SYNGAP1

Scientific Articles on PubMed

• PubMed

Catalog of Genes and Diseases from OMIM

• SYNAPTIC RAS-GTPase-ACTIVATING PROTEIN 1; SYNGAP1

Gene and Variant Databases

• NCBI Gene
• ClinVar

• Aceti M, Creson TK, Vaissiere T, Rojas C, Huang WC, Wang YX, Petralia RS, PageDT, Miller CA, Rumbaugh G. Syngap1 haploinsufficiency damages a postnatalcritical period of pyramidal cell structural maturation linked to corticalcircuit assembly. Biol Psychiatry. 2015 May 1;77(9):805-15. doi:10.1016/j.biopsych.2014.08.001. Epub 2014 Aug 13. Citation on PubMed or Free article on PubMed Central
• Clement JP, Aceti M, Creson TK, Ozkan ED, Shi Y, Reish NJ, Almonte AG, MillerBH, Wiltgen BJ, Miller CA, Xu X, Rumbaugh G. Pathogenic SYNGAP1 mutations impaircognitive development by disrupting maturation of dendritic spine synapses. Cell.2012 Nov 9;151(4):709-723. doi: 10.1016/j.cell.2012.08.045. Citation on PubMed or Free article on PubMed Central
• Clement JP, Ozkan ED, Aceti M, Miller CA, Rumbaugh G. SYNGAP1 links thematuration rate of excitatory synapses to the duration of critical-periodsynaptic plasticity. J Neurosci. 2013 Jun 19;33(25):10447-52. doi:10.1523/JNEUROSCI.0765-13.2013. Citation on PubMed or Free article on PubMed Central
• Kalkman HO. Potential opposite roles of the extracellular signal-regulatedkinase (ERK) pathway in autism spectrum and bipolar disorders. Neurosci BiobehavRev. 2012 Nov;36(10):2206-13. doi: 10.1016/j.neubiorev.2012.07.008. Epub 2012 Aug4. Citation on PubMed
• Mignot C, von Stulpnagel C, Nava C, Ville D, Sanlaville D, Lesca G, RastetterA, Gachet B, Marie Y, Korenke GC, Borggraefe I, Hoffmann-Zacharska D, SzczepanikE, Rudzka-Dybala M, Yis U, Caglayan H, Isapof A, Marey I, Panagiotakaki E, KorffC, Rossier E, Riess A, Beck-Woedl S, Rauch A, Zweier C, Hoyer J, Reis A, MironovM, Bobylova M, Mukhin K, Hernandez-Hernandez L, Maher B, Sisodiya S, Kuhn M,Glaeser D, Weckhuysen S, Myers CT, Mefford HC, Hortnagel K, Biskup S;EuroEPINOMICS-RES MAE working group; Lemke JR, Heron D, Kluger G, Depienne C.Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectualdisability and epilepsy. J Med Genet. 2016 Aug;53(8):511-22. doi:10.1136/jmedgenet-2015-103451. Epub 2016 Mar 17. Erratum In: J Med Genet. 2016Oct;53(10):720. doi: 10.1136/jmedgenet-2015-103451corr1. Citation on PubMed
• O'Roak BJ, Stessman HA, Boyle EA, Witherspoon KT, Martin B, Lee C, Vives L,Baker C, Hiatt JB, Nickerson DA, Bernier R, Shendure J, Eichler EE. Recurrent denovo mutations implicate novel genes underlying simplex autism risk. Nat Commun.2014 Nov 24;5:5595. doi: 10.1038/ncomms6595. Citation on PubMed or Free article on PubMed Central
• Ozkan ED, Creson TK, Kramar EA, Rojas C, Seese RR, Babyan AH, Shi Y, Lucero R,Xu X, Noebels JL, Miller CA, Lynch G, Rumbaugh G. Reduced cognition in Syngap1mutants is caused by isolated damage within developing forebrain excitatoryneurons. Neuron. 2014 Jun 18;82(6):1317-33. doi: 10.1016/j.neuron.2014.05.015. Citation on PubMed or Free article on PubMed Central
• Parker MJ, Fryer AE, Shears DJ, Lachlan KL, McKee SA, Magee AC, Mohammed S,Vasudevan PC, Park SM, Benoit V, Lederer D, Maystadt I, Study D, FitzPatrick DR.De novo, heterozygous, loss-of-function mutations in SYNGAP1 cause a syndromicform of intellectual disability. Am J Med Genet A. 2015 Oct;167A(10):2231-7. doi:10.1002/ajmg.a.37189. Epub 2015 Jun 15. Citation on PubMed or Free article on PubMed Central
• Venkataraman GR, O'Connell C, Egawa F, Kashef-Haghighi D, Wall DP. DE NOVOMUTATIONS IN AUTISM IMPLICATE THE SYNAPTIC ELIMINATION NETWORK. Pac SympBiocomput. 2017;22:521-532. doi: 10.1142/9789813207813_0048. Citation on PubMed
• Wang CC, Held RG, Hall BJ. SynGAP regulates protein synthesis and homeostaticsynaptic plasticity in developing cortical networks. PLoS One. 2013 Dec31;8(12):e83941. doi: 10.1371/journal.pone.0083941. eCollection 2013. Citation on PubMed or Free article on PubMed Central