Mutations in SYNGAP1 Cause Intellectual Disability, Autism, and a Specific Form of Epilepsy by Inducing Haploinsufficiency

Martin H. Berryer, Fadi F. Hamdan, Laura L. Klitten, Rikke S. Møller, Lionel Carmant, Jeremy Schwartzentruber, Lysanne Patry, Sylvia Dobrzeniecka, Daniel Rochefort, Mathilde Neugnot-Cerioli, Jean Claude Lacaille, Zhiyv Niu, Christine M. Eng, Yaping Yang, Sylvain Palardy, Céline Belhumeur, Guy A. Rouleau, Niels Tommerup, Ladonna Immken, Miriam H. BeauchampGayle Simpson Patel, Jacek Majewski, Mark A. Tarnopolsky, Klaus Scheffzek, Helle Hjalgrim, Jacques L. Michaud, Graziella Di Cristo

Research output: Contribution to journalArticlepeer-review

115 Scopus citations


De novo mutations in SYNGAP1, which codes for a RAS/RAP GTP-activating protein, cause nonsyndromic intellectual disability (NSID). All disease-causing point mutations identified until now in SYNGAP1 are truncating, raising the possibility of an association between this type of mutations and NSID. Here, we report the identification of the first pathogenic missense mutations (c.1084T>C [p.W362R], c.1685C>T [p.P562L]) and three novel truncating mutations (c.283dupC [p.H95PfsX5], c.2212_2213del [p.S738X], and (c.2184del [p.N729TfsX31]) in SYNGAP1 in patients with NSID. A subset of these patients also showed ataxia, autism, and a specific form of generalized epilepsy that can be refractory to treatment. All of these mutations occurred de novo, except c.283dupC, which was inherited from a father who is a mosaic. Biolistic transfection of wild-type SYNGAP1 in pyramidal cells from cortical organotypic cultures significantly reduced activity-dependent phosphorylated extracellular signal-regulated kinase (pERK) levels. In contrast, constructs expressing p.W362R, p.P562L, or the previously described p.R579X had no significant effect on pERK levels. These experiments suggest that the de novo missense mutations, p.R579X, and possibly all the other truncating mutations in SYNGAP1 result in a loss of its function. Moreover, our study confirms the involvement of SYNGAP1 in autism while providing novel insight into the epileptic manifestations associated with its disruption.

Original languageEnglish (US)
Pages (from-to)385-394
Number of pages10
JournalHuman mutation
Issue number2
StatePublished - Feb 2013


  • Autism
  • Epilepsy
  • Haploinsufficiency
  • Intellectual disability

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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