Autism spectrum disorder (ASD) is a disease characterized by interaction and communication deficiencies. Patients diagnosed with intellectual disability (ID) exhibit deficiencies in at least two behaviors associated with adaptation skills. The high level of association between neurodevelopmental diseases, especially ID, and ASD clearly reveals the presence of etiopathogenesis with an underlying multi-factorial and possibly a common genetic background. The SYNGAP1 gene has been associated with both ASD and non-syndromic ID. We report the case of a 13-year-old adolescent with SYNGAP1 gene mutation diagnosed with ASD, moderate ID, and epilepsy. The motor development of the patient, who had started walking at the age of 4, was delayed, and his language development was evidently inadequate since he still had no word. Stereotypical behaviors were observed with insufficient social interaction. As a result of the genetic analysis, the patient was determined to be heterozygous for a single nucleotide change (C>T) resulting in a false sense of mutation at position c.3134 in exon 15 of the SYNGAP1 gene. Thus, the present study aimed to contribute to the knowledge base on patients with rare SYNGAP1 mutation that plays a role in the etiological background of ASD, ID, and epilepsy comorbidity. To the best of our knowledge, this variant has not been reported in the scientific literature to date.
1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM-5®). American Psychiatric Publishing; 2013.
2. Kaufman L, Ayub M, Vincent JB. The genetic basis of non-syndromic intellectual disability: a review. J Neurodev Disord 2010; 2:182-209.
3. Devlin B, Scherer SW. Genetic architecture in autism spectrum disorder. Curr Opin Genet Dev 2012; 22:229-237.
4. Vlaskamp DRM, Shaw BJ, Burgess R, Mei D, Montomoli M, Xie H, et al. SYNGAP1 encephalopathy: A distinctive generalized developmental and epileptic encephalopathy. Neurology 2019; 92:e96-e107.
5. Hamdan FF, Daoud H, Piton A, Gauthier J, Dobrzeniecka S, Krebs MO, et al. De novo SYNGAP1 mutations in nonsyndromic intellectual disability and autism. Biol Psychiatry 2011; 69:898-901.
6. Mignot C, von Stülpnagel C, Nava C, Ville D, Sanlaville D, Lesca G, et al. Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy. J Med Genet 2016; 53:511-522.
7. Kim JH, Liao D, Lau LF, Huganir RL. SynGAP: a synaptic RasGAP that associates with the PSD-95/SAP90 protein family. Neuron 1998; 20:683-691.
8. Oh JS, Manzerra P, Kennedy MB. Regulation of the neuron-specific Ras GTPase-activating protein, synGAP, by Ca2+/calmodulin-dependent protein kinase II. J Biol Chem. 2004; 279:17980-17988.
9. Rumbaugh G, Adams JP, Kim JH, Huganir RL. SynGAP regulates synaptic strength and mitogen-activated protein kinases in cultured neurons. Proc Natl Acad Sci U S A 2006; 103:4344-51.
10. Hamdan FF, Gauthier J, Spiegelman D, Noreau A, Yang Y, Pellerin S, et al. Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation. N Engl J Med 2009; 360:599-605.
11. Krepischi AC, Rosenberg C, Costa SS, Crolla JA, Huang S, Vianna-Morgante AM. A novel de novo microdeletion spanning the SYNGAP1 gene on the short arm of chromosome 6 associated with mental retardation. Am J Med Genet A 2010; 152A:2376-2378.
12. Clement JP, Aceti M, Creson TK, Ozkan ED, Shi Y, Reish NJ, et al. Pathogenic SYNGAP1 mutations impair cognitive development by disrupting maturation of dendritic spine synapses. Cell 2012; 151:709-723.
13. Michaelson SD, Ozkan ED, Aceti M, Maity S, Llamosas N, Weldon M, et al. SYNGAP1 heterozygosity disrupts sensory processing by reducing touch-related activity within somatosensory cortex circuits. Nat Neurosci 2018; 21:1-13.
14. Kimura Y, Akahira-Azuma M, Harada N, Enomoto Y, Tsurusaki Y, Kurosawa K. Novel SYNGAP1 variant in a patient with intellectual disability and distinctive dysmorphisms. Congenit Anom (Kyoto) 2018; 58:188-190.
15. Agarwal M, Johnston MV, Stafstrom CE. SYNGAP1 mutations: Clinical, genetic, and pathophysiological features. Int J Dev Neurosci 2019; 78:65-76.