SYNGAP1 Research Articles

Identification of a novel SYNGAP1 mutation in a child with intellectual disability

To report on a child with mental retardation caused by SYNGAP1 gene mutation. Peripheral blood samples were collected from the proband and her parents. High throughput sequencing (HTS) was employed for screening for potential mutation in the patient. Suspected mutation was validated by Sanger sequencing of the child and her parents. By HTS, a previously unknown mutation [c.1656C>A (p.C552*)] was found in exon 10 of the SYNGAP1 gene in the proband. Sanger sequencing confirmed the heterozygous nature of the mutation and that neither of her parents carried the same mutation. The dysmorphism and developmental delay of the child were probably due to the pathogenic mutation of the SYNGAP1 gene. HTS can facilitate elucidation of the genetic etiology with efficiency, which has great significance in the diagnosis, treatment and prognosis of the child.

Chewing induced reflex seizures (“eating epilepsy”) and eye closure sensitivity as a common feature in pediatric patients with SYNGAP1 mutations: Review of literature and report of 8 cases

PurposeHeterozygous SYNGAP1 gene mutations have been associated with several forms of idiopathic generalized epilepsy, autism spectrum disorders and delay of psychomotor development. We report eight patients with a SYNGAP1 mutation and chewing/eating induced reflex seizures as new phenotype and compare them to other patients with eating epilepsy and genetic mutations. MethodsPresentation of clinical and anamnestic features and retrospective analysis of Video-EEG data of a 4 year old index patient with SYNGAP1 mutation and chewing /eating induced seizures. Clinical and anamnestic features and home videos of seven additional patients (4 female; age: 4–14 years) with SYNGAP1 mutation and eating induced reflex seizures were compared. ResultsAll reflex seizures of the index patient showed similar focal EEG pattern with 1–5 seconds high amplitude, irregular 3/sec spike-wave complexes with initiation from left temporo-occipital, right temporo-occipital or bi- occipital / temporo-occipital regions. Eyelid myoclonia, the most common seizure type in all 8 patients, were typically initiated by eating or other simple orofacial stimuli. In the index patient eye closure preceded eating induced-eyelid myoclonia in 30/38 seizures. ConclusionThe main clinical features of our patient (i.e. intellectual disability, epilepsy, autistic features) are compatible with previous reports on patients with SYNGAP1 mutations. This is the first complete description of eating induced seizures in association with SYNGAP1 mutations. Whether eye closure sensitivity (ECS) represents an independent reflex epileptic trait, as seen in other patients with idiopathic “generalized” epilepsies (IGE), or eye closure is part of a complex trigger mechanism in SYNGAP1 patients’ remains to be elucidated.

SYNGAP1-Related Intellectual Disability Syndrome

SRID Syndrome is a neuro genetic disorder caused by the mutation of the SYNGAP1 gene. This syndrome interferes with the ability to think and properly handle everyday life of a person.

Analysis of 31-year-old patient with SYNGAP1 gene defect points to importance of variants in broader splice regions and reveals developmental trajectory of SYNGAP1-associated phenotype: case report

BackgroundWhole exome sequencing is a powerful tool for the analysis of genetically heterogeneous conditions. The prioritization of variants identified often focuses on nonsense, frameshift and canonical splice site mutations, and highly deleterious missense variants, although other defects can also play a role. The definition of the phenotype range and course of rare genetic conditions requires long-term clinical follow-up of patients.Case presentationWe report an adult female patient with severe intellectual disability, severe speech delay, epilepsy, autistic features, aggressiveness, sleep problems, broad-based clumsy gait and constipation. Whole exome sequencing identified a de novo mutation in the SYNGAP1 gene. The variant was located in the broader splice donor region of intron 10 and replaced G by A at position +5 of the splice site. The variant was predicted in silico and shown experimentally to abolish the regular splice site and to activate a cryptic donor site within exon 10, causing frameshift and premature termination. The overall clinical picture of the patient corresponded well with the characteristic SYNGAP1-associated phenotype observed in previously reported patients. However, our patient was 31 years old which contrasted with most other published SYNGAP1 cases who were much younger. Our patient had a significant growth delay and microcephaly. Both features normalised later, although the head circumference stayed only slightly above the lower limit of the norm. The patient had a delayed puberty. Her cognitive and language performance remained at the level of a one-year-old child even in adulthood and showed a slow decline. Myopathic facial features and facial dysmorphism became more pronounced with age. Although the gait of the patient was unsteady in childhood, more severe gait problems developed in her teens. While the seizures remained well-controlled, her aggressive behaviour worsened with age and required extensive medication.ConclusionsThe finding in our patient underscores the notion that the interpretation of variants identified using whole exome sequencing should focus not only on variants in the canonical splice dinucleotides GT and AG, but also on broader splice regions. The long-term clinical follow-up of our patient contributes to the knowledge of the developmental trajectory in individuals with SYNGAP1 gene defects.

Decrease of SYNGAP1 in GABAergic cells impairs inhibitory synapse connectivity, synaptic inhibition and cognitive function.

Haploinsufficiency of the SYNGAP1 gene, which codes for a Ras GTPase-activating protein, impairs cognition both in humans and in mice. Decrease of Syngap1 in mice has been previously shown to cause cognitive deficits at least in part by inducing alterations in glutamatergic neurotransmission and premature maturation of excitatory connections. Whether Syngap1 plays a role in the development of cortical GABAergic connectivity and function remains unclear. Here, we show that Syngap1 haploinsufficiency significantly reduces the formation of perisomatic innervations by parvalbumin-positive basket cells, a major population of GABAergic neurons, in a cell-autonomous manner. We further show that Syngap1 haploinsufficiency in GABAergic cells derived from the medial ganglionic eminence impairs their connectivity, reduces inhibitory synaptic activity and cortical gamma oscillation power, and causes cognitive deficits. Our results indicate that Syngap1 plays a critical role in GABAergic circuit function and further suggest that Syngap1 haploinsufficiency in GABAergic circuits may contribute to cognitive deficits.

A New SYNGAP1 Stop Mutation in a Patient with Idiopathic Generalized Epilepsy Showing Photosensitivity and Electroencephalography Normalization after Eye Opening

Background: SYNGAP1, which encodes a RAS-GTPase-activating protein that influences α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor trafficking and excitatory synaptic transmission, is located on the short arm of chromosome 6 (6p21.3). SYNGAP1 gene mutations have been associated to autism spectrum disorders, delay of psychomotor development, acquired microcephaly, and several forms of idiopathic generalized epilepsy like Tassinari syndrome.

De Novo SYNGAP1 Mutations in Nonsyndromic Intellectual Disability and Autism

Little is known about the genetics of nonsyndromic intellectual disability (NSID). Recently, we reported de novo truncating mutations in the SYNGAP1 gene of 3 of 94 NSID cases, suggesting that its disruption represents a common cause of autosomal dominant NSID. To further explore the involvement of SYNGAP1 in NSID, we sequenced its exons and intronic boundaries in 60 additional sporadic cases of NSID, including 30 patients with autism spectrum disorders (ASD) and 9 with epilepsy, and in 380 control individuals. We identified de novo out-of-frame deletions in two patients with NSID and mild generalized epilepsy (c.2677delC/p.Q893RfsX184 and c.321_324delGAAG/p. K108VfsX25) and a de novo splicing mutation (c.2294 + 1G>A), which results in the creation of a premature stop codon, in a patient with NSID and autism. No splicing or truncating mutations were found in control subjects. We provide evidence that truncating mutations in SYNGAP1 are common in NSID and can be also associated with autism.

A novel de novo microdeletion spanning the SYNGAP1 gene on the short arm of chromosome 6 associated with mental retardation

American Journal of Medical Genetics Part AVolume 152A, Issue 9 p. 2376-2378 Research Letter A novel de novo microdeletion spanning the SYNGAP1 gene on the short arm of chromosome 6 associated with mental retardation† Ana Cristina V. Krepischi, Ana Cristina V. Krepischi Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, Brazil AC Camargo Cancer Hospital, São Paulo, BrazilSearch for more papers by this authorCarla Rosenberg, Carla Rosenberg Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, BrazilSearch for more papers by this authorSilvia S. Costa, Silvia S. Costa Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, BrazilSearch for more papers by this authorJohn A. Crolla, John A. Crolla Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, UK National Genetics Reference Laboratory (Wessex), Salisbury District Hospital, Salisbury, UKSearch for more papers by this authorShuwen Huang, Shuwen Huang National Genetics Reference Laboratory (Wessex), Salisbury District Hospital, Salisbury, UKSearch for more papers by this authorAngela M. Vianna-Morgante, Corresponding Author Angela M. Vianna-Morgante [email protected] Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, BrazilDepartamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, SP 05422-970, Brazil.Search for more papers by this author Ana Cristina V. Krepischi, Ana Cristina V. Krepischi Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, Brazil AC Camargo Cancer Hospital, São Paulo, BrazilSearch for more papers by this authorCarla Rosenberg, Carla Rosenberg Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, BrazilSearch for more papers by this authorSilvia S. Costa, Silvia S. Costa Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, BrazilSearch for more papers by this authorJohn A. Crolla, John A. Crolla Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, UK National Genetics Reference Laboratory (Wessex), Salisbury District Hospital, Salisbury, UKSearch for more papers by this authorShuwen Huang, Shuwen Huang National Genetics Reference Laboratory (Wessex), Salisbury District Hospital, Salisbury, UKSearch for more papers by this authorAngela M. Vianna-Morgante, Corresponding Author Angela M. Vianna-Morgante [email protected] Department of Genetics and Evolutionary Biology, Institute of Biosciences, University of São Paulo, São Paulo, BrazilDepartamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, SP 05422-970, Brazil.Search for more papers by this author First published: 03 August 2010 https://doi.org/10.1002/ajmg.a.33554Citations: 26 † How to Cite this Article: Krepischi ACV, Rosenberg C, Costa SS, Crolla JA, Huang S, Vianna-Morgante AM. 2010. A novel de novo microdeletion spanning the SYNGAP1 gene on the short arm of chromosome 6 associated with mental retardation. Am J Med Genet Part A 152A:2376–2378. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume152A, Issue9September 2010Pages 2376-2378 RelatedInformation