NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

SYNGAP1-Related Intellectual Disability

Synonym: SYNGAP1-Related Developmental and Epileptic Encephalopathy

, MD, PhD, , PhD, and , MD.

Author Information

Initial Posting: .

Estimated reading time: 15 minutes

Summary

Clinical characteristics.

SYNGAP1-related intellectual disability (SYNGAP1-ID) is characterized by developmental delay (DD) or intellectual disability (ID) (100% of affected individuals), generalized epilepsy (~84%), and autism spectrum disorder (ASD) and other behavioral abnormalities (≤50%). To date more than 50 individuals with SYNGAP1-ID have been reported. In the majority DD/ID was moderate to severe; in some it was mild. The epilepsy is generalized; a subset of individuals with epilepsy have myoclonic astatic epilepsy (Doose syndrome) or epilepsy with myoclonic absences. Behavioral abnormalities can include stereotypic behaviors (e.g., hand flapping, obsessions with certain objects) as well as poor social development. Feeding difficulties can be significant in some.

Diagnosis/testing.

The diagnosis of SYNGAP1-ID is established in a proband with developmental delay or intellectual disability in whom molecular genetic testing identifies either a heterozygous pathogenic variant in SYNGAP1 (~89%) or a deletion of 6p21.3 (~11%).

Management.

Treatment of manifestations: DD/ID are managed as per standard practice. No guidelines are available regarding choice of specific antiepileptic drugs (AEDs). In about 50% of patients, the epilepsy responds to a single antiepileptic drug (AED); in the remainder it is pharmacoresistant. Children may qualify for and benefit from interventions used in treatment of ASD. Consultation with a developmental pediatrician may guide parents through appropriate behavioral management strategies and/or provide prescription medications when necessary. Nasogastric/gastrostomy feeding may be required for individuals with persistent feeding issues.

Surveillance: Monitor seizure manifestations and control; behavioral issues; developmental progress and educational needs.

Genetic counseling.

SYNGAP1-ID is inherited in an autosomal dominant manner. To date almost all probands with SYNGAP1-ID whose parents have undergone molecular genetic testing have had a de novo germline pathogenic variant; however, vertical transmission (from a mildly affected, mosaic parent to the proband) has been reported in one family. Thus, while the risk to sibs appears to be low, it is presumed to be greater than in the general population because of the possibility of germline mosaicism in a parent. Once the SYNGAP1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Diagnosis

No formal diagnostic criteria have been published for SYNGAP1-related intellectual disability.

Suggestive Findings

SYNGAP1-related intellectual disability (SYNGAP1-ID) should be considered in individuals with developmental delay or intellectual disability with or without:

  • Generalized epilepsy;
    and/or
  • Autism spectrum disorder (ASD).

Establishing the Diagnosis

The diagnosis of SYNGAP1-ID is established in a proband with developmental delay (DD) or intellectual disability (ID) in whom molecular genetic testing (see Table 1) identifies either:

Molecular genetic testing in a child with DD or an older individual with ID typically begins with chromosomal microarray analysis (CMA). If CMA is not diagnostic, the next step is typically either a multigene panel or exome sequencing. Note: Single-gene testing (sequence analysis of SYNGAP1, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

CMA uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including SYNGAP1) that cannot be detected by sequence analysis. Note: The ability to determine the size of the deletion/duplication depends on the type of microarray used and the density of probes in the 6p21.32 region.

An ID multigene panel that includes SYNGAP1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition in a person with a nondiagnostic CMA at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder, an ID multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Exome sequencing, which does not require the clinician to determine which gene is likely involved, has the advantage over an ID multigene panel of detecting variants in recently identified rare genes not yet included in some ID multigene panels.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in SYNGAP1-Related Intellectual Disability

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method 3
SYNGAP1Sequence analysis 449/55 (89%)
Gene-targeted deletion/duplication analysis 5Unknown, see footnote 6
Chromosomal microarray analysis 76/55 (11%)
1.
2.

Based on a review of published series and case reports

3.
4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

Gene-targeted methods will detect deletions of a single exon up to a whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes may not be determined. If a whole-gene deletion is detected by a gene-targeted deletion/duplication assay, CMA is needed to determine the size of the deletion.

7.

Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the 6p21.3 region; however, some 6p21.3 deletions may not have been detectable by older oligonucleotide or BAC platforms.

Clinical Characteristics

Clinical Description

Since the original description of SYNGAP1-related intellectual disability (SYNGAP1-ID) in three individuals [Hamdan et al 2009], more than 50 affected individuals with detailed clinical information have been reported [Krepischi et al 2010, Pinto et al 2010, Vissers et al 2010, Hamdan et al 2011a, Hamdan et al 2011b, Klitten et al 2011, Zollino et al 2011, de Ligt et al 2012, Rauch et al 2012, Berryer et al 2013, Carvill et al 2013, Writzl & Knegt 2013, Redin et al 2014, Parker et al 2015, Mignot et al 2016, Prchalova et al 2017]. The following description of the phenotypic features associated with this condition is based on these reports.

Developmental delay and intellectual disability. The great majority of affected children present with developmental delay or intellectual disability that is typically moderate to severe but can be mild.

Early motor development is characterized by hypotonia. The average age at walking was 26 months (range: 10.5 months to 5 years). A subset of these children had an ataxic gait that remained stable or improved over time.

Language is generally impaired; a third of individuals age five years or more remain nonverbal. In those who are verbal, language development ranges from use of single words only to four-to-five-word sentences.

Epilepsy. Approximately 84% of individuals with SYNGAP1-ID have generalized epilepsy; a subset of these were diagnosed with myoclonic astatic epilepsy (Doose syndrome) or epilepsy with myoclonic absences [Mignot et al 2016].

While the epilepsy responds to a single antiepileptic drug in approximately half of affected individuals, it is pharmacoresistant in the remainder. Children with refractory seizures may be diagnosed with epileptic encephalopathy (i.e., refractory seizures and cognitive slowing or regression associated with frequent ongoing epileptiform activity).

  • Age at onset of seizures varies between six months and seven years; mean age of seizure onset was 3.5 years in one study [Mignot et al 2016].
  • Seizure types include typical or atypical seizures, myoclonic jerks with or without falls, eyelid myoclonia, tonic-clonic seizures, myoclonic absences, and atonic seizures. In one study, Doose syndrome (myoclonic astatic epilepsy) was diagnosed in three of 17 individuals [Mignot et al 2016].
  • Electroencephalography typically shows generalized epileptic activity, frequently with a posterior predominance. Photosensitivity and fixation-off phenomenon have been observed in a number of individuals.
  • Brain MRI is typically normal; in rare cases, brain atrophy or delayed myelination has been reported.

Autism spectrum disorder (ASD) and other behavioral abnormalities. The occurrence of ASD could be as high as 50%. This includes stereotypic behaviors such as hand flapping, obsessions with certain objects, and poor social development. In addition, inattention, impulsivity, self-directed and other-directed aggressive behavior, elevated pain threshold, hyperacusis, and sleep disorders have been observed.

Other associated features include the following:

  • Acquired microcephaly observed in a minority of affected individuals
  • Eye abnormalities including strabismus
  • Musculoskeletal disorders including hip rotation or dysplasia, kyphoscoliosis, and pes planus
  • Hypertrichosis (predominantly on the limbs and lower spine) occasionally described
  • Gastrointestinal dysfunction (including constipation requiring medical intervention) frequently reported; swallowing difficulties rarely reported
  • Craniofacial features. Although some authors have suggested a subtle but consistent facial appearance (almond-shaped palpebral fissures, mildly myopathic and open-mouthed appearance) [Parker et al 2015], it is unclear if these changes are distinct enough to allow a clinician to suspect the condition in a child.

Life span. It is unknown if life span in SYNGAP1-ID is abnormal. One reported individual is alive at age 31 years [Prchalova et al 2017], demonstrating that survival into adulthood is possible. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.

Genotype-Phenotype Correlations

No definitive phenotype-genotype correlation between the type of SYNGAP1 pathogenic variant (missense, truncating, large intragenic deletion) and cognitive abilities or the occurrence of comorbidities has been observed.

Penetrance

Penetrance is 100%. All individuals with germline pathogenic variants in SYNGAP1 have developmental delay, cognitive dysfunction, intellectual disability, and/or epilepsy.

Prevalence

The prevalence of SYNGAP1 pathogenic variants in two studies was:

Differential Diagnosis

The phenotype associated with SYNGAP1-related intellectual disability (ID) overlaps with that of other disorders of ID and epileptic encephalopathy.

Most genes known to be associated with ID (>50 have been identified; see OMIM Phenotypic Series: Intellectual Disability, Autosomal Dominant) and epileptic encephalopathy (>55 have been identified; see OMIM Phenotypic Series: Epileptic Encephalopathy, Early Infantile) if compatible with walking should be included in the differential diagnosis.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with SYNGAP1-related intellectual disability, the evaluations summarized in Table 2 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Table 2.

Recommended Evaluations Following Initial Diagnosis in Individuals with SYNGAP1-Related Intellectual Disability

System/ConcernEvaluationComment
EyesOphthalmologic evaluationEvidence of strabismus
Gastrointestinal/
Feeding
Baseline evaluation for presence of reflux &/or constipation; assessment for feeding problemsReferral to gastroenterologist &/or feeding therapist for treatment if indicated
MusculoskeletalAssessment for hip rotation/dysplasia, kyphoscoliosis, pes planus
NeurologicNeurologic evaluationTo include EEG & brain MRI, if seizures are suspected
Psychiatric/
Behavioral
Neuropsychiatric evaluationTo include screening for behavioral problems incl sleep disturbances, ADHD, anxiety, &/or traits suggestive of ASD for individuals age >12 mos
Miscellaneous/
Other
Developmental assessmentTo include motor, speech/language evaluation, general cognitive, & vocational skills
Consultation w/clinical geneticist &/or genetic counselor

ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder

Treatment of Manifestations

Table 3.

Treatment of Manifestations in Individuals with SYNGAP1-Related Intellectual Disability

Manifestation/ConcernTreatmentConsiderations/Other
StrabismusStandard treatment(s) as recommended by ophthalmologist
Swallowing dysfunctionNasogastric/gastrostomy feeding may be required for persistent feeding issues.
ConstipationStandard treatment as recommended by gastroenterologistGastroenterology consultation, if severe
Hip rotation/dysplasia, kyphoscoliosis, & pes planusStandard treatment as recommended by orthopedistOrthopedic consultation may be considered.
EpilepsyStandardized treatment w/AEDs by experienced neurologist
  • To date, no guidelines on choice of specific AEDs
  • Anecdotal reports of improved seizure control w/ketogenic diet in some individuals

AEDs = antiepileptic drugs

Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see Epilepsy & My Child Toolkit.

Developmental Disability / Intellectual Disability Educational Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States (US); standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy. In the US, early intervention is a federally funded program available in all states.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed.

Ages 5-21 years

  • In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
  • Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life. Some issues to consider:

  • Private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
  • In the US:
    • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
    • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Motor Dysfunction

Gross motor dysfunction

  • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
  • Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).

Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.

Oral motor dysfunction. Assuming that the individual is safe to eat by mouth, feeding therapy – typically from an occupational or speech therapist – is recommended for affected individuals who have difficulty feeding due to poor oral motor control.

Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties.

Social/Behavioral Difficulties

Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is individualized therapy targeted to each child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one-on-one with a board-certified behavior analyst.

Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavioral management strategies or providing prescription medications when necessary.

Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.

Surveillance

Monitor those with seizures as clinically indicated.

Assess as needed for anxiety, attention, and aggressive or self-injurious behavior.

Monitor developmental progress and educational needs.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

SYNGAP1-related intellectual disability (SYNGAP1-ID) is inherited in an autosomal dominant manner and is typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

Sibs of a proband

Offspring of a proband. Individuals with SYNGAP1-ID are not known to reproduce; the theoretic risk to offspring of mildly affected mosaic individuals [Berryer et al 2013] is up to 50%.

Other family members. Given that most probands with SYNGAP1-ID reported to date have the disorder as a result of a de novo pathogenic variant, the risk to other family members is presumed to be low.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the SYNGAP1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Bridge the Gap – SYNGAP Education & Research Foundation
    15319 Redbud Berry Way
    Cypress TX 77433
    Phone: 832-671-0010
    Fax: 281-746-7732
    Email: admin@bridgesyngap.org
  • Medline Plus
  • VOR: Speaking out for people with intellectual and developmental disabilities
    836 South Arlington Heights Road, #351
    Elk Grove Village IL 60007
    Phone: 877-399-4867
    Fax: 847-253-0675
    Email: info@vor.net
  • American Association on Intellectual and Developmental Disabilities (AAIDD)
    501 3rd Street Northwest
    Suite 200
    Washington DC 20001
    Phone: 202-387-1968
    Fax: 202-387-2193
    Email: sis@aaidd.org
  • National Center on Birth Defects and Developmental Disabilities
    1600 Clifton Road
    MS E-87
    Atlanta GA 30333
    Phone: 800-232-4636 (toll-free); 888-232-6348 (TTY)
    Email: cdcinfo@cdc.gov
  • VOR: Speaking out for people with intellectual and developmental disabilities
    836 South Arlington Heights Road, #351
    Elk Grove Village IL 60007
    Phone: 877-399-4867
    Fax: 847-253-0675
    Email: info@vor.net
  • National Organization for Rare Disorders SYNGAP1 Registry

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

SYNGAP1-Related Intellectual Disability: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
SYNGAP16p21​.32Ras/Rap GTPase-activating protein SynGAPSYNGAP1 databaseSYNGAP1SYNGAP1

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for SYNGAP1-Related Intellectual Disability (View All in OMIM)

603384SYNAPTIC RAS-GTPase-ACTIVATING PROTEIN 1; SYNGAP1
612621MENTAL RETARDATION, AUTOSOMAL DOMINANT 5; MRD5

Gene structure. To date two NCBI reference sequences for human SYNGAP1 have been reported:

Molecular genetic testing for SYNGAP1 pathogenic variants should include all 19 exons present in its largest reference sequence isoform (NM_006772.2).

By comparing human and rodent SYNGAP1 cDNAs, Mignot et al [2016] have recently identified potential additional SYNGAP1 isoforms that could arise from alternative splicing.

Pathogenic variants. The majority of pathogenic SYNGAP1 variants are large deletions or heterozygous loss-of-function alleles such as nonsense and splice variants, frameshift insertions/deletions, and exon deletions; in addition, pathogenic heterozygous missense variants have been reported in a few instances (see review by Mignot et al [2016]). Most pathogenic variants occur de novo.

Normal gene product. The longest SYNGAP1 isoform (NM_006772.2) encodes a protein of 1,343 amino acids that contains pleckstrin homology (PH), C2, RASGAP, SH3-binding, and coiled-coiled domains. Isoform 2 (NM_001130066.1) encodes a protein of 1,292 amino acids that contains the same domains as isoform 1 but has a different C-terminus that includes a QTRV motif required for postsynaptic scaffold protein interaction.

Abnormal gene product. SYNGAP1-ID is caused by haploinsufficiency of SYNGAP1. Pathogenic variants include those likely to result in complete loss of SYNGAP1 protein expression as well as those predicted to cause truncated or misfolded non-functional SYNGAP1.

References

Literature Cited

  • Berryer MH, Hamdan FF, Klitten LL, Møller RS, Carmant L, Schwartzentruber J, Patry L, Dobrzeniecka S, Rochefort D, Neugnot-Cerioli M, Lacaille JC, Niu Z, Eng CM, Yang Y, Palardy S, Belhumeur C, Rouleau GA, Tommerup N, Immken L, Beauchamp MH, Patel GS, Majewski J, Tarnopolsky MA, Scheffzek K, Hjalgrim H, Michaud JL, Di Cristo G. Mutations in SYNGAP1 cause intellectual disability, autism, and a specific form of epilepsy by inducing haploinsufficiency. Hum Mutat. 2013;34:385–94. [PubMed: 23161826]
  • Carvill GL, Heavin SB, Yendle SC, McMahon JM, O'Roak BJ, Cook J, Khan A, Dorschner MO, Weaver M, Calvert S, Malone S, Wallace G, Stanley T, Bye AM, Bleasel A, Howell KB, Kivity S, Mackay MT, Rodriguez-Casero V, Webster R, Korczyn A, Afawi Z, Zelnick N, Lerman-Sagie T, Lev D, Møller RS, Gill D, Andrade DM, Freeman JL, Sadleir LG, Shendure J, Berkovic SF, Scheffer IE, Mefford HC. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat Genet. 2013;45:825–30. [PMC free article: PMC3704157] [PubMed: 23708187]
  • de Ligt J, Willemsen MH, van Bon BW, Kleefstra T, Yntema HG, Kroes T, Vulto-van Silfhout AT, Koolen DA, de Vries P, Gilissen C, del Rosario M, Hoischen A, Scheffer H, de Vries BB, Brunner HG, Veltman JA, Vissers LE. Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med. 2012;367:1921–9. [PubMed: 23033978]
  • Fitzgerald TW, Gerety SS, Jones WD, van Kogelenberg M, King DA, McRae J, Morley KI, Parthiban V, Al-Turki S, Ambridge K, Barrett DM, Bayzetinova T, Clayton S, Coomber EL, Gribble S, Jones P, Krishnappa N, Mason LE, et al. Large-scale discovery of novel genetic causes of developmental disorders. Nature. 2015;519:223–8.
  • Hamdan FF, Daoud H, Piton A, Gauthier J, Dobrzeniecka S, Krebs MO, Joober R, Lacaille JC, Nadeau A, Milunsky JM, Wang Z, Carmant L, Mottron L, Beauchamp MH, Rouleau GA, Michaud JL. De novo SYNGAP1 mutations in nonsyndromic intellectual disability and autism. Biol Psychiatry. 2011a;69:898–901. [PubMed: 21237447]
  • Hamdan FF, Gauthier J, Araki Y, Lin DT, Yoshizawa Y, Higashi K, Park AR, Spiegelman D, Dobrzeniecka S, Piton A, Tomitori H, Daoud H, Massicotte C, Henrion E, Diallo O, Shekarabi M, Marineau C, Shevell M, Maranda B, Mitchell G, Nadeau A, D'Anjou G, Vanasse M, Srour M, Lafrenière RG, Drapeau P, Lacaille JC, Kim E, Lee JR, Igarashi K, Huganir RL, Rouleau GA, Michaud JL, et al. Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability. Am J Hum Genet. 2011b;88:306–16. [PMC free article: PMC3059427] [PubMed: 21376300]
  • Hamdan FF, Gauthier J, Spiegelman D, Noreau A, Yang Y, Pellerin S, Dobrzeniecka S, Côté M, Perreau-Linck E, Carmant L, D'Anjou G, Fombonne E, Addington AM, Rapoport JL, Delisi LE, Krebs MO, Mouaffak F, Joober R, Mottron L, Drapeau P, Marineau C, Lafrenière RG, Lacaille JC, Rouleau GA, Michaud JL, et al. Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation. N Engl J Med. 2009;360:599–605. [PMC free article: PMC2925262] [PubMed: 19196676]
  • Klitten LL, Møller RS, Nikanorova M, Silahtaroglu A, Hjalgrim H, Tommerup N. A balanced translocation disrupts SYNGAP1 in a patient with intellectual disability, speech impairment, and epilepsy with myoclonic absences (EMA). Epilepsia. 2011;52:e190–3. [PubMed: 22050443]
  • 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:2376–8. [PubMed: 20683986]
  • Mignot C, von Stülpnagel C, Nava C, Ville D, Sanlaville D, Lesca G, Rastetter A, Gachet B, Marie Y, Korenke GC, Borggraefe I, Hoffmann-Zacharska D, Szczepanik E, Rudzka-Dybała M, Yiş U, Çağlayan H, Isapof A, Marey I, Panagiotakaki E, Korff C, Rossier E, Riess A, Beck-Woedl S, Rauch A, Zweier C, Hoyer J, Reis A, Mironov M, Bobylova M, Mukhin K, Hernandez-Hernandez L, Maher B, Sisodiya S, Kuhn M, Glaeser D, Weckhuysen S, Myers CT, Mefford HC, Hörtnagel K, Biskup S, Lemke JR, Héron D, Kluger G, Depienne C, et al. Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy. J Med Genet. 2016;53:511–22. [PubMed: 26989088]
  • 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 syndromic form of intellectual disability. Am J Med Genet A. 2015;167A:2231–7. [PMC free article: PMC4744742] [PubMed: 26079862]
  • Pinto D, Pagnamenta AT, Klei L, Anney R, Merico D, Regan R, Conroy J, Magalhaes TR, Correia C, Abrahams BS, Almeida J, Bacchelli E, Bader GD, Bailey AJ, Baird G, Battaglia A, Berney T, Bolshakova N, Bölte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Bryson SE, Carson AR, Casallo G, Casey J, Chung BH, Cochrane L, Corsello C, Crawford EL, Crossett A, Cytrynbaum C, Dawson G, de Jonge M, Delorme R, Drmic I, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Fombonne E, Freitag CM, Gilbert J, Gillberg C, Glessner JT, Goldberg J, Green A, Green J, Guter SJ, Hakonarson H, Heron EA, Hill M, Holt R, Howe JL, Hughes G, Hus V, Igliozzi R, Kim C, Klauck SM, Kolevzon A, Korvatska O, Kustanovich V, Lajonchere CM, Lamb JA, Laskawiec M, Leboyer M, Le Couteur A, Leventhal BL, Lionel AC, Liu XQ, Lord C, Lotspeich L, Lund SC, Maestrini E, Mahoney W, Mantoulan C, Marshall CR, McConachie H, McDougle CJ, McGrath J, McMahon WM, Merikangas A, Migita O, Minshew NJ, Mirza GK, Munson J, Nelson SF, Noakes C, Noor A, Nygren G, Oliveira G, Papanikolaou K, Parr JR, Parrini B, Paton T, Pickles A, Pilorge M, et al. Functional impact of global rare copy number variation in autism spectrum disorders. Nature. 2010;466:368–72. [PMC free article: PMC3021798] [PubMed: 20531469]
  • Prchalova D, Havlovicova M, Sterbova K, Stranecky V, Hancarova M, Sedlacek Z. 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. BMC Med Genet. 2017;18:62. [PMC free article: PMC5457574] [PubMed: 28576131]
  • Rauch A, Wieczorek D, Graf E, Wieland T, Endele S, Schwarzmayr T, Albrecht B, Bartholdi D, Beygo J, Di Donato N, Dufke A, Cremer K, Hempel M, Horn D, Hoyer J, Joset P, Röpke A, Moog U, Riess A, Thiel CT, Tzschach A, Wiesener A, Wohlleber E, Zweier C, Ekici AB, Zink AM, Rump A, Meisinger C, Grallert H, Sticht H, Schenck A, Engels H, Rappold G, Schröck E, Wieacker P, Riess O, Meitinger T, Reis A, Strom TM. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet. 2012;380:1674–82. [PubMed: 23020937]
  • Redin C, Gérard B, Lauer J, Herenger Y, Muller J, Quartier A, Masurel-Paulet A, Willems M, Lesca G, El-Chehadeh S, Le Gras S, Vicaire S, Philipps M, Dumas M, Geoffroy V, Feger C, Haumesser N, Alembik Y, Barth M, Bonneau D, Colin E, Dollfus H, Doray B, Delrue MA, Drouin-Garraud V, Flori E, Fradin M, Francannet C, Goldenberg A, Lumbroso S, Mathieu-Dramard M, Martin-Coignard D, Lacombe D, Morin G, Polge A, Sukno S, Thauvin-Robinet C, Thevenon J, Doco-Fenzy M, Genevieve D, Sarda P, Edery P, Isidor B, Jost B, Olivier-Faivre L, Mandel JL, Piton A. Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing. J Med Genet. 2014;51:724–36. [PMC free article: PMC4215287] [PubMed: 25167861]
  • Vissers LE, de Ligt J, Gilissen C, Janssen I, Steehouwer M, de Vries P, van Lier B, Arts P, Wieskamp N, del Rosario M, van Bon BW, Hoischen A, de Vries BB, Brunner HG, Veltman JA. A de novo paradigm for mental retardation. Nat Genet. 2010;42:1109–12. [PubMed: 21076407]
  • Writzl K, Knegt AC. 6p21.3 microdeletion involving the SYNGAP1 gene in a patient with intellectual disability, seizures, and severe speech impairment. Am J Med Genet A. 2013;161A:1682–5. [PubMed: 23687080]
  • Zollino M, Gurrieri F, Orteschi D, Marangi G, Leuzzi V, Neri G. Integrated analysis of clinical signs and literature data for the diagnosis and therapy of a previously undescribed 6p21.3 deletion syndrome. Eur J Hum Genet. 2011;19:239–42. [PMC free article: PMC3025798] [PubMed: 21119708]

Chapter Notes

Revision History

  • 21 February 2019 (bp) Review posted live
  • 23 October 2017 (jm) Original submission
Copyright © 1993-2019, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2019 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK537721PMID: 30789692

Views

  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Tests in GTR by Gene

Related information

  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...