GeneReviews^® [Internet].

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 withSYNGAP1-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 ofSYNGAP1-ID is established in aproband with developmental delay or intellectual disability in whommolecular genetic testing identifies either aheterozygouspathogenic variant inSYNGAP1 (~89%) or adeletion of 6p21.3 (~11%).

Management.

Treatment of manifestations: DD/ID are managed as per standard practice. No guidelines are available regarding choice of specific anti-seizure medications (ASMs). In about 50% of patients, the epilepsy responds to a single ASM; 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 anautosomal dominant manner. To date almost all probands withSYNGAP1-ID whose parents have undergonemolecular genetic testing have had ade novogermlinepathogenic variant; however, vertical transmission (from a mildly affected, mosaic parent to theproband) 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 ofgermline mosaicism in a parent. Once theSYNGAP1 pathogenic variant has been identified in an affected family member,prenatal testing for a pregnancy at increased risk andpreimplantation genetic testing are possible.

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 ofSYNGAP1-IDis established in aproband with developmental delay (DD) or intellectual disability (ID) in whommolecular genetic testing (seeTable 1) identifies either:

• Aheterozygous pathogenic (orlikely pathogenic) variant inSYNGAP1 (~89%);
  or
• Adeletion of 6p21.3 (~11%).

Note: Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.

Molecular genetic testing in a child with DD or an older individual with ID typically begins withchromosomal microarray analysis (CMA). If CMA is not diagnostic, the next step is typically either amultigene panel orexome sequencing. Note: Single-gene testing (sequence analysis ofSYNGAP1, followed by gene-targeteddeletion/duplication analysis) is rarely useful and typically NOT recommended.

CMA uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (includingSYNGAP1) that cannot be detected bysequence analysis. Note: The ability to determine the size of thedeletion/duplication depends on the type of microarray used and the density of probes in the 6p21.32 region.

An IDmultigene panel that includesSYNGAP1 and other genes of interest (seeDifferential Diagnosis) is most likely to identify the genetic cause of the condition in a person with a nondiagnostic CMA while limiting identification of variants ofuncertain significance and pathogenic variants in genes that do not explain the underlyingphenotype. Note: (1) The genes included in the panel and the diagnosticsensitivity of the testing used for eachgene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in thisGeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focusedexome analysis that includes genes specified by the clinician. (4) Methods used in a panel may includesequence 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 (seeTable 1).

For an introduction to multigene panels clickhere. More detailed information for clinicians ordering genetic tests can be foundhere.

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

For an introduction to comprehensivegenomic testing clickhere. More detailed information for clinicians ordering genomic testing can be foundhere.

Clinical Description

Since the original description ofSYNGAP1-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 withSYNGAP1-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 anti-seizure medication 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, andpes 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 inSYNGAP1-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 definitivephenotype-genotype correlation between the type ofSYNGAP1pathogenic variant (missense, truncating, large intragenicdeletion) and cognitive abilities or the occurrence of comorbidities has been observed.

Penetrance

Penetrance is 100%. All individuals withgermline pathogenic variants inSYNGAP1 have developmental delay, cognitive dysfunction, intellectual disability, and/or epilepsy.

Prevalence

The prevalence ofSYNGAP1 pathogenic variants in two studies was:

• 1% in a series of 500 individuals with epileptic encephalopathy [Carvill et al 2013];
• 0.75% in a large series of 931 unrelated children with intellectual disability [Fitzgerald et al 2015].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed withSYNGAP1-related intellectual disability, the evaluations summarized inTable 2 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

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, seeEpilepsy Foundation Toolbox.

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

SeeGenetic Counseling for issues related to testing of at-risk relatives forgenetic counseling purposes.

Therapies Under Investigation

SearchClinicalTrials.gov in the US andEU 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.

Mode of Inheritance

SYNGAP1-related intellectual disability (SYNGAP1-ID) is inherited in anautosomal dominant manner and is typically caused by ade novopathogenic variant.

Risk to Family Members

Parents of aproband

• Almost all probands withSYNGAP1-ID reported to date whose parents have undergonemolecular genetic testing have the disorder as a result of ade novogermlinepathogenic variant.
• Vertical transmission (from a mildly affected, mosaic parent to theproband) has been reported in one family to date [Berryer et al 2013].
• Molecular genetic testing is recommended for the parents of aproband with an apparentde novopathogenic variant.
• If thepathogenic variant found in theproband cannot be detected in the leukocyte DNA of either parent, the proband most likely has ade novo pathogenic variant. Parentalgermline mosaicism is also a possible explanation; paternal somatic and germline mosaicism has been reported in one family [Berryer et al 2013].
• Note: If the parent is the individual in whom thepathogenic variant first occurred, the parent may have both somatic andgermline mosaicism for the variant and may be mildly affected [Berryer et al 2013].

Sibs of aproband

• The risk to the sibs of theproband depends on the genetic status of the proband's parents.
• Most affected individuals reported to date have had ade novoSYNGAP1pathogenic variant, suggesting a low risk to sibs. However, because of the possibility ofgermline mosaicism in a parent, the risk is presumed to be greater than in the general population [Berryer et al 2013].

Offspring of aproband. Individuals withSYNGAP1-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 withSYNGAP1-ID reported to date have the disorder as a result of ade novopathogenic 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/preimplantation genetic testing is before pregnancy.
• It is appropriate to offergenetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once theSYNGAP1pathogenic variant has been identified in an affected family member, prenatal andpreimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use ofprenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Table A.

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Table B.

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Revision History

• 21 February 2019 (bp) Review posted live
• 23 October 2017 (jm) Original submission

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