Syngap1-Related Intellectual Disability
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 testing 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:
- A heterozygous pathogenic variant in SYNGAP1 (~89%);or
- A deletion of 6p21.3 (~11%).
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 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method 3 |
|---|---|---|
| SYNGAP1 | Sequence analysis 4 | 49/55 (89%) |
| Gene-targeted deletion/duplication analysis 5 | Unknown, see footnote 6 | |
| Chromosomal microarray analysis 7 | 6/55 (11%) |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
Based on a review of published series and case reports
- 3.
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]
- 4.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or 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:
- 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].
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/Concern | Evaluation | Comment |
|---|---|---|
| Eyes | Ophthalmologic eval | Evidence of strabismus |
| Gastrointestinal/ Feeding | Baseline eval for reflux &/or constipation; assessment for feeding problems | Refer to gastroenterologist &/or feeding therapist for treatment if indicated. |
| Musculoskeletal | Assessment for hip rotation/dysplasia, kyphoscoliosis, pes planus | |
| Neurologic | Neurologic eval | Incl EEG & brain MRI if seizures are suspected |
| Psychiatric/ Behavioral | Neuropsychiatric eval | Screen persons age >12 mos for behavior concerns incl sleep disturbances, ADHD, anxiety, &/or traits suggestive of ASD. |
| Miscellaneous/ Other | Developmental assessment | Incl motor, speech/language eval, 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/Concern | Treatment | Considerations/Other |
|---|---|---|
| Strabismus | Standard treatment(s) as recommended by ophthalmologist | |
| Swallowing dysfunction | Nasogastric/gastrostomy feeding may be required for persistent feeding issues. | |
| Constipation | Standard treatment as recommended by gastroenterologist | Gastroenterology consultation, if severe |
| Hip rotation/dysplasia, kyphoscoliosis, & pes planus | Standard treatment as recommended by orthopedist | Orthopedic consultation may be considered. |
| Epilepsy | Standardized treatment w/AEDs by experienced neurologist |
|
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 Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; 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.
Consideration of private supportive therapies based on the affected individual's needs is recommended. 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 Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual 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 behavior 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.