SYNGAP1-Related Intellectual Disability

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 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 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.