Objective:

The goal of this study is to characterize the prevalence and severity of social impairments for children with SYNGAP1-related intellectual disability (SYGNAP1-ID), and to compare the severity of social impairment between patients with SYNGAP1-ID and, the phenotypically similar, Phelan-McDermid Syndrome (PMD).

Background:

Synaptopathies are neurodevelopmental disorders caused by genetic mutations disrupting the development and function of neuronal synapses. SYNGAP1-related intellectual disability is due to either de novo loss-of-function single nucleotide variants in SYNGAP1 or a hemizygous deletion of the chromosome 6p21.3. Phenotypic presentations of SYNGAP1-ID can include epilepsy, intellectual disability, autism, speech impairments, sleep abnormalities, global developmental delays, and behavioral issues.

Design/Methods:

We utilized the validated Social Responsiveness Scale, Second Edition (SRS-2) to investigate the phenotypic presentation of social-behavioral impairments for two synaptopathies—SYNGAP1-ID (n=32) and PMD (n=19). The short form SRS-2, derived for populations with severe intellectual disability by Sturm et al., was also utilized. The short form SRS-2 limits the influence of age, expressive language, behavioral problems, and nonverbal IQ on survey scores, while maintaining a unidimensional factor structure.

Results:

For the full form analysis, both SYNGAP1-ID and PMD had significantly elevated total and subcategory T-scores as compared to controls, with no significant difference between SYNGAP1-ID and PMD. Similarly, the short form analysis showed significantly elevated total scores for both SYNGAP1-ID and PMD as compared to healthy controls, with no significant difference between the two synaptopathies.

Conclusions:

The survey data showed 87.5% of SYNGAP1-ID and 100% of PMD individuals met the criteria for mild to severe deficiencies in reciprocal social behavior—with majority falling within the “Severe” category (68.8%, SYNGAP1-ID; 73.7%, PMD). Survey item completion data suggests improved utility of the Sturm et al. short form assessment for this patient population.