SYNGAP1-Related Intellectual Disability: Meaningful Clinical Outcomes and Development of a Disease Concept Model Draft

Abstract

Background

SYNGAP1 is a heterogeneous genetic disorder associated with intellectual disability, infantile-onset seizures, and other neurological and somatic symptoms. Clinical trial design for SYNGAP1 would benefit from a disease concept model—i.e., enumerating and ranking symptoms based on their impact on affected individuals and their caregivers.

Methods

We developed a disease concept model for SYNGAP1 via five exercises: a scoping review of clinical features, semistructured interviews with caregivers, a survey of caregivers, a survey of clinical experts, and a review of charts of individuals with SYNGAP1 at one center (Weill Cornell Medicine). We provide a narrative summary of the key findings.

Results

We reviewed 19 articles, conducted 16 interviews with caregivers, received survey responses from 90 caregivers and 15 clinical experts, and reviewed seven charts. Integrating findings from these exercises indicates that both caregivers and providers consider seizures/epilepsy, intellectual disability, and emotional regulation to be the most important therapeutic targets. Caregivers also place a high priority on the ability of individuals with SYNGAP1 to communicate. Chart review revealed that some symptoms discussed in the caregiver interviews (i.e., lack of danger awareness, heat/cold intolerance, lack of satiety) are not found in clinicians’ notes.

Conclusions

Seizures, intellectual disability, communication, and emotional regulation are the four most meaningful clinical outcomes to target for investigating clinical interventions for SYNGAP1, according to caregivers and providers.