Background

SYNGAP1 is a genetic cause of intellectual disability (ID) and epilepsy. Changes to individuals’ DNA at the Syngap1 gene leads to moderate-to-severe ID and developmental delay, autism, sensory sensitivities, sleep disturbance and challenging behaviours. Since SYNGAP1-related ID was first discovered in 2009, over 1,700 individuals have been diagnosed (as of March 2026), and estimates suggest that 1% of non-syndromic ID are caused by Syngap1 mutations. 

Why did we do this study?

Bi-annual meetings with a group of parents of children with SYNGAP1-related ID indicate that challenging behaviours are an issue and potentially get worse as children reach adolescence. For this study, we wanted to 1) characterize challenging behaviour, track how behaviour changes over time, and investigate whether there are any physiological mechanisms which underlie behavioural symptoms in SYNGAP1. 

What did we do?

We recruited 24 participants with SYNGAP1 and 17 typically developing children (ages 3-25) to participate in this study. Parents and caregivers completed a series of behaviour questionnaires examining autism, ADHD, emotions, challenging behaviours, sensory sensitivities, and sleep. Additionally, we met participants in person to examine the autonomic nervous system – i.e. their ‘fight or flight’ system. To do this, we took a recording of heart rate (ECG) and a measure of pupil size. We also conducted an EEG to get a measure of overall neural activity. 

What did we find?

We have several key findings from this study:

1. Challenging behaviours are highly prevalent (96% of this cohort engaged in at least one challenging behaviour in the past month), with the most common and severe challenging behaviours including self-injurious behaviours physical aggression, and stereotyped behaviour.
2. Some behaviours change as SYNGAP1 participants get older, specifically we saw that self-injurious behaviours potentially get worse as children with SYNGAP1 age, and that adaptive behaviours do not increase at the rate expected in typically developing populations. Furthermore, we demonstrated that challenging behaviours, including self-injury, physical aggression and stereotyped behaviour were highly persistent across 3 time points over 7 years. 
3. In terms of autonomic function, we saw reduced parasympathetic activity (‘rest-and-digest’) in SYNGAP1 participants compared to typically developing controls in the cardiac (heart rate variability) measures. This means that SYNGAP1 participants spend more time in ‘fight-or-flight’ mode than controls. The pupil measures were not significantly different between groups, demonstrating the need for further research in autonomic function in SYNGAP1.
4. Lastly, we examined whether behaviour was associated with the cardiac measures. We didn’t see any clear relationships, however, some trends observed included relationships between sleep and sensory processing with heart rate. 

Outputs

Analysis for this study is ongoing and the findings are in preparation to be published in peer-reviewed journals. 

Who conducted and funded the project?

This study was run by Sydni Weissgold, and supervised by Andrew Stanfield, Andrew McKechanie and Damien Wright. This project was funded by Syngap1 UK, SIDB, and the Winefride and Booth Smith PhD studentship.