We report the first systematic comparison of the neurodevelopmental and behavioural phenotype of SYNGAP1-ID to children with the same level of intellectual disability due to other heterogeneous genomic conditions. Our results highlight a specific pattern of neuro-behavioural characteristics that should be a focus for clinical care. These characteristics include significant global developmental delay, particularly impacting fine motor and speech and language development, gait abnormalities, autism, and in particular epilepsy. There was a striking propensity for children with SYNGAP1-ID to experience seizures, of which absence and atonic seizures were most commonly observed. Our findings on seizures support the existing literature on the seizure phenotype in SYNGAP1-ID [9].
Another unique feature of the SYNGAP1-ID developmental profile is the pronounced motor control difficulties. Although most children were able to walk independently, ataxia occurred more frequently in SYNGAP1-ID. Hypotonia, however, was a common feature among both groups. This mirrors previous reports of gait abnormalities, particularly ataxia, in this cohort [9, 12]. Locomotor abnormalities have been replicated in SYNGAP1 animal models, which may mirror observed gait abnormalities [28]. Fine motor skills were especially affected in SYNGAP1-ID, with only one child able to do up buttons compared to 50% of the ID-comparison group. Previous case series have reported some delays in fine motor ability, but have not considered functional outcomes [12].
Speech development is also disproportionally affected in SYNGAP1-ID, beyond delays observed in children matched for degree of developmental delay. SYNGAP1-ID children are not only more likely to be non-verbal, but also achieve lower levels of language competency. Similar findings were described in a recent case series, which also highlighted limited language attainment for those children able to speak [12]. Interestingly, we did not observe a difference in emotional and behavioural difficulties, as assessed by SDQ scores, between non-verbal children and those able to speak. Difficulties in language development may be explained by sensory processing difficulties [19]. SYNGAP1 mutations have been shown to lead to dysregulated cortical sensory system development, including atypical sensory map organisation [3, 29]. This results in distorted sensory processing, including the processing of incoming auditory signals. Altered electrophysiological responses to auditory stimuli have been demonstrated in individuals with SYNGAP1 variants when compared to individuals with Trisomy 21 and neurotypical controls [30]. Impaired perception and processing of auditory signals may adversely affect speech and language development, which may contribute to the language delays we observed in our cohort. As such, speech and language therapy should be a therapeutic priority.
The above difficulties, including locomotor, spatial learning, and sensory processing abnormalities, may be further explained by multiple down-stream effects of atypical synaptic formation and function caused by SYNGAP1 mutations [3]. The mutations result in premature functional maturation of excitatory neurones [31]. This in turn results in abnormal cortical circuits and connectivity, which may explain SYNGAP1’s impact on cognition. It may also disrupt more specific processed required to develop fine motor control and language skills [3, 31]. Similarly, atypical cortical connectivity may contribute to the previously described abnormal development of the brain’s sensory systems [3, 31]. Aberrant synaptic plasticity during critical periods of development can also inhibit activity-dependent synapse formation and strengthening, which in turn hinders learning [5, 7, 32]. Lastly, abnormal maturation of excitatory neurones and synapses can result in an imbalance between excitatory and inhibitory neuronal connections (E/I imbalance; Clement et al., 2012). E/I imbalance has been proposed as a hypothesis underlying the development of autism [34] and may explain the high rate (46% of SYNGAP1-ID children) of autism observed in our cohort, which is consistent with that of previous reports [9, 12].
The strength of this study is that it is the first systematic exploration of the neurodevelopmental and behavioural differences between SYNGAP1-ID and children with ID of genetic origin and an equivalent level of developmental delay and ID. Hereby, we provide further insights into behavioural and developmental features unique to SYNGAP1-ID. This may aid clinicians in the assessment and counselling of children and their families. However, we must acknowledge our limited sample size, which may limit the power of our study to detect significant differences in certain characteristics, such as autism, sensory sensitivities, and motor difficulties. Future work should focus on large, pooled cohorts to confirm our findings and further bridge the gap between genotypic diagnosis and phenotypic presentations in SYNGAP1-ID. There is also a need to assess the longitudinal development of these children and consider the clinical utility of therapy implementation.