Dynamic Patterns of Attention in Children with Rare SCN2A Genetic Variants

Background: As described by Stessman in this panel, SCN2A is one of 87 genes that show an overall burden of private disruptive mutations in neurodevelopmental disorders, including ASD. Research in animal models highlights the critical role of SCN2A in controlling voltage-gated ion channels essential for the propagation of action potentials and neurotransmission. Despite extensive knowledge of molecular and cellular disruption, little is known about the neural phenotype associated with SCN2A mutations in humans, including domain general areas of cognition, such as attention.

Objectives:

We aimed to characterize dynamic patterns of attention associated with the SCN2A genetic variant. Targeted recruitment focused on children with ASD who had completed genetic testing in priori studies and had a gene disrupting mutation to SCN2A. Prior studies have found that children with ASD exhibit overall attenuation of the P3 component in response to standard and deviant stimuli (e.g., Salmond et al., 2007; Donkers et al., 2013). However, we hypothesized that children with ASD and a SCN2A mutation may showcase differences in functioning and ongoing changes throughout the duration of the experiment.

Methods: To date, participants (N=30) included children with de novo SCN2A, non-carrier biological siblings, and non-carrier biological parents (see Table 1 for participant demographic data). During EEG acquisition, children watched a video while passively listening to tones that varied in pitch (1000 or 1200 Hz) and duration (50 or 100 ms). In this way, we generated a standard condition (83%) and three possible deviant conditions (e.g., frequency only, duration only, frequency and duration; 5.5% each). A single-trial approach tracked dynamic patterns of attention (i.e., the variability of the P3a over the course of the experiment).

Results:

Preliminary analyses targeted peak latency across frontocentral scalp electrode clusters for the P3a component (180-350 ms). Multilevel models (SAS 9.4) tested habituation differences (i.e., the rate of decreasing P3a latency) in the dynamic context of time related to condition and group. A three way interaction between condition, group, and time was significant, F(2,32000)=4.98, p=.0069 and patterns are illustrated in Figure 1. Pairwise comparisons of habituation patterns show that SCN2A carrier P3a latencies were becoming increasingly faster for both deviant and standard tones. This pattern was significantly different than the slowing P3a latencies exhibited by parents (deviant diff.=-.33, p=.038; standard diff. = -.023, p<.0001) and siblings (standard diff =-.03, p<.0001).

Conclusions: Children with SCN2A mutations exhibit distinct dynamic patterns of attention in comparison to unaffected non-carrier biological relatives. These patterns were consistent, regardless of development, for continuous exposure to standard tones, suggesting an underlying genetically distinct subtype. Specifically, the response is increasing in efficiency for SCN2A carriers, which may suggest a delay in low-level sensory processing. In contrast, in response to deviant tones (i.e., novel stimuli), this pattern of habituation is common to both SCN2A carriers and siblings, but not parents, which may highlight underlying developmental changes. We will discuss implications for the SCN2A neural phenotype at the intersection of dynamic attention, sensory-seeking behaviors, and ASD symptomology.