Atypical Neural Sensory Processing of Auditory Stimulus Change Among Children with De Novo Disruptive Mutations to SCN2A

Background: Recurrent gene disrupting mutations are implicated in 10% of autism spectrum disorder diagnoses (Iossofov et al., 2014). Based on such findings, promising “genetics-first” approaches characterize ASD phenotypes based on known genetic etiologies to parse heterogeneity (Stessman, Bernier, & Eichler, 2014). Unique phenotypic patterns of genetically-defined subtypes have emerged (e.g., CHD8, Bernier et al., 2014). Disruptive mutations to the voltage-gated sodium channel alpha subunit SCN2A are implicated in ASD (Weiss et al., 2003; Sanders et al., 2012) and may represent a unique ASD-related phenotype (Tavassoli et al., 2014). Common ASD behaviors such as atypical behavioral responsivity to sensory stimuli (Liss et al., 2006) are observed in human carriers of SCN2A (Tavassoli et al., 2014) and Scn2a mouse models (Kearney et al., 2001) suggesting that impaired low-level sensory processing may be associated with the SCN2Aphenotype.

Objectives: Characterization of the phenotype associated with disruptive SCN2A mutations is critical to understanding genotype-phenotype relations and illuminating the pathophysiology of ASD in genetically defined subgroups. This study aims to contribute to a fuller description of the SCN2A phenotype by examining neural correlates of sensory processing.

Methods: Children with de novo mutations to SCN2A and their biological siblings participated in an auditory oddball event-related potential task measuring low-level sensory processing of auditory stimulus change. To date, participants included children with de novo SCN2A mutations (n = 8, 5 male, 5 ASD, mean age = 10.77, range = 5.75 - 15.58) and their biological parents (n = 17, mean age­ = 43.35, range = 35.0 – 51.25), siblings (n = 5, 3 male, mean age = 9.18, range = 4.58 - 17.58). ERP Paradigm:Standard pure tones (82%), and deviant tones varying in duration (6%), frequency (6%), and combined duration and frequency (6%) were presented during passive viewing of a silent movie. Responses to deviant tone types were averaged together. Peak latency of the P3a component were extracted from frontocentral medial electrodes.

Results: Preliminary analyses were conducted in SAS 9.4 using multilevel models tested condition and group differences. A random-intercept single-trial analysis was utilized to account for ongoing variance across the session. All groups exhibited a faster P3a latency to deviant compared to standard conditions, F(2, 32000) = 149.65, p < .0001. A group by condition interaction on P3a peak latency, F(2, 32000) = 21.39, p < .0001, indicated that SCN2A carriers had less condition discrimination (diff = 3.56 ms, p = .0033) than parents (diff = 11.12 ms, p < .0001) or siblings (diff = 6.01 ms, p < .0001).

Conclusions:

Compared to non-carrier relatives, SCN2A carriers exhibited reduced neural discrimination between standard and deviant tones as measured by P3a latency. This finding suggests diminished sensory sensitivity to auditory stimulus change among SCN2A carriers and a potential reduction in bottom-up regulatory systems that are critical for attending to and integrating information in the environment. Future efforts to characterize the SCN2A phenotype will examine relationships between atypical sensory processing and behavioral features.