Auditory Evoked Electrophysiological Response Component “M100” Is Delayed in 16p11.2 Deletion but Not Duplication Carriers
Copy number variants in the BP4-BP5 16p11.2 have been associated with cognitive and behavioral anomalies, in many cases reaching diagnostic criteria for autism spectrum disorder (ASD). On the other hand, idiopathic ASD patients have been shown to have a neurophysiologic correlate in latency delays of auditory evoked responses measured using electrophysiological techniques such as magnetoencephalography, (MEG). The neurobiological basis of such latency delays has been speculatively attributed to both white matter conduction deficits and deficiencies in synaptic transmission. However, the underlying genetic etiology has not been explored.
To explore the genetic etiology of neurophysiological responses, namely auditory evoked neuromagnetic response components in child carriers of 16p11.2 deletion and duplication compared to age-matched controls, as part of the Simons VIP project.
Methods: 140 child participants were recruited. After elimination of 25 cases (for incidentally determined drug use/atypical MRI findings) cohorts of 43 carriers of the 16p11.2 deletion, 23 carriers of the 16p11.2 duplication and 49 controls remained. Neuromagnetic recording was performed using 275-channel biomagnetometers during binaural auditory stimulation with sinusoidal stimuli of 300ms duration and frequencies of 200Hz-1000Hz. Auditory evoked responses were modeled in bilateral auditory cortex after artifact elimination and M100 responses were characterized for each hemisphere and condition as that evoked response peak, with appropriate magnetic field topography, occurring after an M50 component and within a latency range of 80-185ms (wide range reflecting the age-distribution). Linear mixed modeling was performed with Subject/Site as random effects and Case, Stimulus and Hemisphere as fixed effects. Age was considered a covariate in all analyses.
Results: Evaluable data were obtained from the majority of the 16p11.2 deletion carriers (37/43) and neurotypical controls (42/49), but fewer of the 16p11.2 duplication carriers (14/23). In this cohort, age did not differ (deletions: 11.4+/-2.6yrs, duplications: 12.1+/-2.8yrs; neurotypical 12.8+/-2.6yrs). Considering M100 latency analysis there was a significant main effect (p<0.05) of Case with 16p11.2 deletion carriers (149+/-3ms) exhibiting a 23ms delay compared to controls (126+/-3ms). Duplication carriers showed no significant difference from neurotypical controls (although trended to a 6ms decrease in latency (118+/-5ms)). This effect persisted across stimulus conditions and hemisphere. Within the subpopulation of carriers meeting ASD diagnostic criteria, there was an additional non-significant M100 delay of 5ms (deletions, N=11).
Conclusions: Significant M100 delay in 16p11.2 deletions compared to controls suggests a genetic etiology for the neurophysiological observation independent of clinical diagnosis. Absence of an analogous delay in duplication carriers points to the specificity of this change, with genetics contributing equally or more than clinical diagnosis to the latency delay. In fact a slight facilitation of the M100 response in 16p11.2 duplication carriers might be further explored as a candidate indicator of a gene dosage effect. The non-significant but additional delay associated with ASD diagnosis suggests that 16p11.2 deletion is not the sole basis for M100 delays, while the delays associated with 16p11.2 in the absence of meeting diagnostic ASD criteria suggest either a non-specificity of the neurophysiologic finding, or sensitivity to sub-clinical neuronal dysfunction, that may be further explored in the broader autism phenotype.