Atypical neural variability in carriers of 16p11.2 copy number variants

Abstract

Copy number variations (CNVs) at the 16p11.2 chromosomal region are associated with myriad clinical features including intellectual disability and autism spectrum disorder. The aim of this study is to determine whether 16p11.2 deletion (DEL) and duplication (DUP) carriers demonstrate a distinct and reciprocal pattern of electroencephalography (EEG) activity as represented by neural variability measures. EEG data were previously collected as part of the Simons Variation in Individuals Project. Variability measures, as estimated by single-trial ERP and spectral power analyses in the alpha and beta frequency bands, in addition to signal-to-noise ratios (SNRs), were analyzed in DEL (n = 20), DUP (n = 8), and typical (n = 11) groups. We also analyzed mean visual evoked potentials and spectral power (alpha and beta power) to facilitate comparisons with other studies of associated disorders and CNVs. From measures of single-trial variability, we found higher intraparticipant variability in P1 amplitude and timecourse amplitude in DEL compared to controls. Compared to DUP, DEL showed higher variability in absolute alpha and absolute beta power but lower variability in P1 latency. SNRs did not differ between the groups. From measures of amplitude, latency, and spectral power, DUP showed lower relative alpha power compared to controls. Although it is yet unclear whether 16p11.2 CNV dosage impacts neural activity in an opposing manner, findings suggest that 16p11.2 DEL impacts the level of variability of neural responses. Higher neural variability may play a role in a range of cognitive processes in 16p11.2 CNV carriers.Lay Summary: The study analyzed the consistency of patterns of brain waves and rhythms in those affected with a loss or gain of DNA material in the 16p11.2 region. Compared with typical individuals, 16p11.2 deletion carriers showed greater inconsistency in the way the brain responds to the same visual event. This high inconsistency in brain activity may play a role in some core symptoms in 16p11.2 copy number variation carriers.

Reduced visual evoked potential amplitude in autism spectrum disorder, a variability effect?

“…This increasing evidence of neural heterogeneity in ASD both at the individual and population level 20,21,47 could explain the failure in identifying biomarkers that are both discriminant with regard to the typical population but also sensitive to variation of clinical symptoms within the spectrum. These results also further support the necessity of developing models that combine multiple clinical scores and neural profiles 20 to better understand the complexity of the spectrum 48 .…”

Objective frequency analysis of transient visual evoked potentials in autistic children

“…A number of VEP studies lowpass filtered responses (≤30 Hz; Al‐Jawahiri et al, 2019; Kovarski et al, 2016, 2019; Milne, 2011)), which might eliminate key distinctions between groups. Here, group differences occurred at high frequencies (≥30 Hz), and an early peak (P 60 ‐N 75 ) correlated with these frequency bands.…”

“…Siper et al (2016, 2018) collected tVEPs to a contrast‐reversing checkerboard pattern and suggested that excitatory activity in visual cortex is attenuated in ASD. Other studies have also suggested that high variability in neural responses may be associated with ASD (Al‐Jawahiri et al, 2019; Dinstein et al, 2012; Edgar et al, 2015; Haigh et al, 2015; Milne, 2011; Weinger et al, 2014).…”

“…Furthermore, these frequency‐domain measures are based on the entire informational content in the response rather than a few select time points, and therefore, are expected to be more reliable measures. The MSC and power measures calculated in this way can be used to derive additional measures of signal power and noise power, which would be useful to explore the increased neural variability reported for autistic individuals (Al‐Jawahiri et al, 2019; Dinstein et al, 2012; Edgar et al, 2015; Haigh et al, 2015; Milne, 2011; Weinger et al, 2014).…”

Novel and de novo point and large microdeletion mutation in PRRT2‐related epilepsy

“…Copy number deletions of this gene such as 16p11.2 deletion are also known to cause PRRT2 ‐related diseases (Dale, Grattan‐Smith, Nicholson, & Peters, 2012; Silveira‐Moriyama et al, 2018; Termsarasab et al, 2014; Weber, Kohler, Hahn, Neubauer, & Muller, 2013). 16p11.2 microdeletion syndrome is a kind of congenital gene deletion disease, with the clinical manifestations as autism, developmental delay, mental retardation, spinal deformity, and a series of neuropsychiatric developmental diseases (Al‐Jawahiri, Jones, & Milne, 2019; Castelein, Steyaert, Peeters, & van Buggenhout, 2019; Hinkley et al, 2019; Li et al, 2018a; Siu et al, 2019). Phenotypic heterogeneity between patients is obvious, and its pathogenic mechanism is not yet clear.…”