Electrophysiological Biomarkers of Dup15q Syndrome: From Mechanism to Clinical Implications of Functional Biomarkers in Autism Genetics

Background: The surge in genetic testing for children with Autism Spectrum Disorder (ASD) has facilitated the identification of causative rare genetic variants and the recognition of clinically meaningful genetic syndromes (Jeste and Geschwind, 2014). Insights into specific neurobiological mechanisms of disease also pave the way for the identification of genetically informed, brain based biomarkers that can enhance translational studies and clinical trials. Duplications of 15q11.2-q13.1 (Dup15q syndrome) are highly penetrant for autism spectrum disorder (ASD), with the duplicated 15q region containing several genes critical for brain development and excitatory/inhibitory balance (UBE3A and GABA_A receptor genes). An electrophysiological (EEG) pattern characterized by excessive activity in the beta (15-30 Hz) band has been noted in clinical reports (Urraca, 2013), likely rooted in disruption of GABAergic tone.

Objectives:  We asked whether spontaneous EEG oscillatory power distinguished children with Dup15q syndrome from those with non-syndromic ASD and then examined the clinical correlates of this electrophysiological biomarker in Dup15q syndrome (Frohlich et al, under review).

Methods: In the first study, we recorded spontaneous EEG from children with Dup15q syndrome (n = 11), age-and-IQ-matched children with ASD (n = 10) and age-matched typically developing (TD) children (n = 9) and computed relative power in 6 frequency bands for 9 regions of interest (ROIs). Group comparisons were made using a repeated measures analysis of variance. In the second study, we partnered with the national Dup15q Alliance and recorded spontaneous EEG from a larger cohort at the biannual Dup15q Family Meeting (n=27). We then examined age, epilepsy, and duplication type as predictors of beta power using linear regressions.

Results: Spontaneous beta1 (12 – 20 Hz) and beta2 (20 – 30 Hz) power were significantly higher in Dup15q syndrome compared with both comparison groups, while delta power (1 – 4 Hz) was significantly lower than both comparison groups. Effect sizes in all three frequency bands were large (|d| > 1, |d|>1.7 in beta2). Beta2 power was significantly related to epilepsy diagnosis in Dup15q syndrome. In a subset of participants with longitudinal data, beta power remained stable over time.

Conclusions:

Our findings have laid the foundation for a larger scale study of the functional and clinical implications of electrophysiological biomarkers in this syndrome. We are examining the stability of beta power and whether it is modulated with cognitive or perceptual tasks, or during sleep. One might hypothesize that persistent beta oscillations in sleep could disrupt sleep architecture enough to impact cognition and behavior in these children. A lack of modulation of EEG oscillations during cognitive tasks also could directly hinder learning. We also are quantifying EEG oscillations in several pre-clinical models of Dup15q syndrome in order to elucidate the specific role of UBE3A and GABA_A receptor gene expression on this biomarker. We consider this study in the context of larger scale efforts in autism genetics to identify biomarkers that may facilitate clinical stratification, treatment monitoring, and measurement of target engagement for future clinical trials that target the putative effects of genes implicated in neurodevelopmental disorders.