Duplications of 15q11.3-21.1 (Dup15q syndrome) are highly penetrant for intellectual disability (ID), autism spectrum disorder (ASD) and epilepsy (Finucane et al., 2016). Several genes in the region, particularly UBE3A and a cluster of GABAA receptor genes, are critical for neural development, disrupting synaptic protein synthesis and degradation as well as inhibitory neurotransmission. In a previous study, we identified an electrophysiological biomarker of this syndrome defined by increased beta band oscillations that likely reflect aberrant GABAergic neurotransmission (Frohlich et al., 2016). As we further explored properties of this biomarker, we discovered that the sleep physiology in these children is profoundly abnormal, with grossly attenuated slow wave sleep and reduced sleep spindle density. Healthy sleep physiology is necessary for robust cognitive development, from early infancy through adulthood, (den Bakker et al., 2018; Fogel & Smith, 2011; Hahn et al., 2018; Tham, Schneider, & Broekman, 2017), and there is extensive evidence of physiological sleep impairment in neurodevelopmental disorders (Gruber & Wise, 2016; Kose, Yilmaz, Ocakoglu, & Ozbaran, 2017; Tessier et al., 2015). We hypothesize that abnormal sleep physiology directly undermines cognitive development in Dup15q syndrome and may serve as a quantifiable and modifiable target for pharmacological or even behavioral interventions. Through a partnership with the Dup15q Alliance (patient advocacy group) and our UCLA Intellectual and Developmental Disabilities Research Center (IDDRC), we propose a comprehensive study of sleep electrophysiology and cognition in Dup15q syndrome. We will collect previously recorded overnight clinical EEG?s from children with Dup15q syndrome across the country and compare these EEG?s to those of children with nonsyndromic ID and typical development. We will ask whether sleep physiology, specifically (1) spindle density, (2) percent slow wave sleep, (3) percent spikes in slow wave sleep and (4) absolute beta power in stage 1 and 2 of sleep differentiates Dup15q syndrome from these comparison groups and whether these variables relate to cognition and adaptive skills. The field of neurodevelopmental disorders has sorely lacked quantifiable electrophysiological biomarkers that relate to disease mechanisms, and sleep EEG may represent a robust biomarker that sheds light on the etiology of cognitive impairment while also serving as a surrogate endpoint in clinical trials, particularly for Dup15q syndrome. Moreover, the pipeline that we have developed, from building a remote clinical EEG repository to performing semi-automated sleep EEG signal processing can inform other biomarker studies in syndromic and nonsyndromic forms of ID.
Dup15q syndrome is a genetic condition strongly associated with Intellectual Disability (ID). Abnormal sleep has been shown to be linked to cognitive impairment. Here, we examine sleep rhythms and cognition in Dup15q syndrome, with the goal of eventually developing a clinical trial to improve sleep and cognition in these children.
