Abnormal sleep physiology in children with 15q11.2-13.1 duplication (Dup15q) syndrome

Abstract

Background Sleep disturbances in autism spectrum disorder (ASD) represent a common and vexing comorbidity. Clinical heterogeneity amongst these warrants studies of the mechanisms associated with specific genetic etiologies. Duplications of 15q11.2-13.1 (Dup15q syndrome) are highly penetrant for neurodevelopmental disorders (NDDs) such as intellectual disability and ASD, as well as sleep disturbances. Genes in the 15q region, particularly UBE3A and a cluster of GABAA receptor genes, are critical for neural development, synaptic protein synthesis and degradation, and inhibitory neurotransmission. During awake electroencephalography (EEG), children with Dup15q syndrome demonstrate increased beta band oscillations (12–30 Hz) that likely reflect aberrant GABAergic neurotransmission. Healthy sleep rhythms, necessary for robust cognitive development, are also highly dependent on GABAergic neurotransmission. We therefore hypothesized that sleep physiology would be abnormal in children with Dup15q syndrome. Methods To test the hypothesis that elevated beta oscillations persist in sleep in Dup15q syndrome and that NREM sleep rhythms would be disrupted, we computed: (1) beta power, (2) spindle density, and (3) percentage of slow-wave sleep (SWS) in overnight sleep EEG recordings from a cohort of children with Dup15q syndrome (n = 15) and compared them to age-matched neurotypical children (n = 12). Results Children with Dup15q syndrome showed abnormal sleep physiology with elevated beta power, reduced spindle density, and reduced or absent SWS compared to age-matched neurotypical controls. Limitations This study relied on clinical EEG where sleep staging was not available. However, considering that clinical polysomnograms are challenging to collect in this population, the ability to quantify these biomarkers on clinical EEG—routinely ordered for epilepsy monitoring—opens the door for larger-scale studies. While comparable to other human studies in rare genetic disorders, a larger sample would allow for examination of the role of seizure severity, medications, and developmental age that may impact sleep physiology. Conclusions We have identified three quantitative EEG biomarkers of sleep disruption in Dup15q syndrome, a genetic condition highly penetrant for ASD. Insights from this study not only promote a greater mechanistic understanding of the pathophysiology defining Dup15q syndrome, but also lay the foundation for studies that investigate the association between sleep and cognition. Abnormal sleep physiology may undermine healthy cognitive development and may serve as a quantifiable and modifiable target for behavioral and pharmacological interventions.

Neural complexity is a common denominator of human consciousness across diverse regimes of cortical dynamics

“…Dup15q, on the other hand, is the genetic converse of AS featuring duplication, rather than deletion, of 15q11.2-q13.1 and is characterized by an abnormally fast, rather than slow, EEG phenotype 13,69 . Given that 60% of children with Dup15q completely lack N3 slow wave sleep in overnight EEGs, there is some evidence that Dup15q presents the opposite paradox as AS, with fast EEG oscillations typical of wakefulness during NREM sleep 18 .…”

“…Specifically, children with AS display lowfrequency delta activity in their wake EEGs typical of slow-wave sleep or anesthesia, even when the children are fully awake and conscious 17 . Conversely, children with Dup15q display highfrequency beta activity in their EEGs that can persist into NREM sleep, often resulting in no identifiable slow-wave sleep 18 . Utilizing these two rare genetic disorders together with NT children, we have created a testbed for biomarkers of conscious state.…”

Evaluation of electroencephalography biomarkers for Angelman syndrome during overnight sleep

“…We next performed a secondary spindle analysis using YASA (Vallat & Walker, 2021), a newer open‐source spindle detector that uses multiple criteria simultaneously to identify spindles (see Methods). YASA was adapted from the “A7” spindle detection algorithm that performed best among five detectors at matching human expert performance (Lacourse et al, 2019), and has been previously used to demonstrate that spindles are impaired during sleep in subjects with 15q11.2–13.1 duplication (Dup15q) syndrome (Saravanapandian et al, 2021). YASA detected a trend toward a decrease in spindles in AS EEGs (Figure 5g; F (2,22) = 3.369, p = 0.0529), but no difference in spindle duration by group (Figure 5h; F (2,16) = 0.5670, p = 0.5782).…”

“…Sleep spindles are short, ~11–16 Hz bursts of activity that are linked to memory consolidation and are impaired in a number of neurodevelopmental and neuropsychiatric disorders (Farmer et al, 2018; Ferrarelli et al, 2007; Gorgoni et al, 2020; Gruber & Wise, 2016; Saravanapandian et al, 2021; Ulrich, 2016). By band‐pass filtering signals in the range of spindles, we are able to quantify spindles in AS EEGs despite increased background delta.…”

Investigating the contributions of circadian pathway and insomnia risk genes to autism and sleep disturbances

“…Insomnia risk genes were associated with insomnia traits without altering sleep duration. Frequently identified circadian and insomnia risk CNVs in both ASD cohorts included well known recurrent CNVs linked to ASD susceptibility and sleep problems, such as 16p11.2 and 15q11.2–13.1 [ 53 – 55 ]. However, sensitivity analyses removing recurrent CNVs yielded the same enrichment of CNVs encompassing circadian and insomnia risk genes in ASD.…”