In this study, we report several novel findings related to sleep and psychiatric symptomatology in 22q11.2 CNV carriers. First, similar to 22qDel, 22qDup was associated with more severe sleep disturbances than typically developing controls. Second, we found these sleep disturbances were independent of psychiatric conditions and medication usage. Third, sleep difficulties negatively impacted psychiatric symptomatology in both 22qDel and 22qDup carriers. Fourth, sleep disturbance had a differential impact on particular psychiatric symptoms in 22q11.2 CNV carriers; specifically, positive psychosis-risk symptoms, withdrawn/depressed symptoms, somatic complaints, social problems, thought problems, attention problems, rule breaking, and aggressive behavior. Lastly, we found differences in reported psychiatric symptomatology between 22q11.2 CNV carriers. The 22qDel group had higher levels of psychosis-risk symptoms, somatic complaints, and thought problems, while the 22qDup was associated with more stereotyped behaviors.
We found 22q11.2 CNV carriers reported significantly poorer sleep than controls, cross-sectionally and longitudinally, even when controlling for psychiatric comorbidities and medications, suggesting sleep disturbance is an independent feature of 22q11.2 CNVs. There was no difference in reported sleep disturbance between the two CNV groups. Increased sleep difficulty in 22qDel has been reported in previous cross-sectional studies [29–32]. In our study, about one-third of subjects in both the 22qDel and 22qDup groups were classified as poor sleepers, while prevalence rates of clinically significant sleep problems was previously reported to be greater than 60% in 22qDel carriers [30, 31]. This discrepancy could be attributed to different questionnaires used to classify significant sleep problems, and differing age groups. Our study reports on a cohort with a wide age range, which includes older adult participants, while previous studies focused exclusively on children. This is the first study to investigate sleep disturbance in 22qDup carriers, so there is no data to compare with our cohort.
Across CNV groups, poor sleepers reported elevated psychiatric symptomatology relative to good sleepers. Poor sleep had a consistently strong effect across psychosis-risk symptom subscales (SIPS) and emotional and behavior problems reported on the CBCL, similar to findings observed in idiopathic psychiatric disorders [47, 53]. This finding is also consistent with and builds upon prior literature in 22qDel carriers, which found poor sleep is associated with anxiety disorders, ADHD, and conduct disorders . Poor sleep had a varying impact on subdomains of ASD-related measures (RBS, SRS) and real-world executive function (BRIEF), such that sleep greatly impacted some subscales and had no significant effect on others. Previous studies in idiopathic ASD found poor sleepers scored higher on ritualistic and compulsive subscales of the RBS compared to good sleepers with ASD . Further, sleep fragmentation was associated with RBS total score and ritualistic, compulsive, need for sameness, and restricted behaviors. Our findings in 22q11.2 CNV carriers are mostly consistent with this finding, except we did not find a significant effect of sleep on compulsive behaviors in either model. Consistent with previous findings in idiopathic ASD , we found total SRS score was significantly associated with sleep cross-sectionally and longitudinally, with poorer sleep associated with elevated SRS scores over time. While no SRS subscales were significantly associated with sleep at baseline, all SRS subscales except motivation was associated with sleep across timepoints. Our finding of a significant effect of sleep on BRIEF global composite is supported by a previous study reporting sleep deficits were associated with a worse global composite score on the BRIEF . Contrary to expectations, the effect of sleep on BRIEF subscales did not reach significance at baseline. Longitudinally shifting, working memory, emotional, and monitor subscales were significantly associated with sleep. The discrepancy between cross-sectional and longitudinal findings on measures of real-world executive function and reciprocal social behavior (the BRIEF and the SRS, respectively) could be attributed to multiple factors. Statistically, it is possible that, despite some participant drop-out at the one-year follow-up, the longitudinal model is better powered to detect effects of sleep across timepoints, due to the addition of the within-subject follow-up data. Theoretically, it is also possible that the SRS and BRIEF measures are not impacted by acute poor sleep, but instead chronic poor sleep over an extended period of time affects these processes.
We found sleep has a greater effect on psychiatric symptomatology – namely, positive psychosis-risk symptoms, and withdrawn/depressed, somatic complaints, social problems, thought problems, attention problems, rule breaking, and aggressive behaviors - in 22qDel carriers relative to 22qDup carriers. This suggests 22qDel carriers are more susceptible to the effects of poor sleep compared to 22qDup, which is consistent with the fact that the 22qDel often confers a more severe phenotype compared to the 22qDup . This finding is also consistent with recent cross-sectional findings from our group that the 22qDel has a greater effect on IQ, psychosis-risk symptoms, and brain morphometry compared to the 22qDup [27, 28]. The differential impact of sleep on psychiatric symptoms in 22q11.2 CNV carriers suggests that gene dosage at the 22q11.2 locus may influence mechanisms involved in sleep’s relationship with symptoms of developmental psychiatric disorders. Further, it provides evidence for a genetic-basis of sleep disturbance in 22q11.2 CNVs, and perhaps idiopathic disorders, such as schizophrenia and ASD. This conclusion is supported by a recent study of the 22q11.2 locus in drosophila, which found knockout of the LZTR1 homolog gene on the 22q11.2 locus caused widespread sleep disturbance . Further experiments revealed this gene affects sleep through GABAergic signaling, disruptions in which are also implicated in schizophrenia and ASD [56–60]. Taken together, these results suggest a genetic basis for sleep disturbance in 22q11.2 CNV carriers and associated psychiatric disorders. Further studies are required, in both humans and animal models, in order to identify underlying genetic and neurobiological mechanisms of sleep in 22q11.2 CNV carriers and determine how 22q11.2 genes impact the relationship between sleep and psychiatric symptoms, and if genes within this locus could contribute to sleep’s role in idiopathic disorders. Future studies should include measures of brain circuitry, sleep physiology, and gene expression.
In addition to studying the association between sleep and 22q11.2 CNVs, we also report a number of group differences between 22qDel and 22qDup carriers that have not previously been reported. First, as in Lin et al , we found decreased stereotyped behaviors and increased positive and negative psychosis-risk symptoms in 22qDel carriers compared to 22qDup carriers. Expanding upon this finding, we also found 22qDel carriers reported more severe disorganized -but not general - psychosis-risk symptoms compared to 22qDup. On the CBCL, there was a trend towards a significant group difference in thought problems and somatic complaints. 22qDel carriers reported more thought problems than 22qDup carriers, which is consistent with increased rates of psychotic disorders in 22qDel carriers and decreased rates in 22qDup carriers [19–23, 25, 26]. Additionally, 22qDel carriers reported more somatic complaints, which could be attributed to increased medical problems reported in this population.
In addition to contributing to the mechanistic understanding of the relationship between sleep and psychopathology, our findings also inform clinical knowledge of treating psychiatric symptoms in 22q11.2 CNV carriers. Our study suggests that an intervention that directly targets sleep could have multiple beneficial effects, with downstream influences on psychiatric symptoms and behavioral problems across diagnostic classifications in 22q11.2 CNV carriers. Further research is needed to test the effectiveness of individual sleep treatments in this population. Potential lines of study include clinical trials in 22q11.2 CNV carriers of behavioral sleep therapies, which have been effective in psychotic populations [6, 61], and melatonin, which has been effective in ASD populations [12, 13]. These clinical trials should not only test the ability of an intervention to treat sleep disturbance, but also its impact on neuropsychiatric symptoms.
As with most studies of rare disorders, there are several limitations of this study to consider. We were unable to collect objective, laboratory-based measures of sleep and did not administer a comprehensive sleep questionnaire. For younger participants, sleep disturbance scores were collected via parent report. While we acknowledge the limitations of this measure, we found our two sleep measures were highly correlated. Further, a recent study found that parent-reported subjective sleep report was as valid as participant-reported subjective sleep report when compared to PSG recording . However, it is important to consider that subjective sleep report and PSG-derived sleep measures capture two related but distinct sleep-related processes. While subjective sleep measures are valid, they do not capture information about sleep physiology and neurobiology, meaning we cannot make inferences about biological underpinnings of the observed relationships. Thus, our study focuses only on subjectively-reported sleep disturbance and does not make inferences about objective measures of sleep or sleep physiology. Further, the nature of our sleep variable does not indicate the type of sleep disturbance exhibited, only its presence and severity. 22q11.2 CNVs are associated with craniofacial abnormalities, which can lead to increased rates of sleep-disordered breathing (SDB), such as obstructive sleep apnea [62, 63]. Sleep disturbance related to SDB confers a different clinical phenotype and affects downstream mechanisms differently than a sleep disturbance related to insufficient sleep [64, 65]. While it is possible that the observed difference in sleep disturbance between 22q11.2 CNV carriers and controls could be driven by higher rates of SDB in 22q11.2 CNV carriers, rates of airway problems and/or craniofacial abnormalities did not differ between poor sleepers and good sleepers (see Supplementary Information), so it is unlikely that these medical conditions accounted for the increased rates of poor sleepers. Nevertheless, future investigation of 22q11.2 CNV carriers should consider the differential impacts of sleep breathing disorders and disorders of insufficient sleep on brain structure, psychiatric symptoms, and neurobehavioral traits.
Another limitation to consider is the small sample size of the 22qDup group compared to that of the 22qDel and control groups. Unlike 22qDel carriers, 22qDup carriers often are not identified through clinical genetic testing due to the highly variable phenotype and less frequent medical comorbidity , posing a recruitment challenge for this population. While the cohort of 22qDup included here is relatively modest, it is one of the largest cohorts reported in the literature to date.