This study represents one of the largest research cohorts of children with a rare neuropsychiatric risk chromosomal variant that has assessed sleep symptomatology, and conducted deep phenotyping across a broad range of psychiatric, neurodevelopmental and cognitive domains. Children were ascertained on the basis on genetic liability rather than psychiatric diagnosis, allowing for prospective transdiagnostic assessment of childhood development and psychiatric outcomes.
This study details the range of sleep symptomatology present across a range of rare neurodevelopmental risk genetic variants. We found that children with a ND-GC had an increased prevalence of insomnia compared to control siblings (41% vs 7%), and were more likely to experience at least one sleep related symptom compared to control siblings (66% vs 39%). The prevalence of insomnia reported is in line with a recent meta-analysis, whereby 45% of children with a rare genetic condition experienced insomnia(Agar et al., 2021). Our study goes a step further, by investigating detailed clinical features of insomnia, and finding that all stages of the sleep cycle are disrupted, with initial (falling to sleep), middle (during the night) and early (morning) insomnia showing increased prevalence in children with a ND-GC compared to controls (initial insomnia 14% vs 3%; middle insomnia 14% vs 2%; early insomnia 25% vs 4%). Furthermore, sleep problems were found to onset early in childhood, particularly so for ND-GC children where the average onset was 2.8 years (vs 5.5 years for sibling controls). This highlights that many children with insomnia may have longstanding difficulties, but it also points towards opportunity for early detection of children who are not only at high risk of continuing sleep problems but also at higher risk of psychopathological outcomes. Beyond insomnia, our study details the broad range of sleep symptomatology experienced by children with ND-CG, including increased symptoms of tiredness, fatiguability, restlessness, feeling unrested and night terrors compared to controls. Parents reported sleep problems impacted more on a range of psychosocial contexts for children with ND-CG than their siblings, including in the home, school, community and with peers.
Using sleep symptomatology data, three sleep subtypes could be defined and these corresponded to transdiagnostic risk of a range of co-occurring psychiatric symptoms. Two high symptomatology subgroups were identified which, although overlapping in symptom profiles, were distinguishable: High-Insomnia was distinguished by a high prevalence of insomnia and parasomnias, whereas High-Tiredness was characterised by higher prevalence of hypersomnia and extreme feelings of daytime tiredness. Within children with a ND-GC, sleep class subgroup status was found to successfully stratify psychiatric risk. The two high symptomatology subtypes when contrasted to the low symptomatology subtype, indexed higher rates of psychiatric conditions (OR = 32.0-21.5), including ADHD (OR = 3.3–3.4), anxiety (OR = 3.1-4.0), depression (OR = 7.3–21.5) and ODD (OR = 2.0-2.6). The two high symptomatology subgroups did not differ from the low subgroup in cognitive ability. The High-Insomnia subgroup was additionally at increased risk for autism, OCD, and tic disorder, relative to the Low subgroup (OR = 2.7–2.9). The High-Tiredness subgroup was additionally at increased risk for psychotic experiences (OR = 2.6). Our findings support a “combined risk liability model” whereby sleep problems, a) are elevated within children with a ND-GC, and b) predict individual variability in psychiatric outcome. This extends previous findings for 22q11.2 Deletion Syndrome which found that that sleep symptoms indexed higher rates of a range of psychiatric conditions(Moulding et al., 2020), and findings of bidirectional relationships between sleep disturbance and psychiatric outcomes in the general population(Dauvilliers et al., 2013; Halstead et al., 2021; Jeppesen et al., 2015; Lopez et al., 2017).
This study has identified subgroups of children with high sleep symptomatology who are also particularly vulnerable to risk of a transdiagnostic range of psychiatric problems. Within this study design it is not possible to infer causality, as sleep problems could be an independent marker of psychiatric vulnerability, or sleep problems could be a consequence of the onset psychiatric conditions(Dauvilliers et al., 2013; Faulkner & Bee, 2016). However, our findings do indicate that sleep problems often start from a young age, suggesting they may represent an early marker of later atypical psychiatric development. Furthermore, whether or not sleep problems or psychiatric symptoms are the root cause, the presence of sleep problems in the context of psychiatric symptoms requires clinical attention as sleep disturbance is known to exacerbate psychiatric symptoms and lead to worse prognosis in children(Van Dyk et al., 2016). By starting from genetic risk, we were able to establish risk indicators based on childhood sleep symptom patterns. This demonstrates the potential of genotype-first study designs for uncovering transdiagnostic risk mechanisms for the development of psychiatric conditions.
Our study finds the profile of sleep symptomatology to be broadly similar across different rare psychiatric risk variants. This is consistent with previous work by our group showing that neurodevelopmental and psychiatric traits are broadly similar across ND-GCs, although subtle differences may be present(Chawner, Doherty, et al., 2021; Chawner et al., 2019). Similarly, a meta-analysis of sleep disorders in individuals with rare genetic conditions reported that the rate of insomnia was similar across rare conditions(Agar et al., 2021). Our work highlights sleep problems as non-specific features of rare psychiatric risk variants, that often emerge early in development and are associated with markedly increased psychiatric risk.
This work has some limitations. Children with ND-GCs were identified via medical genetic clinics to which referral is often for developmental issues, which is likely to introduce ascertainment bias. Furthermore, there is likely to be bias in terms of those families who take part in research. This could potentially reduce the variability of the sample and make the sample biased towards higher symptomatology. Our reported rates of sleep symptoms may not be representative of the population, but nonetheless this information has clinical utility for informing families currently receiving genetic diagnoses. Although population-based studies exist(Olsen et al., 2018; Sánchez et al., 2022) they often do not include detailed information on sleep symptoms and rely on medical records. Furthermore, although we identify sleep as a transdiagnostic marker, the causes of the sleep problems from which our sleep subtypes were derived could have a range of heterogeneous causes. Recent work in children with 22q11.2 Deletion Syndrome found that, during NREM sleep, deletion carriers exhibited increased power in slow delta and sigma oscillations, increased slow-wave and spindle amplitudes, and altered coupling between spindles and slow-waves(Donnelly et al., 2021). Future work needs to expand this neurobiological approach across a range of rare psychiatric variants to determine whether mechanisms are common across genomic loci.