Rare genetic variants that confer large effects on neurodevelopment and behavioral phenotypes can reveal novel gene‐brain‐behavior relationships relevant to autism. Copy number variation at the ...22q11.2 locus offer one compelling example, as both the 22q11.2 deletion (22qDel) and duplication (22qDup) confer increased likelihood of autism spectrum disorders (ASD) and cognitive deficits, but only 22qDel confers increased psychosis risk. Here, we used the Penn Computerized Neurocognitive Battery (Penn‐CNB) to characterized neurocognitive profiles of 126 individuals: 55 22qDel carriers (MAge = 19.2 years, 49.1% male), 30 22qDup carriers (MAge = 17.3 years, 53.3% male), and 41 typically developing (TD) subjects (MAge = 17.3 years, 39.0% male). We performed linear mixed models to assess group differences in overall neurocognitive profiles, domain scores, and individual test scores. We found all three groups exhibited distinct overall neurocognitive profiles. 22qDel and 22qDup carriers showed significant accuracy deficits across all domains relative to controls (episodic memory, executive function, complex cognition, social cognition, and sensorimotor speed), with 22qDel carriers exhibiting more severe accuracy deficits, particularly in episodic memory. However, 22qDup carriers generally showed greater slowing than 22qDel carriers. Notably, slower social cognition speed was uniquely associated with increased global psychopathology and poorer psychosocial functioning in 22qDup. Compared to TD, 22q11.2 copy number variants (CNV) carriers failed to show age‐associated improvements in multiple cognitive domains. Exploratory analyses revealed 22q11.2 CNV carriers with ASD exhibited differential neurocognitive profiles, based on 22q11.2 copy number. These results suggest that there are distinct neurocognitive profiles associated with either a loss or gain of genomic material at the 22q11.2 locus.
Lay Summary
This study examined reciprocal deletions and duplications at Chromosome 22q11.2, which strongly impact brain development, cognition, and behavior. We found that there are distinct patterns of cognitive performance that characterize these disorders, and that better social cognition was uniquely associated with less severe psychopathology and better psychosocial functioning in individuals with a 22q11.2 Duplication.
22q11.2 deletions and duplications are copy number variations (CNVs) that predispose to developmental neuropsychiatric disorders. Both CNVs are associated with autism spectrum disorder (ASD), while ...the deletion confers disproportionate risk for schizophrenia. Neurobehavioral profiles associated with these reciprocal CNVs in conjunction with brain imaging measures have not been reported.
We profiled the impact of 22q11.2 CNVs on neurobehavioral measures relevant to ASD and psychosis in 106 22q11.2 deletion carriers, 38 22q11.2 duplication carriers, and 82 demographically matched healthy control subjects. To determine whether brain–behavior relationships were altered in CNV carriers, we further tested for interactions between group and regional brain structure on neurobehavioral domains.
Cognitive deficits were observed in both CNV groups, with the lowest IQs in deletion carriers. ASD and dimensionally measured ASD traits were elevated in both CNV groups; however, duplication carriers exhibited increased stereotypies compared to deletion carriers. Moreover, discriminant analysis using ASD subdomains distinguished between CNV cases with 76% accuracy. Both psychotic disorder diagnosis and dimensionally measured positive and negative symptoms were elevated in deletion carriers. Finally, healthy control subjects showed an inverse relationship between processing speed and cortical thickness in heteromodal association areas, which was absent in both CNV groups.
22q11.2 CNVs differentially modulate intellectual functioning and psychosis-related symptomatology but converge on broad ASD-related symptomatology. However, subtle differences in ASD profiles distinguish CNV groups. Processing speed impairments, coupled with the lack of normative relationship between processing speed and cortical thickness in CNV carriers, implicate aberrant development of the cortical mantle in the pathology underlying impaired processing speed ability.
Sleep disturbance is common, impairing, and may affect symptomatology in developmental neuropsychiatric disorders. Here, we take a genetics-first approach to study the complex role of sleep in ...psychopathology. Specifically, we examine severity of sleep disturbance in individuals with a reciprocal copy number variant (CNV) at the 22q11.2 locus and determine sleep's effect on psychiatric symptoms. CNVs (deletion or duplication) at this locus confer some of the greatest known risks of neuropsychiatric disorders; recent studies suggest the 22q11.2 deletion negatively impacts sleep, but sleep disruption associated with 22q11.2 duplication has not been investigated.
We compared subjective sleep disturbance and its relationship to psychiatric symptoms cross-sectionally and longitudinally over 1 year in 107 22q11.2 deletion (22qDel) carriers (14.56±8.0 years; 50% male), 42 22q11.2 duplication (22qDup) carriers (16.26±13.1 years; 54.8% male), and 88 age- and sex-matched controls (14.65±7.4 years; 47.1% male). Linear mixed models were used to compare sleep disturbance, assessed via the Structured Interview for Psychosis-Risk Syndromes (SIPS), across groups. Next, CNV carriers were categorized as good or poor sleepers to investigate sleep effects on multiple neurobehavioral traits: psychosis-risk symptoms (SIPS), autism-related behaviors (Repetitive Behavior Scale (RBS) and Social Responsiveness Scale (SRS)), real-world executive function (Behavior Rating Inventory of Executive Function (BRIEF)), and emotional/behavioral problems (Child Behavior Checklist (CBCL)). Linear mixed models tested the effect of sleep category and a group-by-sleep interaction on each measure, cross-sectionally and longitudinally.
22qDel and 22qDup carriers both reported poorer sleep than controls, but did not differ from each other. Cross-sectionally and longitudinally, poor sleepers scored higher on positive symptoms, anxious/depressed, somatic complaints, thought problems, and aggressive behavior, as well as RBS and SRS total scores. There were significant group-by-sleep interactions for positive symptoms and the majority of CBCL subdomains, in which the difference between good and poor sleepers was larger in 22qDel compared to 22qDup.
Our findings indicate that CNVs at the 22q11.2 locus impact sleep which, in turn, influences psychopathology. Sleep disturbances can differentially impact psychopathology, depending on 22q11.2 gene dosage. Our findings serve as a starting point for exploring a genetic basis for sleep disturbance in developmental neuropsychiatric disorders.
Abstract
Introduction
There is compelling evidence that sleep spindles, electroencephalogram (EEG) signatures of non-rapid eye movement sleep, are reliable markers of thalamocortical dysfunction in ...Schizophrenia. While promising, this research is limited by traditional sleep EEG methods, which cultivate small, non-representative samples. Wearable EEG headbands could be used to study naturalistic sleep across several nights in individuals who cannot tolerate standard sleep assessments, but this has yet to be tested. We aim to test feasibility of using a dry-EEG headband to measure sleep spindles in adolescents with a neurodevelopmental disorder, 22q11.2 Deletion Syndrome (22q11DS).
Methods
Adolescents with 22q11DS (n=7; 3 Females; Age: 15-28 years) were asked to sleep in their own bed wearing a dry-EEG headband (Dreem 3). Feasibility of data acquisition was determined by the ability of the participants to record at least 3 consecutive nights. We performed visual artifact detection and examined the ability to detect sleep spindles using the well-validated Ferrarelli Spindle Detection Algorithm on the F7-O2 electrode.
Results
All subjects completed at least 3 nights of recording (range: 3-5 nights), suggesting the device was well-tolerated. The data contained minimal artifact; 17 out of the 22 nights available for analysis contained artifact in < 20% of sleep epochs. The best night contained artifact in only 6% of sleep epochs. Sleep spindles were successfully detected using an automatic detector (M= 1.92 spindles/minute).
Conclusion
This pilot study suggests dry-EEG headbands offer a feasible method to measure sleep spindles in individuals with neurodevelopmental disorders. This new technology could allow for scalable biomarkers of atypical neurodevelopment associated with psychiatric disorders.
Support (if any)
RO1 MH085953; U01MH10171; UCLA Center for Autism Research Pilot Grant; Dreem Coup de Coeur Award
Prader Willi Syndrome (PWS) is a genetic disorder caused by the absence of expression of the paternal copies of maternally imprinted gene(s) located at 15q11-q13. While the physical and medical ...characteristics of PWS, including short stature, hyperphagia and endocrine dysfunction are well-characterized, systematic investigation of the long-recognized psychiatric manifestations has been recent.
Here, we report on the first remote (web-based) assessment of neurobehavioral traits, including psychosis-risk symptoms (Prodromal Questionnaire-Brief Version; PQ-B) and sleep behaviors (Pittsburgh Sleep Quality Index), in a cohort of 128 participants with PWS, of whom 48% had a paternal deletion, 36% uniparental disomy, 2.4% an imprinting mutation and 13% unknown mutation (mean age 19.3 years ± 8.4; 53.9% female). We aimed to identify the most informative variables that contribute to psychosis-risk symptoms. Multiple domains of cognition (accuracy and speed) were also assessed in a subset of PWS participants (
= 39) using the Penn Computerized Neurocognitive Battery (Penn-CNB).
Individuals with PWS reported a range of psychosis-risk symptoms, with over half reporting cognitive disorganization (63.1%) and about one third reporting unusual beliefs (38.6%) and/or suspiciousness (33.3%). Subjectively-reported sleep quality, nap frequency, sleep duration, sleep disturbance, and daytime dysfunction were significant predictors of psychosis-risk symptom frequency and severity (all
< 0.029). Sleep disturbance ratings were the strongest predictors of psychosis-risk symptoms. Regarding cognition, individuals with PWS showed the most prominent deficits in accuracy on measures of social cognition involving faces, namely Face Memory, Age Differentiation and Emotion Recognition, and greatest slowing on measures of Attention and Emotion Recognition. However, there were no significant differences in psychosis-risk symptoms or cognitive performance as a function of PWS genetic subtype.
PWS is associated with a high prevalence of distressing psychosis-risk symptoms, which are associated with sleep disturbance. Findings indicate that self/parent-reported neurobehavioral symptoms and cognition can be assessed remotely in individuals with PWS, which has implications for future large-scale investigations of rare neurogenetic disorders.
Abstract
Recurrent, de novo, meiotic non-allelic homologous recombination events between low copy repeats, termed LCR22s, leads to the 22q11.2 deletion syndrome (22q11.2DS; velo-cardio-facial ...syndrome/DiGeorge syndrome). Although most 22q11.2DS patients have a similar sized 3 million base pair (Mb), LCR22A-D deletion, some have nested LCR22A-B or LCR22A-C deletions. Our goal is to identify additional recurrent 22q11.2 deletions associated with 22q11.2DS, serving as recombination hotspots for meiotic chromosomal rearrangements. Here, using data from Affymetrix 6.0 microarrays on 1680 22q11.2DS subjects, we identified what appeared to be a nested proximal 22q11.2 deletion in 38 (2.3%) of them. Using molecular and haplotype analyses from 14 subjects and their parent(s) with available DNA, we found essentially three types of scenarios to explain this observation. In eight subjects, the proximal breakpoints occurred in a small sized 12 kb LCR distal to LCR22A, referred to LCR22A+, resulting in LCR22A+-B or LCR22A+-D deletions. Six of these eight subjects had a nested 22q11.2 deletion that occurred during meiosis in a parent carrying a benign 0.2 Mb duplication of the LCR22A-LCR22A+ region with a breakpoint in LCR22A+. Another six had a typical de novo LCR22A-D deletion on one allele and inherited the LCR22A-A+ duplication from the other parent thus appearing on microarrays to have a nested deletion. LCR22A+ maps to an evolutionary breakpoint between mice and humans and appears to serve as a local hotspot for chromosome rearrangements on 22q11.2.
Abstract Introduction A 22q11.2 deletion (22qDel), is a recurrent copy number variant with profound impacts on neurodevelopment. Disruptions in non-rapid eye movement (NREM) sleep neurophysiology ...have been observed across idiopathic psychiatric disorders. However, it is unknown whether NREM disruptions exist in 22qDel carriers, who have elevated risk of developing psychiatric disorders. Here, we test the hypothesis that 22qDel carriers will exhibit disrupted NREM sleep neurophysiology across the power spectrum. Methods 22qDel carriers (n=12, Mage=20.42, 13-28 years, 58.3% males) and TD controls (n=11; Mage=19.18, 13-23 years, 27.3% males) completed multiple nights (89 nights total; 1-6 nights per subject; median=3 nights) of sleep EEG recordings with a wearable headband (Dreem 3). 30-second epochs were excluded for visual artifact or high 20-40Hz power. Relative power in the F7-O2 channel during NREM sleep was calculated using multitaper spectral estimation. Differences in relative power between 22qDel carriers and TD controls were tested across 0.5-20Hz using linear mixed-effects models controlling for age and sex. False Discovery Rate (FDR) was used to correct for multiple comparisons. Results There was increased NREM power in slow delta frequencies (0.76-0.85 Hz; q< 0.05) and theta/alpha frequencies (5.95-9.73 Hz; q< 0.05) in 22qDel carriers, relative to TD controls. There were increases in the alpha/sigma range (9.73-12.63 Hz) in 22qDel carriers, but these results did not survive FDR correction (q< 0.10). Conclusion These findings suggest that neural mechanisms of NREM sleep regulation, particularly homeostatic sleep regulation, may be dysregulated in 22qDel carriers. Next steps will involve examining group differences in specific features of NREM sleep physiology (e.g., slow waves). Support (if any) R01MH085953; UCLA Center for Autism Research Pilot Grant; Autism Speaks Predoctoral Fellowship #13530
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