Abstract
Studies of 16p11.2 copy number variants (CNVs) provide an avenue to identify mechanisms of impairment and develop targeted treatments for individuals with neurodevelopmental disorders. 16p11.2 deletion and duplication phenotypes are currently being ascertained; however, sleep disturbances are minimally described. In this study, we examine sleep disturbance in a well-characterized national sample of 16p11.2 CNVs, the Simons Foundation Autism Research Initiative (SFARI) database of youth and adults (n = 692). Factor analyses and multilevel models of derived sleep questionnaires for youth (n = 345) and adults (n = 347) indicate that 16p11.2 carriers show elevated sleep disturbance relative to community controls. Non-carrier family members also show elevated sleep disturbance. However, sleep duration does not differ between carriers and controls. Further studies of sleep in 16p11.2 are needed.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Notes
Fisher-Freeman-Halton exact tests determine whether observed values differ from expected values overall for all groups, but do not allow for firm conclusions about which specific differences are significant.
Notation: PSQij = Pediatric sleep questionnaire score (outcome variable); γ00 = Level 2 intercept/grand mean across level 2 units; u0j = random error term; rij = Level 1 residual error term.
All contrasts here and throughout met the assumption of residual variances not differing across families.
References
Achenbach, T. M., & Rescorla, L. A. (2000). Manual for the ASEBA preschool forms and profiles. University of Vermont, Research Center for Children, Youth, & Families.
Acock, A. C. (2005). Working with missing values. Journal of Marriage and Family, 67, 1012–1028. https://doi.org/10.1111/j.1741-3737.2005.00191.x
American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Author.
Angelakos, C. C., Watson, A. J., O’Brien, T., Krainock, K. S., Nickl-Jockschat, T., & Abel, T. (2017). Hyperactivity and male-specific sleep deficits in the 16p11.2 deletion mouse model of autism. Autism Research, 10, 572–584. https://doi.org/10.1002/aur.1707
Baio, J., Wiggins, L., Christensen, D. L., Maenner, M. J., Daniels, J., Warren, Z., & Dowling, N. F. (2018). Prevalence of autism spectrum disorder among children aged 8 years—Autism and developmental disabilities monitoring network, 11 sites, U.S., 2014. Morbidity and Mortality Weekly Report Surveillance Summaries, 67, 1–23. https://doi.org/10.15585/mmwr.ss6706a1
Bazzano, A., Wolfe, C., Zylowska, L., Wang, S., Schuster, E., Barrett, C., & Lehrer, D. (2015). Mindfulness based stress reduction (MBSR) for parents and caregivers of individuals with developmental disabilities: A community-based approach. Journal of Child and Family Studies, 24, 298–308. https://doi.org/10.1007/s10826-013-9836-9
Beauchaine, T. P., & Constantino, J. N. (2017). Redefining the endophenotype concept to accommodate transdiagnostic vulnerabilities and etiological complexity. Biomarkers in Medicine, 11, 769–780. https://doi.org/10.2217/bmm-2017-0002
Beauchaine, T. P., & Hinshaw, S. P. (2020). RDoC and psychopathology among youth: Misplaced assumptions and an agenda for future research. Journal of Clinical Child and Adolescent Psychology, 49, 322–340. https://doi.org/10.1080/15374416.2020.1750022
Betancur, C. (2011). Etiological heterogeneity in autism spectrum disorders: More than 100 genetic and genomic disorders and still counting. Brain Research, 1380, 42–77. https://doi.org/10.1016/j.brainres.2010.11.078
Chervin, R. D., Hedger, K., Dillon, J. E., & Pituch, K. J. (2000). Pediatric sleep questionnaire (PSQ): Validity and reliability of scales for sleep-disordered breathing, snoring, sleepiness, and behavioral problems. Sleep Medicine, 1, 21–32. https://doi.org/10.1016/S1389-9457(99)00009-X
Cohen, S., Fulcher, B. D., Rajaratnam, S. M. W., Conduit, R., Sullivan, J. P., St. Hilaire, M. A., & Lockley, S. W. (2018). Sleep patterns predictive of daytime challenging behavior in individuals with low-functioning autism. Autism Research, 11, 391–403. https://doi.org/10.1002/aur.1899
Constantino, J. N. (2002). Social responsiveness scale – adult version (SRS). Los Angeles, CA: Western Psychological Services.
Constantino, J. N. & Gruber, C. P. (2005). Social responsiveness scale (SRS). Los Angeles, CA: Western Psychological Services.
D’Angelo, D., Lebon, S., Chen, Q., Martin-Brevet, S., Green Snyder, L., Hippolyte, L., & Chung, W. K. (2016). Defining the effect of the 16p11.2 duplication on cognition, behavior, and medical comorbidities. JAMA Psychiatry, 73, 20–30. https://doi.org/10.1001/jamapsychiatry.2015.2123
DiStefano, C., Zhu, M., & Mîndrilă, D. (2009). Understanding and using factor scores: Considerations for the applied researcher. Practical Assessment, Research and Evaluation, 14, 1–11. https://doi.org/10.7275/da8t-4g52
Duyzend, M. H., & Eichler, E. E. (2015). Genotype-first analysis of the 16p11.2 deletion defines a new type of “autism.” Biological Psychiatry, 77, 769–771. https://doi.org/10.1016/j.biopsych.2015.02.032
Elliott, C. D. (2007). Differential ability scales (2nd ed.). Harcourt Assessment Inc.
Esler, A. N., Hus Bal, V., Guthrie, W., Wetherby, A., Ellis Weismer, S., & Lord, C. (2015). The autism diagnostic observation schedule, toddler module: Standardized severity scores. Journal of Autism and Developmental Disorders, 45, 2704–2720. https://doi.org/10.1007/s10803-015-2432-7
España, R. A., & Scammell, T. E. (2011). Sleep neurobiology from a clinical perspective. Sleep, 34, 845–858. https://doi.org/10.5665/SLEEP.1112
Fernandez, B. A., Roberts, W., Chung, B., Weksberg, R., Meyn, S., Szatmari, P., & Scherer, S. W. (2010). Phenotypic spectrum associated with de novo and inherited deletions and duplications at 16p11.2 in individuals ascertained for diagnosis of autism spectrum disorder. Journal of Medical Genetics, 47, 195–203. https://doi.org/10.1136/jmg.2009.069369
Geschwind, D. H. (2008). Autism: Many genes, common pathways? Cell, 135, 391–395. https://doi.org/10.1016/j.cell.2008.10.016
Geschwind, D. H. (2011). Genetics of autism spectrum disorders. Trends in Cognitive Science, 15, 409–416. https://doi.org/10.1016/j.tics.2011.07.003
Gold, A. K., & Sylvia, L. G. (2016). The role of sleep in bipolar disorder. Nature and Science of Sleep, 8, 207–214. https://doi.org/10.2147/NSS.S85754
Goldman, S. E., Richdale, A. L., Clemons, T., & Malow, B. A. (2012). Parental sleep concerns in autism spectrum disorders: Variations from childhood to adolescence. Journal of Autism and Developmental Disorders, 42, 531–538. https://doi.org/10.1007/s10803-011-1270-5
Gotham, K., Pickles, A., & Lord, C. (2009). Standardizing ADOS scores for a measure of severity in autism spectrum disorders. Journal of Autism and Developmental Disorders, 39, 693–705. https://doi.org/10.1007/s10803-008-0674-3
Graham, J. W. (2009). Missing data analysis: Making it work in the real world. Annual Review of Psychology, 60, 549–576. https://doi.org/10.1146/annurev.psych.58.110405.085530
Green, E. K., Rees, E., Walters, J. T. R., Smith, K.-G., Forty, L., Grozeva, D., & Kirov, G. (2016). Copy number variation in bipolar disorder. Molecular Psychiatry, 21, 89–93. https://doi.org/10.1038/mp.2014.174
Green Snyder, L., D’Angelo, D., Chen, Q., Bernier, R., Goin-Kochel, R. P., Stevens Wallace, A., & Hanson, E. (2016). Autism spectrum disorder, developmental and psychiatric features in 16p11.2 duplication. Journal of Autism and Developmental Disorders, 46, 2734–2748. https://doi.org/10.1007/s10803-016-2807-4
Grondhuis, S. N., Lecavalier, L., Arnold, E., Handen, B. L., Scahill, L., McDougle, C. J., & Aman, M. G. (2018). Differences in verbal and nonverbal IQ test scores in children with autism spectrum disorder. Research in Autism Spectrum Disorders, 49, 47–55. https://doi.org/10.1016/j.rasd.2018.02.001
Hallet, V., Lecavalier, L., Sukhodolsky, D. G., Cipriano, N., Aman, M. G., McCracken, J. T., & Scahill, L. (2013). Exploring the manifestations of anxiety in children with autism spectrum disorders. Journal of Autism and Developmental Disorders, 43, 2341–2352. https://doi.org/10.1007/s10803-013-1775-1
Hanson, E., Bernier, R., Porche, K., Jackson, F. I., Goin-Kochel, R. P., Green Snyder, L., & Chung, W. K. (2015). The cognitive and behavioral phenotype of the 16p11.2 deletion in a clinically ascertained population. Biological Psychiatry, 77, 785–793. https://doi.org/10.1016/j.biopsych.2014.04.021
Hanson, E., Nasir, R. H., Fong, A., Lian, A., Hundley, R., Shen, Y., & Miller, D. T. (2010). Cognitive and behavioral characterization of 16p11.2 deletion syndrome. Journal of Developmental and Behavioral Pediatrics, 31, 649–657. https://doi.org/10.1097/DBP.0b013e3181ea50ed
Harvey, A. G., Murray, G., Chandler, R. A., & Soehner, A. (2011). Sleep disturbance as transdiagnostic: Considerations of neurobiological mechanisms. Clinical Psychology Review, 31, 225–235. https://doi.org/10.1016/j.cpr.2010.04.003
Hippolyte, L., Maillard, A. M., Rodriguez-Herreros, B., Pain, A., Martin-Brevet, S., Ferrari, C., & Jacquemont, S. (2016). The number of genomic copies at the 16p11.2 locus modulates language, verbal memory, and inhibition. Biological Psychiatry, 80, 129–139. https://doi.org/10.1016/j.biopsych.2015.10.021
Hollway, J. A., Aman, M. G., & Butter, E. (2013). Correlates and risk markers for sleep disturbance in participants of the Autism Treatment Network. Journal of Autism and Developmental Disorders, 43, 2830–2843. https://doi.org/10.1007/s10803-013-1830-y
Horev, G., Ellegood, J., Lerch, J. P., Son, Y.-E.E., Muthuswamy, L., & Mills, A. A. (2011). Dosage-dependent phenotypes in models of 16p11.2 lesions found in autism. PNAS, 108, 17076–17081. https://doi.org/10.1073/pnas.1114042108
Hus, V., & Lord, C. (2014). The Autism Diagnostic Observation Schedule, module 4: Revised algorithm and standardized severity scores. Journal of Autism and Developmental Disorders, 44, 1996–2012. https://doi.org/10.1007/s10803-014-2080-3
Ingersoll, B., & Hambrick, D. Z. (2011). The relationship between the broader autism phenotype, child severity, and stress and depression in parents of children with autism spectrum disorders. Research in Autism Spectrum Disorders, 5, 337–344. https://doi.org/10.1016/j.rasd.2010.04.017
Jacquemont, S., Reymond, A., Zufferey, F., Harewood, L., Walters, R. G., Kutalik, Z., & Froguel, P. (2011). Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus. Nature, 478, 97–102. https://doi.org/10.1038/nature10406
Johansson, A. E. E., Rohay, J. M., & Chasens, E. R. (2018). Psychometric properties of the simons simplex collection sleep interview. Journal of Nursing Measurement, 26, 453–469. https://doi.org/10.1891/1061-3749.26.3.453
Kalkman, H. O. (2012). Potential opposite roles of the extracellular signal-regulated kinase (ERK) pathway in autism spectrum and bipolar disorders. Neuroscience and Biobehavioral Reviews, 36, 2206–2213. https://doi.org/10.1016/j.neubiorev.2012.07.008
Kamara, D., & Beauchaine, T. P. (2020). A review of sleep disturbances among infants and children with neurodevelopmental disorders. Review Journal of Autism and Developmental Disorders, 7, 278–294. https://doi.org/10.1007/s40489-019-00193-8
Katz, T., Shui, A. M., Johnson, C. R., Richdale, A. L., Reynolds, A. M., Scahill, L., & Malow, B. A. (2018). Modification of the Children’s Sleep Habits Questionnaire for Children with Autism Spectrum Disorder. Journal of Autism and Developmental Disorders, 48, 2629–2641. https://doi.org/10.1016/j.sleep.2015.12.005
Kumar, R. A., KaraMohamed, S., Sudi, J., Conrad, D. F., Brune, C., Badner, J. A., & Christian, S. L. (2008). Recurrent 16p11.2 microdeletions in autism. Human Molecular Genetics, 17, 628–638. https://doi.org/10.1093/hmg/ddm376
Lecavalier, L. (2006). Behavioral and emotional problems in young people with pervasive developmental disorders: Relative prevalence, effects of subject characteristics, and empirical classification. Journal of Autism and Developmental Disorders, 36, 1101–1114. https://doi.org/10.1007/s10803-006-0147-5
Limoges, É., Mottron, L., Bolduc, C., Berthiaume, C., & Godbout, R. (2005). Atypical sleep architecture and the autism phenotype. Brain, 128, 1049–1061. https://doi.org/10.1093/brain/awh425
Lord, C., Risi, S., Lambrecht, L., Cook, E. H., Jr., Leventhal, B. L., DiLavore, P. C., & Rutter, M. (2000). The Autism Diagnostic Observation Schedule – generic: A standard measure of social and communication deficits associated with the spectrum of autism. Journal of Autism and Developmental Disorders, 30, 205–223. https://doi.org/10.1023/A:1005592401947
Lu, H.-C., Pollack, H., Lefante, J. J., Mills, A. A., & Tian, D. (2019). Altered sleep architecture, rapid eye movement sleep, and neural oscillation in a mouse model of human chromosome 16p11.2 microdeletion. Sleep, 42, 1–16. https://doi.org/10.1093/sleep/zsy253
Maillard, A. M., Ruef, A., Pizzagalli, F., Migliavacca, E., Hippolyte, L., Adaszewski, S., & Jacquemont, S. (2015). The 16p11.2 locus modulates brain structures common to autism, schizophrenia and obesity. Molecular Psychiatry, 20, 140–147. https://doi.org/10.1038/mp.2014.145
McCarthy, S., Makarov, V., Kirov, G., Addington, A., McClellan, J., Yoon, S., & Sebat, J. (2009). Microduplications of 16p11.2 are associated with schizophrenia. Nature Genetics, 41, 1223–1227. https://doi.org/10.1038/ng.474
Meltzer, L. J. (2017). Future directions in sleep and developmental psychopathology. Journal of Clinical Child and Adolescent Psychology, 46, 295–301. https://doi.org/10.1080/15374416.2016.1236727
Meltzer, L. J., & Mindell, J. A. (2006). Sleep and sleep disorders in children and adolescents. Psychiatric Clinics of North America, 29, 1059–1076. https://doi.org/10.1016/j.psc.2006.08.004
Meltzer, L. J., & Montgomery-Downs, H. E. (2011). Sleep in the family. Pediatric Clinics of North America, 58, 765–774. https://doi.org/10.1016/j.pcl.2011.03.010
Mong, J. A., & Cusmano, D. M. (2016). Sex differences in sleep: Impact of biological sex and sex steroids. Philosophical Transactions of the Royal Society of London, Series B, Biological Sciences, 371, 20150110. https://doi.org/10.1098/rstb.2015.0110
Mullen, E. M. (1995). Mullen scales of early learning (AGS). American Guidance Service.
Owens, J. A., Spirito, A., & McGuinn, M. (2000). The Children’s Sleep Habits Questionnaire (CSHQ): Psychometric properties of a survey instrument for school-aged children. Sleep, 23, 1043–1052. https://doi.org/10.1037/t33022-000
Pedhazur, E. J. (1997). Multiple regression in behavioral research (3rd ed.). Harcourt Brace.
Prinz, P. N., Vitiello, M. V., Raskind, M. A., & Thorpy, M. J. (1990). Sleep disorders and aging. New England Journal of Medicine, 323, 520–526. https://doi.org/10.1056/NEJM199008233230805
Pucilowska, J., Vithayathil, J., Pagani, M., Kelly, C., Karlo, J. C., Robol, C., & Landreth, G. E. (2018). Pharmacological inhibition of ERK signaling rescues pathophysiology and behavioral phenotype associated with 16p11.2 chromosomal deletion in mice. The Journal of Neuroscience, 38, 6640–6652. https://doi.org/10.1523/JNEUROSCI.0515-17.2018
Qureshi, A. Y., Mueller, S., Snyder, A. Z., Mukherjee, P., Berman, J. I., Roberts, T. P. L., & Buckner, R. L. (2014). Opposing brain differences in 16p11.2 deletion and duplication carriers. Neurobiology of Disease, 34, 11199–11211. https://doi.org/10.1523/JNEUROSCI.1366-14.2014
Raudenbush, S. W., Bryk, A. S., Cheong, A. S., Fai, Y. F., Congdon, R. T., & du Toit, M. (2011). HLM 7: Hierarchical linear and nonlinear modeling. Lincolnwood, IL: Scientific Software International.
Reynolds, A. M., & Malow, B. A. (2011). Sleep and autism spectrum disorders. Pediatric Clinics of North America, 58, 685–698. https://doi.org/10.1007/s10803-013-1866-z
Samuels, I. S., Saitta, S. C., & Landreth, G. E. (2009). MAP’ing CNS development and cognition: An ERKsome process. Neuron, 61, 160–167. https://doi.org/10.1016/j.neuron.2009.01.001
Simons VIP Consortium. (2012). Simons variation in individuals project (Simons VIP): A genetics-first approach to studying autism spectrum and related neurodevelopmental disorders. Neuron, 73, 1063–1067. https://doi.org/10.1016/j.neuron.2012.02.014
Stefansson, H., Meyer-Lindenberg, A., Steinberg, S., Magnusdottir, B., Morgen, K., Arnarsdottir, S., & Stefansson, K. (2014). CNVs conferring risk of autism or schizophrenia affect cognition in controls. Nature, 505, 361–366. https://doi.org/10.1038/nature12818
Tabet, A.-C., Pilorge, M., Delorme, R., Amsellem, F., Pinard, J.-M., Leboyer, M., & Betancur, C. (2012). Autism multiplex family with 16p11.2p12.2 microduplication syndrome in monozygotic twins and distal 16p11.2 deletion in their brother. European Journal of Human Genetics, 20, 540–546. https://doi.org/10.1038/ejhg.2011.244
Thapar, A., & Cooper, M. (2013). Copy number variation: What is it and what has it taught us about child psychiatric disorders? Journal of the American Academy of Child & Adolescent Psychiatry, 52, 772–772. https://doi.org/10.1016/j.jaac.2013.05.013
Tudor, M. E., Walsh, C. E., Mulder, E. C., & Lerner, M. D. (2015). Pain as a predictor of sleep problems in youth with autism spectrum disorders. Autism, 19, 1–9. https://doi.org/10.1177/1362361313518994
Wechsler, D. (1999). Wechsler abbreviated scale of intelligence. The Psychological Corporation.
Weiss, L. A., Shen, Y., Korn, J. M., Arking, D. E., Miller, D. T., Fossdal, R., & Daly, M. J. (2008). Associations between microdeletion and microduplication at 16p11.2 and autism. The New England Journal of Medicine, 358, 667–675. https://doi.org/10.1056/NEJMoa075974
Wiggs, L., & Stores, G. (2004). Sleep patterns and sleep disorders in children with autistic spectrum disorders: Insights using parent report and actigraphy. Developmental Medicine and Child Neurology, 46, 372–380. https://doi.org/10.1017/S0012162204000611
Williams, P. G., Sears, L. L., & Allard, A. (2004). Sleep problems in children with autism. Journal of Sleep Research, 13, 265–268. https://doi.org/10.1111/j.1365-2869.2004.00405.x
Acknowledgements
Preparation of this article was supported in part by Grants UH2DE025980 and UL1TR002733 from the National Institutes of Health. The authors would like to thank Drs. Nicholas J. Rockwood, Andrea N. Witwer, and Michael Vasey for their feedback and contributions. In addition, we would like to thank the Simons Foundation and Simons VIP participating sites and families for making this work possible. The authors declare they have no conflicts of interest. All authors contributed to the conceptualization of the project and manuscript development. Data analysis was completed by the primary author with guidance from Drs. Beauchaine and De Boeck.
Author information
Authors and Affiliations
Contributions
All authors contributed to the conceptualization of the project and manuscript preparation. DK prepared data and completed analyses with guidance from TB and PDB.
Corresponding author
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Kamara, D., De Boeck, P., Lecavalier, L. et al. Characterizing Sleep Problems in 16p11.2 Deletion and Duplication. J Autism Dev Disord 53, 1462–1475 (2023). https://doi.org/10.1007/s10803-021-05311-2
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10803-021-05311-2