Journal of Autism and Developmental Disorders

, Volume 46, Issue 8, pp 2734–2748 | Cite as

Autism Spectrum Disorder, Developmental and Psychiatric Features in 16p11.2 Duplication

  • LeeAnne Green Snyder
  • Debra D’Angelo
  • Qixuan Chen
  • Raphael Bernier
  • Robin P. Goin-Kochel
  • Arianne Stevens Wallace
  • Jennifer Gerdts
  • Stephen Kanne
  • Leandra Berry
  • Lisa Blaskey
  • Emily Kuschner
  • Timothy Roberts
  • Elliot Sherr
  • Christa L. Martin
  • David H. Ledbetter
  • John E. Spiro
  • Wendy K. Chung
  • Ellen Hanson
  • on behalf of the Simons VIP consortium
Original Paper

Abstract

The 16p11.2 duplication (BP4–BP5) is associated with Autism Spectrum Disorder (ASD), although significant heterogeneity exists. Quantitative ASD, behavioral and neuropsychological measures and DSM-IV diagnoses in child and adult carriers were compared with familial non-carrier controls, and to published results from deletion carriers. The 16p11.2 duplication phenotype ranges widely from asymptomatic presentation to significant disability. The most common diagnoses were intellectual disability, motor delays and Attention Deficit Hyperactivity Disorder in children, and anxiety in adults. ASD occurred in nearly 20 % of child cases, but a majority of carriers did not show the unique social features of ASD. The 16p11.2 duplication phenotype is characterized by wider variability than the reciprocal deletion, likely reflecting contributions from additional risk factors.

Keywords

16p11.2 duplication Genetics Neuropsychological Autism Intellectual disability Cognitive 

Supplementary material

10803_2016_2807_MOESM1_ESM.pdf (48 kb)
Supplementary material 1 (PDF 48 kb)
10803_2016_2807_MOESM2_ESM.docx (1.9 mb)
Supplementary material 2 (DOCX 1911 kb)

References

  1. Achenbach, T. M., & Dumenci, L. (2001). Advances in empirically based assessment: revised cross-informant syndromes and new DSM-oriented scales for the CBCL, YSR, and TRF: Comment on Lengua, Sadowski, Friedrich, and Fischer. Journal of Consulting and Clinical Psychology, 69, 699–702.CrossRefPubMedGoogle Scholar
  2. Achenbach, T., & Rescorla, L. (2001). The manual for the ASEBA school-age forms and profiles. Burlington: University of Vermont, Research Center for Children, Youth, and Families.Google Scholar
  3. Achenbach, T. M., & Rescorla, L. A. (2003). Manual for the ASEBA adult forms and profiles. Burlington: University of Vermont, Research Center for Children, Youth, and Families.Google Scholar
  4. American Psychiatric Association. (2000). Diagnostic and statistical manual of mental disorders (4th ed.). Washington, DC: American Psychiatric Association.Google Scholar
  5. Benjamini, Y., & Hochberg, Y. (1995). Controlling the false discovery rate: A practical and powerful approach to multiple testing. Journal of the Royal Statistical Society: Series B, 57, 289–300.Google Scholar
  6. Betancur, C. (2011). Etiological heterogeneity in autism spectrum disorders: More than 100 genetic and genomic disorders and still counting. Brain Research, 1380, 42–77.CrossRefPubMedGoogle Scholar
  7. Bijlsma, E. K., Gijsbers, A. C., Schuurs-Hoeijmakers, J. H., van Haeringen, A., Fransen van de Putte, D. E., Anderlid, B. M., et al. (2009). Extending the phenotype of recurrent rearrangements of 16p11.2: Deletions in mentally retarded patients without autism and in normal individuals. European Journal of Medical Genetics, 52, 77–87.CrossRefPubMedGoogle Scholar
  8. Buxbaum, J. D., Daly, M. J., Devlin, B., Lehner, T., Roeder, K., & State, M. W. (2012). The autism sequencing consortium: Large scale, high throughput sequencing in autism spectrum disorders. Neuron, 76, 1052–1056.CrossRefPubMedGoogle Scholar
  9. Carrow-Woolfolk, E. (1999). Comprehensive assessment of spoken language. Torrance: Western Psychological Services.Google Scholar
  10. Constantino, J. N., & Gruber, C. P. (2005). The social responsiveness scale manual. Los Angeles: Western Psychological Services.Google Scholar
  11. Constantino, J. N., & Todd, R. D. (2005). Intergenerational transmission of subthreshold autistic traits in the general population. Biological Psychiatry, 57, 655–660.CrossRefPubMedGoogle Scholar
  12. D’Angelo, D., Lebon, S., Chen, Q., Martin-Brevet, S., Green Snyder, L., Hippolyte, L., et al. (2016). Defining the effect of the 16p11.2 duplication on cognition, behavior, and medical comorbidities. JAMA Psychiatry, 73(1), 20–30.CrossRefPubMedGoogle Scholar
  13. De Rubeis, S., He, X., Goldberg, A., Poultney, C. S., Samocha, K., Cicek, A. E., et al. (2014). Synaptic, transcriptional and chromatin genes disrupted in autism. Nature, 515(7526), 209.CrossRefPubMedPubMedCentralGoogle Scholar
  14. Degenhardt, F., Priebe, L., Herms, S., Mattheisen, M., Mühleisen, T. W., Meier, S., et al. (2012). Association between copy number variants in 16p11.2 and major depressive disorder in a German case–control sample. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 159B, 263–273.CrossRefGoogle Scholar
  15. Derogatis, L. (1994). Symptom Checklist-90-R. Minneapolis: Pearson Assessments.Google Scholar
  16. Duyzend, M. H., Nuttle, X., Coe, B. P., Baker, C., Nickerson, D., Bernier, R., & Eichler, E. E. (2016). Maternal modifiers and parent-of-origin bias of the autism-associated 16p11.2 cnv. The American Journal of Human Genetics, 98, 45–57.CrossRefPubMedGoogle Scholar
  17. Elliott, C. D. (2007). Differential ability scales (2nd ed.). San Antonio: Harcourt Assessment.Google Scholar
  18. Fernandez, B. A., Roberts, W., Chung, B., Weksberg, R., Meyn, S., Szatmari, P., et al. (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.CrossRefPubMedGoogle Scholar
  19. Fisher, P., & Lucas, C. (2006). Diagnostic interview schedule for children (DISC-IV)-young child. New York: Columbia University.Google Scholar
  20. Gaugler, T., Klei, L., Sanders, S. J., Bodea, C. A., Goldberg, A. P., Lee, A. B., et al. (2014). Most genetic risk for autism resides with common variation. Nature Genetics, 46, 881–885.CrossRefPubMedPubMedCentralGoogle Scholar
  21. Ghebranious, N., Giampietro, P. F., Wesbrook, F. P., & Rezkalla, S. H. (2007). A novel microdeletion at 16p11. 2 harbors candidate genes for aortic valve development, seizure disorder, and mild mental retardation. American Journal of Medical Genetics Part A, 143A, 1462–1471.CrossRefPubMedGoogle Scholar
  22. Giaroli, G., Bass, N., Strydom, A., Rantell, K., & McQuillin, A. (2014). Does rare matter? Copy number variants at 16p11.2 and the risk of psychosis: A systematic review of literature and meta-analysis. Schizophrenia Research, 159, 340–346.CrossRefPubMedGoogle Scholar
  23. Girirajan, S., Dennis, M. Y., Baker, C., Malig, M., Coe, B. P., Campbell, C. D., et al. (2013). Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder. The American Journal of Human Genetics, 92, 221–237.CrossRefPubMedGoogle Scholar
  24. Gotham, K., Pickles, A., & Lord, C. (2009). Standardizing ADOS scores for a measure of severity in autism spectrum disorders. Journal of Autism and Development Disorders, 39, 693–705.CrossRefGoogle Scholar
  25. Hanson, E., Bernier, R., Porche, K., Jackson, F. I., Goin-Kochel, R. P., Green Snyder, L., et al. (2015). The cognitive and behavioral phenotype of the 16p11.2 deletion in a clinically ascertained population. Biological Psychiatry, 77, 785–793.CrossRefPubMedGoogle Scholar
  26. Hanson, E., Sideridis, G., Jackson, F., Porche, K., Campe, K., & Huntington, N. (in press). Behavior and Sensory Interests Questionnaire: validation in a sample of children with autism spectrum disorder and other developmental disability. Research in Developmental Disabilities.Google Scholar
  27. Hurley, R. S., Losh, M., Parlier, M., Reznick, J. S., & Piven, J. (2007). The broad autism phenotype questionnaire. Journal of Autism and Developmental Disorders, 37, 1679–1690.Google Scholar
  28. Institute, S. A. S. (2013). SAS institute publication. Cary: SAS Institute Inc.Google Scholar
  29. Iossifov, I., O’Roak, B. J., Sanders, S. J., Ronemus, M., Krumm, N., Levy, D., et al. (2014). The contribution of de novo coding mutations to autism spectrum disorder. Nature, 515, 216–221.CrossRefPubMedPubMedCentralGoogle Scholar
  30. Jacquemont, S., Reymond, A., Zufferey, F., Harewood, L., Walters, R. G., Kutalik, Z., et al. (2011). Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus. Nature, 478, 97–102.CrossRefPubMedPubMedCentralGoogle Scholar
  31. Kirov, G., Pocklington, A. J., Holmans, P., Ivanov, D., Ikeda, M., Ruderfer, D., et al. (2012). De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia. Molecular Psychiatry, 17, 142–153.CrossRefPubMedGoogle Scholar
  32. Klei, L., Sanders, S. J., Murtha, M. T., Hus, V., Lowe, J. K., Willsey, A. J., et al. (2012). Common genetic variants, acting additively, are a major source of risk for autism. Molecular Autism, 3(1), 9.CrossRefPubMedPubMedCentralGoogle Scholar
  33. Kumar, R. A., & Christian, S. L. (2009). Genetics of autism spectrum disorders. Current Neurology and Neuroscience Reports, 9, 188–197.CrossRefPubMedGoogle Scholar
  34. Kumar, R. A., KaraMohamed, S., Sudi, J., Conrad, D. F., Brune, C., Badner, J. A., et al. (2008). Recurrent 16p11.2 microdeletions in autism. Human Molecular Genetics, 17, 628–638.CrossRefPubMedGoogle Scholar
  35. Kumar, R. A., Marshall, C. R., Badner, J. A., Babatz, T. D., Mukamel, Z., Aldinger, K. A., et al. (2009). Association and mutation analyses of 16p11.2 autism candidate genes. PLoS ONE, 4, e4582.CrossRefPubMedPubMedCentralGoogle Scholar
  36. Lord, C., Risi, S., Lambrecht, L., Cook, E. H., Leventhal, B. L., & DiLavore, P. C. (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.CrossRefPubMedGoogle Scholar
  37. Lord, C., Rutter, M., DiLavore, P. C., Risi, S., Gotham, K., & Bishop, S. (2012). Autism diagnostic observation schedule (2nd ed.). Torrance: Western Psychological Services.Google Scholar
  38. Lord, C., Rutter, M., & Le Couteur, A. (1994). Autism diagnostic interview-revised: A revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. Journal of Autism and Developmental Disorders, 24, 659–685.CrossRefPubMedGoogle Scholar
  39. Marshall, C. R., Noor, A., Vincent, J. B., Lionel, A. C., Feuk, L., Skaug, J., et al. (2008). Structural variation of chromosomes in autism spectrum disorder. The American Journal of Human Genetics, 82, 477–488.CrossRefPubMedGoogle Scholar
  40. McCarthy, S., Makarov, V., Kirov, G., Addington, A., McClellan, J., Yoon, S., et al. (2009). Microduplications of 16p11.2 are associated with schizophrenia. Nature Genetics, 41, 1223–1227.CrossRefPubMedPubMedCentralGoogle Scholar
  41. Mefford, H. C., Cooper, G. M., Zerr, T., Smith, J. D., Baker, C., Shafer, N., et al. (2009). A method for rapid, targeted CNV genotyping identifies rare variants associated with neurocognitive disease. Genome Research, 19, 1579–1585.CrossRefPubMedPubMedCentralGoogle Scholar
  42. Miller, D. T., Nasir, R., Sobeih, M. M., Shen, Y., Wu, B. L., & Hanson, E. (2009). 16p11.2 Microdeletion. In R. A. Pagon, M. P. Adam, T. D. Bird, C. R. Dolan, C. T. Fong, & K. Stephens (Eds.), GeneReviews. Seattle: University of Washington.Google Scholar
  43. Moens, L. N., De Rijk, P., Reumers, J., Van Den Bossche, M. J. A., & Glassee, W. (2011). Sequencing of DISC1 pathway genes reveals Increased burden of rare missense variants in schizophrenia patients from a northern Swedish population. PLoS ONE, 6, e23450.CrossRefPubMedPubMedCentralGoogle Scholar
  44. Moreira, D. P., Griesi-Oliveira, K., Bossolani-Martins, A. L., Lourenço, N. C. V., Takahashi, V. N. O., da Rocha, K. M., et al. (2014). Investigation of 15q11-q13, 16p11.2 and 22q13 CNVs in autism spectrum disorder brazilian individuals with and without epilepsy. PLoS ONE, 9, e107705.CrossRefPubMedPubMedCentralGoogle Scholar
  45. Moreno-De-Luca, A., Myers, S. M., Challman, T. D., Moreno-De-Luca, D., Evans, D. W., & Ledbetter, D. H. (2013). Developmental brain dysfunction: Revival and expansion of old concepts based on new genetic evidence. The Lancet Neurology, 12, 406–414.CrossRefPubMedPubMedCentralGoogle Scholar
  46. Mullen, E. M. (1995). Mullen scales of early learning (AGS ed.). Circle Pines: Pearson Assessments.Google Scholar
  47. Oldfield, R. C. (1971). The assessment and analysis of handedness: The Edinburgh inventory. Neuropsychologia, 9, 97–113.CrossRefPubMedGoogle Scholar
  48. O’Roak, B. J., Deriziotis, P., Lee, C., Vives, L., Schwartz, J. J., Girirajan, S., et al. (2011). Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nature Genetics, 43, 585–589.CrossRefPubMedPubMedCentralGoogle Scholar
  49. O’Roak, B. J., Vives, L., Girirajan, S., Karakoc, E., Krumm, N., Coe, B. P., et al. (2012). Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature, 485, 246–250.CrossRefPubMedPubMedCentralGoogle Scholar
  50. Rutter, M., Bailey, A., & Lord, C. (2003). Social communication questionnaire (SCQ). Torrance: Western Psychological Services.Google Scholar
  51. Sahoo, T., Theisen, A., Rosenfeld, J. A., Lamb, A. N., Ravnan, J. B., Schultz, R. A., et al. (2011). Copy number variants of schizophrenia susceptibility loci are associated with a spectrum of speech and developmental delays and behavior problems. Genetics in Medicine, 13, 868–880.CrossRefPubMedGoogle Scholar
  52. Sanders, S. J., Ercan-Sencicek, A. G., Hus, V., Luo, R., Murtha, M. T., Moreno-De-Luca, D., et al. (2011). Multiple recurrent de novo copy number variations (CNVs), including duplications of the 7q11.23 Williams-Beuren syndrome region, are strongly associated with autism. Neuron, 70, 863–885.CrossRefPubMedPubMedCentralGoogle Scholar
  53. Schaaf, C. P., Goin-Kochel, R. P., Nowell, K. P., Hunter, J. V., Aleck, K. A., Cox, S., et al. (2011). Expanding the clinical spectrum of the 16p11.2 chromosomal rearrangements: Three patients with syringomyelia. European Journal of Human Genetics, 19, 152–156.CrossRefPubMedGoogle Scholar
  54. Sebat, J., Lakshmi, B., Malhotra, D., Troge, J., Lese-Martin, C., Walsh, T., et al. (2007). Strong association of de novo copy number mutations with autism. Science, 316, 445–449.CrossRefPubMedPubMedCentralGoogle Scholar
  55. Shaffer, D., Fisher, P., Lucas, C., Dulcan, M. K., & Schwab-Stone, M. (2000). NIMH diagnostic interview schedule for children, version IV (NIMH DISC-IV): Description, differences from previous versions and reliability of some common diagnoses. Jouranl of the American Academy of Child and Adolescent Psychiatry, 39, 28–38.CrossRefGoogle Scholar
  56. Shinawi, M., Liu, P., Kang, S. H. L., Shen, J., Belmont, J. W., Scott, D. A., et al. (2010). Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size. Journal of Medical Genetics, 47, 332–341.CrossRefPubMedGoogle Scholar
  57. 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.CrossRefGoogle Scholar
  58. Sparrow, S. S., Chicchetti, D. V., & Balla, D. A. (2005). Vineland adaptive behavior scales (2nd ed.). Circle Pines: Pearson Assessments.Google Scholar
  59. Stefansson, H., Meyer-Lindenberg, A., Steinberg, S., Magnusdottir, B., Morgen, K., Arnarsdottir, S., et al. (2014). CNVs conferring risk of autism or schizophrenia affect cognition in controls. Nature, 505(7483), 361–366.CrossRefPubMedGoogle Scholar
  60. Steinberg, S., de Jong, S., Mattheisen, M., Costas, J., Demontis, D., Jamain, S., et al. (2014). Common Variant at 16p11.2 Conferring Risk of Psychosis. Molecular Psychiatry, 19, 108–114.CrossRefPubMedGoogle Scholar
  61. The Centers for Disease Control and Prevention Autism and Developmental Disabilities Monitoring Network Surveillance Year 2010 Principal Investigators. (2014). Prevalence of autism spectrum disorder among children aged 8 years: Autism and developmental disabilities monitoring network, 11 Sites, United States, 2010. Surveillance Summaries, 63(SS02), 1–21.Google Scholar
  62. The International Schizophrenia Consortium (ISC). (2008). Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature, 455, 237–241.CrossRefGoogle Scholar
  63. Wagner, R. K., Torgesen, J. K., & Rashotte, C. A. (1999). Comprehensive Test of Phonological Processing (CTOPP). Austin, TX: Pro Ed Publishing Co.Google Scholar
  64. Walsh, K. M., & Bracken, M. B. (2011). Copy number variation in the dosage-sensitive 16p11.2 interval accounts for only a small proportion of autism incidence: A systematic review and meta-analysis. Genetics in Medicine, 13, 377–384.CrossRefPubMedGoogle Scholar
  65. Walsh, T., McClellan, J. M., McCarthy, S. E., Addington, A. M., Pierce, S. B., Cooper, G. M., et al. (2008). Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science, 320, 539–543.CrossRefPubMedGoogle Scholar
  66. Wechsler, D. (1999). Wechsler abbreviated scale of intelligence. San Antonio: The Psychological Corporation.Google Scholar
  67. Wechsler, D. (2009). Wechsler individual achievement test. San Antonio: The Psychological Corporation.Google Scholar
  68. Weiss, L. A., Shen, Y., Korn, J. M., Arking, D. E., Miller, D. T., Fossdal, R., et al. (2008). Association between microdeletion and microduplication at 16p11.2 and Autism. New England Journal of Medicine, 358, 667–675.CrossRefPubMedGoogle Scholar
  69. Williams, N. M., Zaharieva, I., Martin, A., Langley, K., Mantripragada, K., Fossdal, R., et al. (2010). Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: A genome-wide analysis. The Lancet, 376, 1401–1408.CrossRefGoogle Scholar
  70. Zufferey, F., Sherr, E. H., Beckmann, N. D., Hanson, E., Maillard, A. M., Hippolyte, L., et al. (2012). A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders. Journal of Medical Genetics, 49, 660–668.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • LeeAnne Green Snyder
    • 1
  • Debra D’Angelo
    • 2
  • Qixuan Chen
    • 2
  • Raphael Bernier
    • 4
  • Robin P. Goin-Kochel
    • 5
  • Arianne Stevens Wallace
    • 4
  • Jennifer Gerdts
    • 4
  • Stephen Kanne
    • 6
  • Leandra Berry
    • 5
  • Lisa Blaskey
    • 8
  • Emily Kuschner
    • 7
  • Timothy Roberts
    • 7
  • Elliot Sherr
    • 9
  • Christa L. Martin
    • 10
  • David H. Ledbetter
    • 10
  • John E. Spiro
    • 1
  • Wendy K. Chung
    • 1
    • 3
  • Ellen Hanson
    • 11
  • on behalf of the Simons VIP consortium
  1. 1.Simons FoundationNew YorkUSA
  2. 2.Department of BiostaticsColumbia UniversityNew YorkUSA
  3. 3.Department of Clinical GeneticsColumbia UniversityNew YorkUSA
  4. 4.Department of Psychiatry and Behavioral SciencesUniversity of WashingtonSeattleUSA
  5. 5.Department of PediatricsBaylor College of MedicineHoustonUSA
  6. 6.Thompson CenterUniversity of MissouriColumbiaUSA
  7. 7.Department of RadiologyChildren’s Hospital PhiladelphiaPhiladelphiaUSA
  8. 8.Department of Child and Adolescent Psychiatry and Behavioral SciencesChildren’s Hospital PhiladelphiaPhiladelphiaUSA
  9. 9.University of California San Francisco School of MedicineSan FranciscoUSA
  10. 10.Autism and Developmental Medicine InstituteGeisinger Health SystemDanvilleUSA
  11. 11.Developmental MedicineChildren’s Hospital Boston/Harvard Medical SchoolBostonUSA

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