Skip to main content
SpringerLink
Log in

Array-CGH Analysis in a Cohort of Phenotypically Well-Characterized Individuals with “Essential” Autism Spectrum Disorders

  • Original Paper
  • Published:
Journal of Autism and Developmental Disorders Aims and scope Submit manuscript

Abstract

Copy-number variants (CNVs) are associated with susceptibility to autism spectrum disorder (ASD). To detect the presence of CNVs, we conducted an array-comparative genomic hybridization (array-CGH) analysis in 133 children with “essential” ASD phenotype. Genetic analyses documented that 12 children had causative CNVs (C-CNVs), 29 children had non-causative CNVs (NC-CNVs) and 92 children without CNVs (W-CNVs). Results on clinical evaluation showed no differences in cognitive abilities among the three groups, and a higher number of ASD symptoms and of non-verbal children in the C-CNVs group compared to the W-CNVs and NC-CNVs groups. Our results highlighted the importance of the array-CGH analyses and showed that the presence of specific CNVs may differentiate clinical outputs in children with ASD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Al-Mamari, W., Al-Saegh, A., Al-Kindy, A., Bruwer, Z., Al-Murshedi, F., & Al-Thihli, K. (2015). Diagnostic yield of chromosomal microarray analysis in a cohort of patients with autism spectrum disorders from a highly consanguineous population. Journal of Autism and Developmental Disorders, 45(8), 2323–2328. doi:10.1007/s10803-015-2394-9. doi.

    Article  PubMed  Google Scholar 

  • American Psychiatric Association, & American Psychiatric Association. (2000). DSM-IV-TR: Diagnostic and statistical manual of mental disorders, text revision. Washington, DC: American Psychiatric Association.

    Google Scholar 

  • American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (DSM-5®). Washington, DC: American Psychiatric Publication.

    Book  Google Scholar 

  • Battaglia, A., Doccini, V., Bernardini, L., Novelli, A., Loddo, S., Capalbo, A., et al. (2013). Confirmation of chromosomal microarray as a first-tier clinical diagnostic test for individuals with developmental delay, intellectual disability, autism spectrum disorders and dysmorphic features. European Journal of Paediatric Neurology, 17(6), 589–599. doi:10.1016/j.ejpn.2013.04.010.

    Article  PubMed  Google Scholar 

  • Beaudet, A. L. (2013). The utility of chromosomal microarray analysis in developmental and behavioral pediatrics. Child Development, 84(1), 121–132. doi:10.1111/cdev.12050.

    Article  PubMed  Google Scholar 

  • Beaudet, A. L. (2014). Reaching a CNV milestone. Nature Genetics, 46(10), 1046–1048. doi:10.1038/ng.3106.

    Article  PubMed  Google Scholar 

  • Bremer, A., Giacobini, M., Eriksson, M., Gustavsson, P., Nordin, V., Fernell, E., et al. (2011). Copy number variation characteristics in subpopulations of patients with autism spectrum disorders. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 156(2), 115–124. doi:10.1002/ajmg.b.31142.

    Article  Google Scholar 

  • Buxbaum, J. D., Silverman, J. M., Smith, C. J., Greenberg, D. A., Kilifarski, M., Reichert, J., et al. (2002). Association between a GABRB3 polymorphism and autism. Molecular Psychiatry, 7(3), 311–316. doi:10.1038/sj/mp/4001011.

    Article  PubMed  Google Scholar 

  • Carreira, I. M., Ferreira, S. I., Matoso, E., Pires, L. M., Ferrão, J., Jardim, A., et al. (2015). Copy number variants prioritization after array-CGH analysis–a cohort of 1000 patients. Molecular Cytogenetics, 8(1), 103. doi 10.1186/s13039-015-0202-z.

    Article  PubMed  PubMed Central  Google Scholar 

  • Coe, B. P., Witherspoon, K., Rosenfeld, J. A., Van Bon, B. W., Vulto-van Silfhout, A. T., Bosco, P., et al. (2014). Refining analyses of copy number variation identifies specific genes associated with developmental delay. Nature Genetics, 46(10), 1063–1071. doi:10.1038/ng.3092.

    Article  PubMed  PubMed Central  Google Scholar 

  • Conrad, D. F., Pinto, D., Redon, R., Feuk, L., Gokcumen, O., Zhang, Y., et al. (2010). Origins and functional impact of copy number variation in the human genome. Nature, 464(7289), 704–712. doi:10.1038/nature08516.

    Article  PubMed  Google Scholar 

  • Eapen, V., Crncec, R., & Walter, A. (2013). Exploring links between genotypes, phenotypes, and clinical predictors of response to early intensive behavioral intervention in autism spectrum disorder. Frontiers in Human Neuroscience, 11(7), 1662–5161. doi:10.3389/fnhum.2013.00567.

    Google Scholar 

  • Fombonne, E., Quirke, S., & Hagen, A. (2011). Epidemiology of pervasive developmental disorders. In D. G. Amaral, G. Dawson & D. H. Geschwind (Eds.), Autism spectrum disorders (pp. 90–111). New York: Oxford University Press.

    Chapter  Google Scholar 

  • 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(5), 693–705. doi:10.1007/s10803-008-0674-3.

    Article  PubMed  Google Scholar 

  • Hogart, A., Wu, D., LaSalle, J. M., & Schanen, N. C. (2010). The comorbidity of autism with the genomic disorders of chromosome 15q11. 2-q13. Neurobiology of Disease, 38(2), 181–191. doi:10.1016/j.nbd.2008.08.011.

    Article  PubMed  Google Scholar 

  • Ingram, D. G., Takahashi, T. N., & Miles, J. H. (2008). Defining autism subgroups: a taxometric solution. Journal of Autism and Developmental Disorders, 38(5), 950–960.

    Article  PubMed  Google Scholar 

  • Jacquemont, M. L., Sanlaville, D., Redon, R., Raoul, O., Cormier-Daire, V., Lyonnet, S., et al. (2006). Array-based comparative genomic hybridisation identifies high frequency of cryptic chromosomal rearrangements in patients with syndromic autism spectrum disorders. Journal of Medical Genetics, 43(11), 843–849. doi:10.1136/jmg.2006.043166.

    Article  PubMed  PubMed Central  Google Scholar 

  • Jeste, S. S., & Geschwind, D. H. (2014). Disentangling the heterogeneity of autism spectrum disorder through genetic findings. Nature Reviews Neurology, 10(2), 74–81. doi:10.1038/nrneurol.2013.278.

    Article  PubMed  PubMed Central  Google Scholar 

  • Kaminsky, E. B., Kaul, V., Paschall, J., Church, D. M., Bunke, B., Kunig, D., et al. (2011). An evidence-based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities. Genetics in Medicine, 13(9), 777–784. doi:10.1097/GIM.0b013e31822c79f9.

    Article  PubMed  PubMed Central  Google Scholar 

  • Kearney, H. M., Thorland, E. C., Brown, K. K., Quintero-Rivera, F., & South, S. T. (2011). American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants. Genetics in Medicine, 13(7), 680–685. doi:10.1097/GIM.0b013e3182217a3a.

    Article  PubMed  Google Scholar 

  • Lai, M. C., Lombardo, M. V., & Baron-Cohen, S. (2014). Autism. Lancet, 383(9920), 896–910. doi:10.1016/S0140-6736(13)61539-1.

    Article  PubMed  Google Scholar 

  • Lord, C., Risi, S., Lambrecht, L., Cook, E. H., Leventhal, B. L., & DiLavore, P. C. .et al. (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(3), 205–223. doi:10.1023/A:1005592401947.

    Article  PubMed  Google Scholar 

  • Lord, C., Rutter, M., & 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(5), 659–685. doi:10.1007/BF02172145.

    Article  PubMed  Google Scholar 

  • Luiz, D., Barnard, A., Knoesen, N., Kotras, N., Horrocks, S., McAlinden, P., et al. (2006). GMDS-ER 2–8—Griffiths Mental Development Scales—Extended Revised: 2 to 8 years. In C. Cianchetti & G. S. Fancello (Eds.), Firenze: Giunti Organizzazioni Speciali.

    Google Scholar 

  • Merikangas, A. K., Segurado, R., Heron, E. A., Anney, R. J. L., Paterson, A. D., Cook, E. H., et al. (2015). The phenotypic manifestations of rare genic CNVs in autism spectrum disorder. Molecular Psychiatry, 20(11), 1366–1372. doi:10.1038/mp.2014.150.

    Article  PubMed  Google Scholar 

  • Miles, J. H. (2011). Autism spectrum disorders—a genetics review. Genetics in Medicine, 13(4), 278–294. doi:10.1097/GIM.0b013e3181ff67ba.

    Article  PubMed  Google Scholar 

  • Miles, J. H., Takahashi, T. N., Bagby, S., Sahota, P. K., Vaslow, D. F., Wang, C. H., et al. (2005). Essential versus complex autism: Definition of fundamental prognostic subtypes. American Journal of Medical Genetics Part A, 135(2), 171–180. doi:10.1002/ajmg.a.30590.

    Article  PubMed  Google Scholar 

  • Miller, D. T., Adam, M. P., Aradhya, S., Biesecker, L. G., Brothman, A. R., Carter, N. P., et al. (2010). Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. The American Journal of Human Genetics, 86(5), 749–764. doi:10.1016/j.ajhg.2010.04.006.

    Article  PubMed  Google Scholar 

  • Murdoch, J. D., & State, M. W. (2013). Recent developments in the genetics of autism spectrum disorders. Current Opinion in Genetics & Development, 23(3), 310–315. doi:10.1016/j.gde.2013.02.003.

    Article  Google Scholar 

  • Oikonomakis, V., Kosma, K., Mitrakos, A., Sofocleous, C., Pervanidou, P., Syrmou, A., et al. (2016). Recurrent copy number variations as risk factors for autism spectrum disorders: analysis of the clinical implications. Clinical Genetics. doi:10.1111/cge.12740.

    PubMed  Google Scholar 

  • Ozgen, H. M., Staal, W. G., Barber, J. C., de Jonge, M. V., Eleveld, M. J., Beemer, F. A., et al. (2009). A novel 6.14 Mb duplication of chromosome 8p21 in a patient with autism and self mutilation. Journal of Autism and Developmental Disorders, 39(2), 322–329. doi:10.1007/s10803-008-0627-x.

    Article  PubMed  Google Scholar 

  • Ozonoff, S., Young, G. S., Carter, A., Messinger, D., Yirmiya, N., Zwaigenbaum, L., et al. (2011). Recurrence risk for autism spectrum disorders: A Baby Siblings Research Consortium study. Pediatrics, 128(3), e488–e495.

    PubMed  PubMed Central  Google Scholar 

  • Pang, A. W., MacDonald, J. R., Pinto, D., Wei, J., Rafiq, M. A., Conrad, D. F., et al. (2010). Towards a comprehensive structural variation map of an individual human genome. Genome Biology, 11(5), R52. doi:10.1186/gb-2010-11-5-r52.

    Article  PubMed  PubMed Central  Google Scholar 

  • Pinto, D., Pagnamenta, A. T., Klei, L., Anney, R., Merico, D., Regan, R., et al. (2010). Functional impact of global rare copy number variation in autism spectrum disorders. Nature, 466(7304), 368–372.

    Article  PubMed  PubMed Central  Google Scholar 

  • Posthuma, D., & Polderman, T. J. (2013). What have we learned from recent twin studies about the etiology of neurodevelopmental disorders? Current Opinion in Neurology, 26(2), 111–121. doi:10.1097/WCO.0b013e32835f19c3.

    Article  PubMed  Google Scholar 

  • Postorino, V., Fatta, L. M., Sanges, V., Giovagnoli, G., De Peppo, L., Vicari, S., & Mazzone, L. (2016). Intellectual disability in autism spectrum disorder: Investigation of prevalence in an Italian sample of children and adolescents. Research in Developmental Disabilities, 48, 193–201. doi:10.1016/j.ridd.2015.10.020.

    Article  PubMed  Google Scholar 

  • Qiao, Y., Riendeau, N., Koochek, M., Liu, X., Harvard, C., Hildebrand, M. J., et al. (2009). Phenomic determinants of genomic variation in autism spectrum disorders. Journal of Medical Genetics, 46(10), 680–688. doi:10.1136/jmg.2009.066795.

    Article  PubMed  Google Scholar 

  • Roid, G., & Miller, L. (1997). Leiter international performance scale–revised. Wood Dale, IL: Stoelting.

    Google Scholar 

  • Ronald, A., & Hoekstra, R. A. (2011). Autism spectrum disorders and autistic traits: a decade of new twin studies. American Journal of Medical Genetics Part B, 156(3), 255–274. doi:10.1002/ajmg.b.31159.

    Article  Google Scholar 

  • Sanders, S. J., Murtha, M. T., Gupta, A. R., Murdoch, J. D., Raubeson, M. J., Willsey, A. J., et al. (2012). De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature, 485(7397), 237–241. doi:10.1038/nature10945.

    Article  PubMed  PubMed Central  Google Scholar 

  • Schaefer, G. B. (2016). Clinical genetic aspects of autism spectrum disorders. International Journal of Molecular Sciences, 17(2), 180. doi:10.3390/ijms17020180.

    Article  PubMed Central  Google Scholar 

  • Schaefer, G. B., & Mendelsohn, N. J. & Professional Practice and Guidelines Committee. (2013). Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. Genetics in Medicine, 15(5), 399–407. doi:10.1038/gim.2013.32.

    Article  PubMed  Google Scholar 

  • Schaefer, G. B., Starr, L., Pickering, D., Skar, G., DeHaai, K., & Sanger, W. G. (2010). Array comparative genomic hybridization findings in a cohort referred for an autism evaluation. Journal of Child Neurology, 25(12), 1498–1503. doi:10.1177/0883073810370479.

    Article  PubMed  Google Scholar 

  • Shaffer, L. G., McGowan-Jordan, J., & Schmid, M. (Eds.) (2013). ISCN 2013: An international system for human cytogenetic nomenclature (2013). Basel: Karger Medical and Scientific Publishers.

    Google Scholar 

  • Shen, Y., Dies, K. A., Holm, I. A., Bridgemohan, C., Sobeih, M. M., Caronna, E. B., et al. (2010). Clinical genetic testing for patients with autism spectrum disorders. Pediatrics, 125(4), e727–e735. doi:10.1542/peds.2009-1684.

    Article  PubMed  PubMed Central  Google Scholar 

  • Sorte, H. S., Gjevik, E., Sponheim, E., Eiklid, K. L., & Rødningen, O. K. (2013). Copy number variation findings among 50 children and adolescents with autism spectrum disorder. Psychiatric Genetics, 23(2), 61–69. doi:10.1097/YPG.0b013e32835d718b.

    Article  PubMed  Google Scholar 

  • Stankiewicz, P., & Lupski, J. R. (2010). Structural variation in the human genome and its role in disease. Annual Review of Medicine, 61, 437–455. doi:10.1146/annurev-med-100708-204735.

    Article  PubMed  Google Scholar 

  • Tabet, A. C., Verloes, A., Pilorge, M., Delaby, E., Delorme, R., Nygren, G., et al. (2015). Complex nature of apparently balanced chromosomal rearrangements in patients with autism spectrum disorder. Molecular Autism, 6(1), 19. doi:10.1186/s13229-015-0015-2.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We thank the families that participated in this study. The authors would like to thank Paola Giovanna Volpi for her help with the manuscript.

Funding

There was no funding for this paper.

Authors’ Contributions

EN participated the design of the study and coordination, performed the measurement and drafted the manuscript; SR conceived of the study, participated in its design and coordination and drafted the manuscript; LC participated in the design and coordination of the study, performed the measurement and helped to draft the manuscript; VA performed the measurement and participated in interpretation of the data; FAA performed the measurement; AA participated the design of the study, revised critically the manuscript and participated in interpretation of the data; AN participated the design of the study and interpretation of the data; GV participated the design of the study and coordination, interpretation of the data and helped to draft the manuscript; DM participated in the design, interpretation of the data, performed the statistical analysis and helped to draft the manuscript; SV participated the design of the study and coordination, interpretation of the data and helped to draft the manuscript. All authors read and approved the final manuscript.

Author information

Authors and Affiliations

  1. Department of Neurosciences, Child Neuropsychiatry Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy

    Eleonora Napoli, Laura Casula, Filomena Alessandra Amendola, Giovanni Valeri, Deny Menghini & Stefano Vicari

  2. Laboratory of Medical Genetics, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy

    Serena Russo, Viola Alesi, Adriano Angioni & Antonio Novelli

Authors
  1. Eleonora Napoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Serena Russo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Laura Casula
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Viola Alesi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Filomena Alessandra Amendola
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Adriano Angioni
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Antonio Novelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Giovanni Valeri
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Deny Menghini
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Stefano Vicari
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stefano Vicari.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 29 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Napoli, E., Russo, S., Casula, L. et al. Array-CGH Analysis in a Cohort of Phenotypically Well-Characterized Individuals with “Essential” Autism Spectrum Disorders. J Autism Dev Disord 48, 442–449 (2018). https://doi.org/10.1007/s10803-017-3329-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10803-017-3329-4

Keywords

Search

Navigation