Skip to main content

Advertisement

SpringerLink
Log in

The Cognitive and Behavioral Phenotypes of Individuals with CHRNA7 Duplications

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

An Erratum to this article was published on 06 February 2017

Abstract

Chromosome 15q11q13 is among the least stable regions in the genome due to its highly complex genomic architecture. Low copy repeat elements at 15q13.3 facilitate recurrent copy number variants (CNVs), with deletions established as pathogenic and CHRNA7 implicated as a candidate gene. However, the pathogenicity of duplications of CHRNA7 is unclear, as they are found in affected probands as well as in reportedly healthy parents and unaffected control individuals. We evaluated 18 children with microduplications involving CHRNA7, identified by clinical chromosome microarray analysis (CMA). Comprehensive phenotyping revealed high prevalence of developmental delay/intellectual disability, autism spectrum disorder, and attention deficit/hyperactivity disorder. As CHRNA7 duplications are the most common CNVs identified by clinical CMA, this study provides anticipatory guidance for those involved with care of affected individuals.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Bernier, R., Steinman, K. J., Reilly, B., Wallace, A. S., Sherr, E. H., Pojman, N., et al. (2015). Clinical phenotype of the recurrent 1q21.1 copy-number variant. Genetics in Medicine: Official Journal of the American College of Medical Genetics. doi:10.1038/gim.2015.78.

    Google Scholar 

  • Flomen, R., Collier, D., Osborne, S., Munro, J., Breen, G., & Clair, S. T. (2006). Association study of CHRFAM7A copy number and 2 bp deletion polymorphisms with schizophrenia and bipolar affective disorder. American Journal of Medical Genetics Part B, Neuropsychiatric Genetics: The Official Publication of the International Society of Psychiatric Genetics, 141B(6), 571–575. doi:10.1002/ajmg.b.30306.

    Article  Google Scholar 

  • Gillentine, M. A., & Schaaf, C. P. (2015). The human clinical phenotypes of altered CHRNA7 copy number. Biochemical Pharmacology, 97(4), 352–362. doi:10.1016/j.bcp.2015.06.012.

    Article  PubMed  PubMed Central  Google Scholar 

  • Girirajan, S., & Eichler, E. (2010). Phenotypic variability and genetic susceptibility to genomic disorders. Human Molecular Genetics, 19(R2), R176–87. doi:10.1093/hmg/ddq366.

    Article  PubMed  PubMed Central  Google Scholar 

  • Girirajan, S., Rosenfeld, J. A., Coe, B. P., Parikh, S., Friedman, N., Goldstein, A., et al. (2012). Phenotypic heterogeneity of genomic disorders and rare copy-number variants. The New England Journal of Medicine, 367(14), 1321–1331. doi:10.1056/NEJMoa1200395.

    Article  PubMed  PubMed Central  Google Scholar 

  • Hanson, E., Nasir, R. H., Fong, A., Lian, A., Hundley, R., Shen, Y., et al. (2010). Cognitive and behavioral characterization of 16p11.2 deletion syndrome. Journal of Developmental and Behavioral Pediatrics: JDBP, 31(8), 649–657. doi:10.1097/DBP.0b013e3181ea50ed.

    Article  Google Scholar 

  • Helbig, I., Mefford, H. C., Sharp, A. J., Guipponi, M., Fichera, M., Franke, A., et al. (2009). 15q13.3 microdeletions increase risk of idiopathic generalized epilepsy. Nature Genetics, 41(2), 160–162. doi:10.1038/ng.292.

    Article  PubMed  PubMed Central  Google Scholar 

  • Lowther, C., Costain, G., Stavropoulos, D., Melvin, R., Silversides, C., Andrade, D., et al. (2014). Delineating the 15q13.3 microdeletion phenotype: A case series and comprehensive review of the literature. Genetics in Medicine: Official Journal of the American College of Medical Genetics. doi:10.1038/gim.2014.83.

    Google Scholar 

  • Männik, K., Mägi, R., Macé, A., Cole, B., Guyatt, A. L., Shihab, H. A., et al. (2015). Copy number variations and cognitive phenotypes in unselected populations. JAMA: The Journal of the American Medical Association, 313(20), 2044–2054. doi:10.1001/jama.2015.4845.

    Article  PubMed  Google Scholar 

  • Mathews, C. A., & Reus, V. I. (2001). Assortative mating in the affective disorders: A systematic review and meta-analysis. Comprehensive Psychiatry, 42(4), 257–262. doi:10.1053/comp.2001.24575.

    Article  PubMed  Google Scholar 

  • Rozycka, A., Dorszewska, J., Steinborn, B., Lianeri, M., Winczewska-Wiktor, A., Sniezawska, A., et al. (2013). Association study of the 2-bp deletion polymorphism in exon 6 of the CHRFAM7A gene with idiopathic generalized epilepsy. DNA and Cell Biology, 32(11), 640–647. doi:10.1089/dna.2012.1880.

    Article  PubMed  PubMed Central  Google Scholar 

  • Shinawi, M., Schaaf, C. P., Bhatt, S. S., Xia, Z., Patel, A., Cheung, S. W., et al. (2009). A small recurrent deletion within 15q13.3 is associated with a range of neurodevelopmental phenotypes. Nature Genetics, 41(12), 1269–1271. doi:10.1038/ng.481.

    Article  PubMed  PubMed Central  Google Scholar 

  • Sinkus, M. L., Graw, S., Freedman, R., Ross, R. G., Lester, H. A., & Leonard, S. (2015). The human CHRNA7 and CHRFAM7A genes: A review of the genetics, regulation, and function. Neuropharmacology, 96(Pt B), 274–288. doi:10.1016/j.neuropharm.2015.02.006.

    Article  PubMed  PubMed Central  Google Scholar 

  • Soler-Alfonso, C., Carvalho, C., Ge, J., Roney, E., Bader, P., Kolodziejska, K., et al. (2014). CHRNA7 triplication associated with cognitive impairment and neuropsychiatric phenotypes in a three-generation pedigree. European Journal of Human Genetics: EJHG. doi:10.1038/ejhg.2013.302.

    PubMed  PubMed Central  Google Scholar 

  • 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. doi:10.1038/nature12818.

    Article  PubMed  Google Scholar 

  • Szafranski, P., Schaaf, C. P., Person, R. E., Gibson, I. B., Xia, Z., Mahadevan, S., et al. (2010). Structures and molecular mechanisms for common 15q13.3 microduplications involving CHRNA7: Benign or pathological? Human Mutation, 31(7), 840–850. doi:10.1002/humu.21284.

    Article  PubMed  PubMed Central  Google Scholar 

  • Williams, N. M., Franke, B., Mick, E., Anney, R. J., Freitag, C. M., Gill, M., et al. (2012). Genome-wide analysis of copy number variants in attention deficit hyperactivity disorder: The role of rare variants and duplications at 15q13.3. The American Journal of Psychiatry, 169(2), 195–204. doi:10.1176/appi.ajp.2011.11060822.

    Article  PubMed  PubMed Central  Google Scholar 

  • 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. Lancet, 376(9750), 1401–1408. doi:10.1016/S0140-6736(10)61109-9.

    Article  PubMed  PubMed Central  Google Scholar 

  • Ziats, M. N., Goin-Kochel, R. P., Berry, L. N., Ali, M., Ge, J., Guffey, D., et al. (2016). The complex behavioral phenotype of 15q13.3 microdeletion syndrome. Genetics in Medicine: Official Journal of the American College of Medical Genetics. doi:10.1038/gim.2016.9.

    Google Scholar 

Download references

Acknowledgments

This work was generously supported by the Doris Duke Charitable Foundation Grant #2011034. The project was supported in part by IDDRC Grant Number 1U54 HD083092 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development. Cores: Tissue culture core, translational core. Miss Gillentine was supported by Grant Number T32GM008307 from the National Institute of General Medical Sciences. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences or the National Institutes of Health. Dr. Schaaf was generously supported by the Joan and Stanford Alexander Family.

Author Contributions

MAG drafted the manuscript and performed statistical analysis, LNB and RPGK performed behavioral assays on probands, MAA helped in recruitment of probands and obtaining clinical data, JG performed MLPA, DG performed statistical analyses, JAR performed database analysis and helped with patient recruitment, VH, MP, MS, BHG, AL, SRL, JR, MC, and TG helped in recruitment of probands from their institutions, CGM provided guidance in statistical analysis, PS and ALB participated in study design and coordination, CPS conceived of the study, and participated in its design and coordination and helped to draft the manuscript.

Author information

Authors and Affiliations

  1. Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

    M. A. Gillentine, M. A. Ali, J. Ge, J. A. Rosenfeld, B. H. Graham, S. R. Lalani, P. Stankiewicz, A. L. Beaudet & C. P. Schaaf

  2. Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Moursund Street, Ste. 1325, Houston, TX, USA

    M. A. Gillentine, M. A. Ali & C. P. Schaaf

  3. Autism Center, Texas Children’s Hospital, Houston, TX, USA

    L. N. Berry & R. P. Goin-Kochel

  4. Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA

    L. N. Berry, R. P. Goin-Kochel & M. Proud

  5. Dan L. Duncan Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, USA

    D. Guffey & C. G. Minard

  6. Department of Pediatrics, Vanderbilt University Medical Center, Nashville, USA

    V. Hannig

  7. Northeast Indiana Genetics, Fort Wayne, IN, USA

    P. Bader

  8. Department of Neurology, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, USA

    M. Proud

  9. Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, USA

    M. Shinawi

  10. Medical Genetics, MassGeneral Hospital for Children, Harvard Medical School, Boston, MA, USA

    A. Lin

  11. Medical Genetics, Shodair Children’s Hospital, Helena, MT, USA

    J. Reynolds

  12. Department of Pediatrics-Diabetes and Endocrinology, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, USA

    M. Chen

  13. Department of Child Health, Division of Genetics and Metabolism, Phoenix Children’s Hospital, University of Arizona College of Medicine, Phoenix, AZ, USA

    T. Grebe

Authors
  1. M. A. Gillentine
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L. N. Berry
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R. P. Goin-Kochel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. A. Ali
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J. Ge
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D. Guffey
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J. A. Rosenfeld
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. V. Hannig
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. P. Bader
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. M. Proud
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. M. Shinawi
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. B. H. Graham
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. A. Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. S. R. Lalani
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. J. Reynolds
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. M. Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. T. Grebe
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. C. G. Minard
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. P. Stankiewicz
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. A. L. Beaudet
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. C. P. Schaaf
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C. P. Schaaf.

Ethics declarations

Conflict of interest

All 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.

Additional information

The original version of this article was revised: The author name T. Grebe was misspelled as T. Greb. This has been corrected in this version.

An erratum to this article is available at http://dx.doi.org/10.1007/s10803-017-3047-y.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gillentine, M.A., Berry, L.N., Goin-Kochel, R.P. et al. The Cognitive and Behavioral Phenotypes of Individuals with CHRNA7 Duplications. J Autism Dev Disord 47, 549–562 (2017). https://doi.org/10.1007/s10803-016-2961-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10803-016-2961-8

Keywords

Search

Navigation