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Copy number variation at 22q11.2: from rare variants to common mechanisms of developmental neuropsychiatric disorders

Molecular Psychiatry volume 18, pages 1153–1165 (2013)Cite this article

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Abstract

Recently discovered genome-wide rare copy number variants (CNVs) have unprecedented levels of statistical association with many developmental neuropsychiatric disorders, including schizophrenia, autism spectrum disorders, intellectual disability and attention deficit hyperactivity disorder. However, as CNVs often include multiple genes, causal genes responsible for CNV-associated diagnoses and traits are still poorly understood. Mouse models of CNVs are in use to delve into the precise mechanisms through which CNVs contribute to disorders and associated traits. Based on human and mouse model studies on rare CNVs within human chromosome 22q11.2, we propose that alterations of a distinct set of multiple, noncontiguous genes encoded in this chromosomal region, in concert with modulatory impacts of genetic background and environmental factors, variably shift the probabilities of phenotypes along a predetermined developmental trajectory. This model can be further extended to the study of other CNVs and may serve as a guide to help characterize the impact of genes in developmental neuropsychiatric disorders.

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Acknowledgements

We thank Drs Herb Lachman, Santhosh Girirajan and Edward Brodkin for their invaluable comments on an early draft of this paper. This work was supported by the NIH (R21HD05311 and R01MH099660), NARSAD Independent Investigator Award and the Maltz Foundation to NH; funds from the Ministry of Defense, Japan, to TT; the Uehara fellowship and a Senshin Medical Research Foundation fellowship, Japan, to SB; funds from Kobe University Graduate School of Medicine to AH; and Grants-in-Aid for Scientific Research (24591674) from the Society for Promotion of Science, Japan, to TI.

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  1. Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, NY, USA

    N Hiroi, T Takahashi, A Hishimoto, T Izumi, S Boku & T Hiramoto

  2. Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA

    N Hiroi

  3. Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA

    N Hiroi

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Hiroi, N., Takahashi, T., Hishimoto, A. et al. Copy number variation at 22q11.2: from rare variants to common mechanisms of developmental neuropsychiatric disorders. Mol Psychiatry 18, 1153–1165 (2013). https://doi.org/10.1038/mp.2013.92

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