Abstract
Individuals with autism are more likely to carry rare inherited and de novo copy number variants (CNVs). However, further research is needed to establish which CNVs are causal and the mechanisms by which these CNVs influence autism. We examined genomic DNA of children with autism (N=41) and healthy controls (N=367) for rare CNVs using a high-resolution array comparative genomic hybridization platform. We show that individuals with autism are more likely to harbor rare CNVs as small as ∼10 kb, a threshold not previously detectable, and that CNVs in cases disproportionately affect genes involved in transcription, nervous system development, and receptor activity. We also show that a subset of genes that have known or suspected allele-specific or imprinting effects and are within rare-case CNVs may undergo loss of transcript expression. In particular, expression of CNTNAP2 and ZNF214 are decreased in probands compared with their unaffected transmitting parents. Furthermore, expression of PRODH and ARID1B, two genes affected by de novo CNVs, are decreased in probands compared with controls. These results suggest that for some genes affected by CNVs in autism, reduced transcript expression may be a mechanism of pathogenesis during neurodevelopment.
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Acknowledgements
This work was supported by the National Institutes of Health grants R01MH083989, R01MH076431, R01HG004222, U54MH066398, U01HD045023, U54MH066673, U54MH068172, U54MH066418, U54MH066494, 5T32ES007032, and T32ES015459.
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Bryan H King, MD, Seattle Children's Hospital, University of Washington, Seattle, WA; Eric Hollander, MD, Institute of Clinical Neuroscience, New York, NY; Linmarie Sikich, MD University of North Carolina, Chapel Hill, NC; James T McCracken, MD, University of California at Los Angeles, Los Angeles, CA; Lawrence Scahill MSN, PhD, Yale University, New Haven, CT; Joel D Bregman, MD, North Shore–Long Island Jewish Health System, Great Neck, NY; Craig L Donnelly, MD, Dartmouth Medical School, Hanover, NH; Kimberly Dukes, PhD, Boston University, Boston, MA; Deborah Hirtz, MD, National Institute of Neurological Disorders and Stroke, Bethesda, MD; Ann Wagner, PhD, National Institute of Mental Health, Rockville, MD.
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Nord, A., Roeb, W., Dickel, D. et al. Reduced transcript expression of genes affected by inherited and de novo CNVs in autism. Eur J Hum Genet 19, 727–731 (2011). https://doi.org/10.1038/ejhg.2011.24
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DOI: https://doi.org/10.1038/ejhg.2011.24
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