Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders.
Archive ouverte
Pinto, Dalila | Delaby, Elsa | Merico, Daniele | Barbosa, Mafalda | Merikangas, Alison | Klei, Lambertus | Thiruvahindrapuram, Bhooma | Xu, Xiao | Ziman, Robert | Wang, Zhuozhi | Vorstman, Jacob, A. S. | Thompson, Ann | Regan, Regina | Pilorge, Marion | Pellecchia, Giovanna | Pagnamenta, Alistair, T. | Oliveira, Bárbara | Marshall, Christian, R. | Magalhaes, Tiago, R. | Lowe, Jennifer, K. | Howe, Jennifer, L. | Griswold, Anthony, J. | Gilbert, John | Duketis, Eftichia | Dombroski, Beth, A. | de Jonge, Maretha, V. | Cuccaro, Michael | Crawford, Emily, L. | Correia, Catarina, T. | Conroy, Judith | Conceição, Inês, C. | Chiocchetti, Andreas, G. | Casey, Jillian, P. | Cai, Guiqing | Cabrol, Christelle | Bolshakova, Nadia | Bacchelli, Elena | Anney, Richard | Gallinger, Steven | Cotterchio, Michelle | Casey, Graham | Zwaigenbaum, Lonnie | Wittemeyer, Kerstin | Wing, Kirsty | Wallace, Simon | van Engeland, Herman | Tryfon, Ana | Thomson, Susanne | Soorya, Latha | Rogé, Bernadette | Roberts, Wendy | Poustka, Fritz | Mouga, Susana | Minshew, Nancy | Mcinnes, Alison, L. | Mcgrew, Susan, G. | Lord, Catherine | Leboyer, Marion | Le Couteur, Ann, S. | Kolevzon, Alexander | Jiménez González, Patricia | Jacob, Suma | Holt, Richard | Guter, Stephen | Green, Jonathan | Green, Andrew | Gillberg, Christopher | Fernandez, Bridget, A. | Duque, Frederico | Delorme, Richard | Dawson, Geraldine | Chaste, Pauline | Café, Cátia | Brennan, Sean | Bourgeron, Thomas | Bolton, Patrick, F. | Bölte, Sven | Bernier, Raphael | Baird, Gillian | Bailey, Anthony, J. | Anagnostou, Evdokia | Almeida, Joana | Wijsman, Ellen, M. | Vieland, Veronica, J. | Vicente, Astrid, M. | Schellenberg, Gerard, D. | Pericak-Vance, Margaret | Paterson, Andrew, D. | Parr, Jeremy, R. | Oliveira, Guiomar | Nurnberger, John, I. | Monaco, Anthony, P. | Maestrini, Elena | Klauck, Sabine, M. | Hakonarson, Hakon | Haines, Jonathan, L. | Geschwind, Daniel, H. | Freitag, Christine, M. | Folstein, Susan, E. | Ennis, Sean | Coon, Hilary | Battaglia, Agatino | Szatmari, Peter | Sutcliffe, James, S. | Hallmayer, Joachim | Gill, Michael | Cook, Edwin, H. | Buxbaum, Joseph, D. | Devlin, Bernie | Gallagher, Louise | Betancur, Catalina | Scherer, Stephen, W.
Edité par
CCSD ; Elsevier (Cell Press) -
International audience.
Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.
