Convergence of genes and cellular pathways dysregulated in autism spectrum disorders

Dalila Pinto, Elsa Delaby, Daniele Merico, Mafalda Barbosa, Alison Merikangas, Lambertus Klei, Bhooma Thiruvahindrapuram, Xiao Xu, Robert Ziman, Zhuozhi Wang, Jacob A. S. Vorstman, Ann P. Thompson, Regina Regan, Marion Pilorge, Giovanna Pellecchia, Alistair T. Pagnamenta, Bárbara Oliveira, Christian R. Marshall, Tiago R. Magalhães, Jennifer K. Lowe, Jennifer L. Howe, Anthony J. Griswold, John Gilbert, Eftichia Duketis, Beth A. Dombroski, Maretha de Jonge, Michael L. Cuccaro, Emily L. Crawford, Catarina T. Correia, Judith Conroy, Inȇs C. Conceição, Andreas G. Chiocchetti, Jillian P. Casey, Guiqing Cai, Christelle Cabrol, Nadia Bolshakova, Elena Bacchelli, Richard Anney, Steven Gallinger, Michelle Cotterchio, Graham Casey, Lonnie Zwaigenbaum, Kerstin Wittemeyer, Kirsty Wing, Simon Wallace, Herman van Engeland, Ana Tryfon, Susanne Thomson, Latha Soorya, Bernadette Roge, Wendy Roberts, Fritz Poustka, Susana Mouga, Nancy J. Minshew, L. Alison McInnes, Susan G. McGrew, Catherine Lord, Marion Leboyer, Ann Le Couteur, Alexander Kolevzon, Patricia Jiménez González, Suma Jacob, Richard Holt, Stephen J. Guter, Jonathan Green, Andrew Green, Christopher Gillberg, Bridget A. Fernandez, Frederico Duque, Richard Delorme, Geraldine Dawson, Pauline Chaste, Cátia Café, Sean Brennan, Thomas Bourgeron, Patrick F. Bolton, Sven Bölte, Raphael Bernier, Gillian Baird, Anthony J. Bailey, Evdokia Anagnostou, Joana Almeida, Ellen M. Wijsman, Veronica J. Vieland, Astrid M. Vicente, Gerard D. Schellenberg, Margaret Ann Pericak-Vance, Andrew D. Paterson, Jeremy R. Parr, Guiomar Oliveira, John I. Nurnberger, Anthony P. Monaco, Elena Maestrini, Sabine M. Klauck, Hakon Hakonarson, Jonathan L. Haines, Daniel H. Geschwind, Christine M. Freitag, Susan E. Folstein, Sean Ennis, Hilary Coon, Agatino Battaglia, Peter Szatmari, James S. Sutcliffe, Joachim Hallmayer, Michael Gill, Edwin H. Cook, Joseph D. Buxbaum, Bernie Devlin, Louise Gallagher, Catalina Betancur, Stephen W. Scherer

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
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.
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Author:Dalila Pinto, Elsa Delaby, Daniele Merico, Mafalda Barbosa, Alison Merikangas, Lambertus Klei, Bhooma Thiruvahindrapuram, Xiao Xu, Robert Ziman, Zhuozhi Wang, Jacob A. S. Vorstman, Ann P. Thompson, Regina Regan, Marion Pilorge, Giovanna Pellecchia, Alistair T. Pagnamenta, Bárbara Oliveira, Christian R. Marshall, Tiago R. Magalhães, Jennifer K. Lowe, Jennifer L. Howe, Anthony J. Griswold, John Gilbert, Eftichia Duketis, Beth A. Dombroski, Maretha de Jonge, Michael L. Cuccaro, Emily L. Crawford, Catarina T. Correia, Judith Conroy, Inȇs C. Conceição, Andreas G. Chiocchetti, Jillian P. Casey, Guiqing Cai, Christelle Cabrol, Nadia Bolshakova, Elena Bacchelli, Richard Anney, Steven Gallinger, Michelle Cotterchio, Graham Casey, Lonnie Zwaigenbaum, Kerstin Wittemeyer, Kirsty Wing, Simon Wallace, Herman van Engeland, Ana Tryfon, Susanne Thomson, Latha Soorya, Bernadette Roge, Wendy Roberts, Fritz Poustka, Susana Mouga, Nancy J. Minshew, L. Alison McInnes, Susan G. McGrew, Catherine Lord, Marion Leboyer, Ann Le Couteur, Alexander Kolevzon, Patricia Jiménez González, Suma Jacob, Richard Holt, Stephen J. Guter, Jonathan Green, Andrew Green, Christopher Gillberg, Bridget A. Fernandez, Frederico Duque, Richard Delorme, Geraldine Dawson, Pauline Chaste, Cátia Café, Sean Brennan, Thomas Bourgeron, Patrick F. Bolton, Sven Bölte, Raphael Bernier, Gillian Baird, Anthony J. Bailey, Evdokia Anagnostou, Joana Almeida, Ellen M. Wijsman, Veronica J. Vieland, Astrid M. Vicente, Gerard D. Schellenberg, Margaret Ann Pericak-Vance, Andrew D. Paterson, Jeremy R. Parr, Guiomar Oliveira, John I. Nurnberger, Anthony P. Monaco, Elena Maestrini, Sabine M. Klauck, Hakon Hakonarson, Jonathan L. Haines, Daniel H. Geschwind, Christine M. Freitag, Susan E. Folstein, Sean Ennis, Hilary Coon, Agatino Battaglia, Peter Szatmari, James S. Sutcliffe, Joachim Hallmayer, Michael Gill, Edwin H. Cook, Joseph D. Buxbaum, Bernie Devlin, Louise Gallagher, Catalina Betancur, Stephen W. Scherer
URN:urn:nbn:de:hebis:30:3-353971
DOI:http://dx.doi.org/10.1016/j.ajhg.2014.03.018
ISSN:1537-6605
ISSN:0002-9297
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=24768552
Parent Title (English):The American journal of human genetics
Publisher:Cell Press
Place of publication:New York, NY [u.a.]
Document Type:Article
Language:English
Date of Publication (online):2014/04/24
Date of first Publication:2014/04/24
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2014/11/04
Volume:94
Issue:5
Pagenumber:18
First Page:677
Last Page:694
Note:
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
HeBIS PPN:366673998
Institutes:Medizin
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung-Nicht kommerziell-Keine Bearbeitung 3.0

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