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Convergence of genes and cellular pathways dysregulated in autism spectrum disorders

Authors :
Pinto, Dalila
Delaby, Elsa
Merico, Daniele
Barbosa, Mafalda
Merikangas, Alison
Klei, Lambertus
Thiruvahindrapuram, Bhooma
Xu, Xiao
Ziman, Robert
Wang, Zhuozhi
Vorstman, Jacob AS
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, L Alison
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
Source :
American journal of human genetics, vol 94, iss 5
Publication Year :
2014
Publisher :
eScholarship, University of California, 2014.

Abstract

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.

Details

Database :
OpenAIRE
Journal :
American journal of human genetics, vol 94, iss 5
Accession number :
edsair.od.......325..41ef0c71be8a4388da39ddef51ba6b9c