Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders Academic Article uri icon

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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.

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, James Raymond
  • 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
  • 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

publication date

  • May 2014