Convergence of genes and cellular pathways dysregulated in autism spectrum disorders.
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.
Pinto, D; Delaby, E; Merico, D; Barbosa, M; Merikangas, A; Klei, L; Thiruvahindrapuram, B; Xu, X; Ziman, R; Wang, Z; Vorstman, JAS; Thompson, A; Regan, R; Pilorge, M; Pellecchia, G; Pagnamenta, AT; Oliveira, B; Marshall, CR; Magalhaes, TR; Lowe, JK; Howe, JL; Griswold, AJ; Gilbert, J; Duketis, E; Dombroski, BA; De Jonge, MV; Cuccaro, M; Crawford, EL; Correia, CT; Conroy, J; Conceição, IC; Chiocchetti, AG; Casey, JP; Cai, G; Cabrol, C; Bolshakova, N; Bacchelli, E; Anney, R; Gallinger, S; Cotterchio, M; Casey, G; Zwaigenbaum, L; Wittemeyer, K; Wing, K; Wallace, S; van Engeland, H; Tryfon, A; Thomson, S; Soorya, L; Rogé, B; Roberts, W; Poustka, F; Mouga, S; Minshew, N; McInnes, LA; McGrew, SG; Lord, C; Leboyer, M; Le Couteur, AS; Kolevzon, A; Jiménez González, P; Jacob, S; Holt, R; Guter, S; Green, J; Green, A; Gillberg, C; Fernandez, BA; Duque, F; Delorme, R; Dawson, G; Chaste, P; Café, C; Brennan, S; Bourgeron, T; Bolton, PF; Bölte, S; Bernier, R; Baird, G; Bailey, AJ; Anagnostou, E; Almeida, J; Wijsman, EM; Vieland, VJ; Vicente, AM; Schellenberg, GD; Pericak-Vance, M; Paterson, AD; Parr, JR; Oliveira, G; Nurnberger, JI; Monaco, AP; Maestrini, E; Klauck, SM; Hakonarson, H; Haines, JL; Geschwind, DH; Freitag, CM; Folstein, SE; Ennis, S; Coon, H; Battaglia, A; Szatmari, P; Sutcliffe, JS; Hallmayer, J; Gill, M; Cook, EH; Buxbaum, JD; Devlin, B; Gallagher, L; Betancur, C; Scherer, SW
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