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.
Convergence of genes and cellular pathways dysregulated in autism spectrum disorders / Pinto D; Delaby E; Merico D; Barbosa M; Merikangas A; Klei L; Thiruvahindrapuram B; Xu X; Ziman R; Wang Z; Vorstman JA; 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.. - In: AMERICAN JOURNAL OF HUMAN GENETICS. - ISSN 0002-9297. - STAMPA. - 94:(2014), pp. 677-694. [10.1016/j.ajhg.2014.03.018]
Convergence of genes and cellular pathways dysregulated in autism spectrum disorders.
BACCHELLI, ELENA;MAESTRINI, ELENA;
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
