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 Vorstman; Ann Thompson; Regina Regan; Marion Pilorge; Giovanna Pellecchia; Alistair Pagnamenta; Bárbara Oliveira; Christian Marshall; Tiago Magalhaes; Jennifer Lowe; Jennifer Howe; Anthony Griswold; John Gilbert; Eftichia Duketis; Beth Dombroski; Maretha De Jonge; Michael Cuccaro; Emily Crawford; Catarina Correia; Judith Conroy; Inês Conceição; Andreas Chiocchetti; Jillian 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 Rogé; Wendy Roberts; Fritz Poustka; Susana Mouga; Nancy Minshew; Alison Mcinnes; Susan Mcgrew; Catherine Lord; Marion Leboyer; Ann Le Couteur; Alexander Kolevzon; Patricia Jiménez González; Suma Jacob; Richard Holt; Stephen Guter; Jonathan Green; Andrew Green; Christopher Gillberg; Bridget Fernandez; Frederico Duque; Richard Delorme; Geraldine Dawson; Pauline Chaste; Cátia Café; Sean Brennan; Thomas Bourgeron; Patrick Bolton; Sven Bölte; Raphael Bernier; Gillian Baird; Anthony Bailey; Evdokia Anagnostou; Joana Almeida; Ellen Wijsman; Veronica Vieland; Astrid Vicente; Gerard Schellenberg; Margaret Pericak-Vance; Andrew Paterson; Jeremy Parr; Guiomar Oliveira; John Nurnberger; Anthony Monaco; Elena Maestrini; Sabine Klauck; Hakon Hakonarson; Jonathan Haines; Daniel Geschwind; Christine Freitag; Susan Folstein; Sean Ennis; Hilary Coon; Agatino Battaglia; Peter Szatmari; James Sutcliffe; Joachim Hallmayer; Michael Gill; Edwin Cook; Joseph Buxbaum; Bernie Devlin; Louise Gallagher; Catalina Betancur; Stephen Scherer

doi:10.1016/j.ajhg.2014.03.018

Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders.

Dalila Pinto ^{1, 2, 3, 4, 5, 6} Elsa Delaby ⁷ Daniele Merico ⁸ Mafalda Barbosa ^{1, 2, 3} Alison Merikangas ⁹ Lambertus Klei ¹⁰ Bhooma Thiruvahindrapuram ⁸ Xiao Xu ^{1, 2, 3} Robert Ziman ⁸ Zhuozhi Wang ⁸ Jacob Vorstman ¹¹ Ann Thompson ¹² Regina Regan ¹³ Marion Pilorge ⁷ Giovanna Pellecchia ⁸ Alistair Pagnamenta ¹⁴ Bárbara Oliveira ¹⁵ Christian Marshall ^{8, 16} Tiago Magalhaes ^{13, 15, 17} Jennifer Lowe ^{18, 19} Jennifer Howe ⁸ Anthony Griswold ²⁰ John Gilbert ²⁰ Eftichia Duketis ²¹ Beth Dombroski ^{22, 23} Maretha De Jonge ¹¹ Michael Cuccaro ²⁰ Emily Crawford ^{24, 25} Catarina Correia ^{15, 26} Judith Conroy ¹³ Inês Conceição ¹⁵ Andreas Chiocchetti ^{21, 27} Jillian Casey ¹³ Guiqing Cai ^{1, 2, 3} Christelle Cabrol ⁷ Nadia Bolshakova ⁹ Elena Bacchelli ²⁸ Richard Anney ⁹ Steven Gallinger ²⁹ Michelle Cotterchio ³⁰ Graham Casey ³¹ Lonnie Zwaigenbaum ³² Kerstin Wittemeyer ³³ Kirsty Wing ¹⁴ Simon Wallace ³⁴ Herman Van Engeland ¹¹ Ana Tryfon ^{2, 3} Susanne Thomson ^{25, 24} Latha Soorya ^{2, 3} Bernadette Rogé ³⁵ Wendy Roberts ³⁶ Fritz Poustka ²¹ Susana Mouga ^{37, 38} Nancy Minshew ¹⁰ Alison Mcinnes ^{2, 3} Susan Mcgrew ³⁹ Catherine Lord ⁴⁰ Marion Leboyer ^{41, 42} Ann Le Couteur ^{43, 44} Alexander Kolevzon ^{2, 3, 4, 45} Patricia Jiménez González ⁴⁶ Suma Jacob ⁴⁷ Richard Holt ¹⁴ Stephen Guter ⁴⁷ Jonathan Green ⁴⁸ Andrew Green ¹³ Christopher Gillberg ^{49, 50} Bridget Fernandez ^{51, 52} Frederico Duque ³⁷ Richard Delorme ⁵³ Geraldine Dawson ⁵⁴ Pauline Chaste ¹⁰ Cátia Café ³⁷ Sean Brennan ⁹ Thomas Bourgeron ⁵³ Patrick Bolton ^{55, 56} Sven Bölte ²¹ Raphael Bernier ⁵⁷ Gillian Baird ⁵⁸ Anthony Bailey ^{59, 60} Evdokia Anagnostou ⁶¹ Joana Almeida ³⁷ Ellen Wijsman ^{62, 63} Veronica Vieland ⁶⁴ Astrid Vicente ^{15, 17} Gerard Schellenberg ^{22, 65} Margaret Pericak-Vance ²⁰ Andrew Paterson ⁸ Jeremy Parr ^{66, 67} Guiomar Oliveira ^{37, 38} John Nurnberger ⁶⁸ Anthony Monaco ¹⁴ Elena Maestrini ²⁸ Sabine Klauck ⁶⁹ Hakon Hakonarson ^{70, 71} Jonathan Haines ^{24, 25} Daniel Geschwind ¹⁸ Christine Freitag ²¹ Susan Folstein ^{20, 72, 73} Sean Ennis ¹³ Hilary Coon ⁷⁴ Agatino Battaglia ⁷⁵ Peter Szatmari ¹² James Sutcliffe ^{24, 25} Joachim Hallmayer ⁷⁶ Michael Gill ⁹ Edwin Cook ^{47, 77} Joseph Buxbaum ^{1, 2, 3, 4, 5, 78} Bernie Devlin ¹⁰ Louise Gallagher ⁹ Catalina Betancur ^{7, *} Stephen Scherer ^{8, 16, *}

* Auteur correspondant

1 Departments of Psychiatry, Genetics and Genomic Sciences

2 Department of Psychiatry

3 Seaver Autism Center for Research and Treatment

4 Friedman Brain Institute

5 The Mindich Child Health and Development Institute

6 The Icahn Institute for Genomics and Multiscale Biology

7 NPS - Neuroscience Paris Seine

8 Program in Genetics and Genomic Biology

9 Department of Psychiatry

10 Department of Psychiatry [Pittsburgh]

11 Department of Psychiatry

12 Department of Psychiatry and Behavioural Neurosciences

13 ACoRD - Academic Centre on Rare Diseases

14 Wellcome Trust Centre for Human Genetics

15 Instituto Nacional de Saude Dr Ricardo Jorge

16 McLaughlin Centre

17 BioFIG

18 Department of Neurology

19 Fisico-Quimica Biologica

20 John P. Hussman Institute for Human Genomics

21 Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy

22 Pathology and Laboratory Medicine

23 Department of Pathology

24 Vanderbilt Brain Institute

25 Department of Molecular Physiology & Biophysics and Psychiatry

26 LAMBE - UMR 8587 - Laboratoire Analyse et Modélisation pour la Biologie et l'Environnement

27 Division of Molecular Genome Analysis

28 Department of Pharmacy and Biotechnology

29 Familial Gastrointestinal Cancer Registry

30 Prevention & Cancer Control

31 Department of Preventive Medicine

32 Department of Pediatrics

33 School of Education

34 Department of Psychiatry

35 Octogone - Octogone Unité de Recherche Interdisciplinaire

36 Autism Research Unit

37 UNDA - Unidade de Neurodesenvolvimento e Autismo

38 Institute for Biomedical Imaging and Life Science

39 Department of Pediatrics

40 CADB - Center for Autism and the Developing Brain

41 IMRB - Institut Mondor de Recherche Biomédicale

42 Service de psychiatrie

43 Institute of Health and Society

44 Department of Child and Adolescent Psychiatry

45 Department of Pediatrics

46 Child Developmental and Behavioral Unit

47 Department of Psychiatry

48 Manchester Academic Health Sciences Centre

49 Gillberg Neuropsychiatry Centre

50 Institute of Child Health

51 Memorial University of Newfoundland [St. John's]

52 Disciplines of Genetics and Medicine

53 Génétique Humaine et Fonctions Cognitives

54 Department of Psychiatry and Behavioral Sciences

55 Institute of Psychiatry

56 Department of Child and Adolescent Psychiatry

57 Department of Psychiatry and Behavioral Sciences

58 Paediatric Neurodisability

59 SGDP - MRC Social, Genetic and Developmental Psychiatry Centre

60 Department of Psychiatry

61 Bloorview Research Institute

62 Division of Medical Genetics [Seattle]

63 Departments of Biostatistics and Medicine

64 Battelle Center for Mathematical Medicine

65 Pathology and Laboratory Medicine

66 ION - Institute of Neuroscience [Newcastle]

67 Institutes of Neuroscience and Health and Society

68 Department of Psychiatry

69 Division of Molecular Genome Analysis

70 The Center for Applied Genomics

71 Department of Pediatrics

72 Utah Autism Research Program

73 Department of Psychiatry

74 Department of Developmental Neuroscience

75 Department of Psychiatry

76 Stanford University School of Medicine [Stanford]

77 Institute for Juvenile Research

78 Department of Neuroscience

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.

Keywords : SETD5 autism rare CNV de novo inherited gene networks pathways Copy Number Variation CHD2 HDAC4 GDI1

Type de document :

Article dans une revue

American Journal of Human Genetics, Elsevier (Cell Press), 2014, 94 (5), pp.677-694. 〈10.1016/j.ajhg.2014.03.018〉

Domaine :

Sciences du Vivant [q-bio] / Génétique

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http://www.hal.inserm.fr/inserm-00986225
Contributeur : Catalina Betancur <>
Soumis le : jeudi 1 mai 2014 - 20:51:48
Dernière modification le : jeudi 27 septembre 2018 - 15:40:02
Document(s) archivé(s) le : lundi 10 avril 2017 - 18:07:22

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