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

Journal articles

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

* Corresponding author

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 - Neurosciences 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 The Wellcome Trust Centre for Human Genetics [Oxford]

15 INSA - Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal]

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 Division of Molecular Genome Analysis

27 Department of Pharmacy and Biotechnology

28 Familial Gastrointestinal Cancer Registry

29 Prevention & Cancer Control

30 Department of Preventive Medicine

31 Department of Pediatrics

32 School of Education

33 Department of Psychiatry

34 Octogone - Octogone Unité de Recherche Interdisciplinaire

35 Autism Research Unit

36 UNDA - Unidade de Neurodesenvolvimento e Autismo

37 Institute for Biomedical Imaging and Life Science

38 Department of Pediatrics

39 CADB - Center for Autism and the Developing Brain

40 IMRB - Institut Mondor de Recherche Biomédicale

41 Service de psychiatrie

42 Institute of Health and Society

43 Department of Child and Adolescent Psychiatry

44 Department of Pediatrics

45 Child Developmental and Behavioral Unit

46 Department of Psychiatry

47 Manchester Academic Health Sciences Centre

48 Gillberg Neuropsychiatry Centre [Göteborg, Sueden]

49 Institute of Child Health

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

51 Disciplines of Genetics and Medicine

52 Génétique Humaine et Fonctions Cognitives

53 Department of Psychiatry and Behavioral Sciences

54 Institute of Psychiatry

55 Department of Child and Adolescent Psychiatry

56 Department of Psychiatry and Behavioral Sciences

57 Paediatric Neurodisability

58 SGDP - MRC Social, Genetic and Developmental Psychiatry Centre

59 Department of Psychiatry

60 Bloorview Research Institute

61 Division of Medical Genetics [Seattle]

62 Departments of Biostatistics and Medicine

63 Battelle Center for Mathematical Medicine

64 Pathology and Laboratory Medicine

65 ION - Institute of Neuroscience [Newcastle]

66 Institutes of Neuroscience and Health and Society

67 Department of Psychiatry

68 Division of Molecular Genome Analysis

69 The Center for Applied Genomics

70 Department of Pediatrics

71 Utah Autism Research Program

72 Department of Psychiatry

73 Department of Developmental Neuroscience

74 Department of Psychiatry and Behavioral Sciences [Stanford]

75 Stanford School of Medicine [Stanford]

76 Institute for Juvenile Research

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

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Journal articles

Domain :

Life Sciences [q-bio] / Genetics

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