title: Microduplication of the ARID1A gene causes intellectual disability with recognizable syndromic features.
abstract: To determine whether duplication of the ARID1A gene is responsible for a new recognizable syndrome.
  
  
  
  We describe four patients with a 1p36.11 microduplication involving ARID1A as identified by array-comparative genomic hybridization . We performed comparative transcriptomic analysis of patient-derived fibroblasts using RNA sequencing and evaluated the impact of ARID1A duplication on the cell cycle using fluorescence-activated cell sorting. Functional relationships between differentially expressed genes were investigated with ingenuity pathway analysis (IPA).
  
  
  
  Combining the genomic data, we defined a small (122 kb), minimally critical region that overlaps the full ARID1A gene. The four patients shared a strikingly similar phenotype that included intellectual disability and microcephaly. Transcriptomic analysis revealed the deregulated expression of several genes previously linked to microcephaly and developmental disorders as well as the involvement of signaling pathways relevant to microcephaly, among which the polo-like kinase (PLK) pathway was especially notable. Cell-cycle analysis of patient-derived fibroblasts showed a significant increase in the proportion of cells in G1 phase at the expense of G2-M cells.
  
  
  
  Our study reports a new microduplication syndrome involving the ARID1A gene. This work is the first step in clarifying the pathophysiological mechanism that links changes in the gene dosage of ARID1A with intellectual disability and microcephaly.Genet Med advance online publication 01 December 2016.
authors.affiliation: UF Clinatec, Pôle Recherche, INSERM UMR 1205, CHU de Grenoble, Grenoble, France.|Université Grenoble-Alpes, Grenoble, France.
authors.forename: Marie
authors.identifier: 0000-0003-4092-1253
authors.initials: M
authors.lastname: Bidart
authors.affiliation: UF Clinatec, Pôle Recherche, INSERM UMR 1205, CHU de Grenoble, Grenoble, France.|Université Grenoble-Alpes, Grenoble, France.
authors.forename: Michèle
authors.identifier: 0000-0003-1814-2720
authors.initials: M
authors.lastname: El Atifi
authors.affiliation: UF Clinatec, Pôle Recherche, INSERM UMR 1205, CHU de Grenoble, Grenoble, France.|Université Grenoble-Alpes, Grenoble, France.
authors.forename: Sarra
authors.identifier: 0000-0002-9139-3449
authors.initials: S
authors.lastname: Miladi
authors.affiliation: Université Grenoble-Alpes, Grenoble, France.|Département de Biochimie Toxicologie et Pharmacologie, Département de Biochimie Génétique et Moléculaire, Centre Hospitalier Universitaire de Grenoble, Grenoble, France.
authors.forename: John
authors.initials: J
authors.lastname: Rendu
authors.affiliation: Université Grenoble-Alpes, Grenoble, France.|Département de Génétique et Procréation, Hôpital Couple-Enfant, CHU de Grenoble, Grenoble, France.|Equipe "Genetics Epigenetics and Therapies of Infertility," Institut Albert Bonniot, INSERM U823, La Tronche, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Satre
authors.affiliation: Université Grenoble-Alpes, Grenoble, France.|Département de Biochimie Toxicologie et Pharmacologie, Département de Biochimie Génétique et Moléculaire, Centre Hospitalier Universitaire de Grenoble, Grenoble, France.|Equipe "Genetics Epigenetics and Therapies of Infertility," Institut Albert Bonniot, INSERM U823, La Tronche, France.
authors.forename: Pierre F
authors.initials: PF
authors.lastname: Ray
authors.affiliation: Département de Biochimie Toxicologie et Pharmacologie, Département de Biochimie Génétique et Moléculaire, Centre Hospitalier Universitaire de Grenoble, Grenoble, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Bosson
authors.affiliation: Département de Génétique et Procréation, Hôpital Couple-Enfant, CHU de Grenoble, Grenoble, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Devillard
authors.affiliation: Service de Génétique, INSERM U781, Hôpital Necker-Enfants Malades, Institut Imagine, University Sorbonne-Paris-Cité, Paris, France.
authors.forename: Daphné
authors.identifier: 0000-0002-2193-8685
authors.initials: D
authors.lastname: Lehalle
authors.affiliation: Service de Cytogénétique et UMR_S1163, IHU Imagine, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Valérie
authors.identifier: 0000-0002-3450-4958
authors.initials: V
authors.lastname: Malan
authors.affiliation: Service de Génétique, INSERM U781, Hôpital Necker-Enfants Malades, Institut Imagine, University Sorbonne-Paris-Cité, Paris, France.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Amiel
authors.affiliation: Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Mencarelli
authors.affiliation: Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.|Medical Genetics, University of Siena, Siena, Italy.
authors.forename: Margherita
authors.identifier: 0000-0002-0391-1980
authors.initials: M
authors.lastname: Baldassarri
authors.affiliation: Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.|Medical Genetics, University of Siena, Siena, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Renieri
authors.affiliation: Manchester Centre for Genomic Medicine, Central Manchester University Hospitals, Manchester Academic Health Sciences Centre, Manchester, UK.
authors.forename: Jill
authors.initials: J
authors.lastname: Clayton-Smith
authors.affiliation: Département de Génétique et Procréation, Hôpital Couple-Enfant, CHU de Grenoble, Grenoble, France.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Vieville
authors.affiliation: Centre de Génétique et Centre de Référence "Anomalies du Développement et Syndromes Malformatifs," Hôpital d'Enfants, CHU Dijon, Dijon, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Thevenon
authors.affiliation: Département de Génétique et Procréation, Hôpital Couple-Enfant, CHU de Grenoble, Grenoble, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Amblard
authors.affiliation: UF Clinatec, Pôle Recherche, INSERM UMR 1205, CHU de Grenoble, Grenoble, France.|Université Grenoble-Alpes, Grenoble, France.
authors.forename: François
authors.identifier: 0000-0001-7221-0718
authors.initials: F
authors.lastname: Berger
authors.affiliation: Université Grenoble-Alpes, Grenoble, France.|Département de Génétique et Procréation, Hôpital Couple-Enfant, CHU de Grenoble, Grenoble, France.
authors.forename: Pierre-Simon
authors.identifier: 0000-0001-8301-320X
authors.initials: PS
authors.lastname: Jouk
authors.affiliation: Université Grenoble-Alpes, Grenoble, France.|Département de Génétique et Procréation, Hôpital Couple-Enfant, CHU de Grenoble, Grenoble, France.|Equipe "Genetics Epigenetics and Therapies of Infertility," Institut Albert Bonniot, INSERM U823, La Tronche, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Coutton
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002878:Chromosomes, Human, Pair 1; D004268:DNA-Binding Proteins; D005260:Female; D020440:Gene Duplication; D020869:Gene Expression Profiling; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics*; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C112476:ARID1A protein, human; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors