Marie Bidart1,2, Michèle El Atifi1,2, Sarra Miladi1,2, John Rendu2,3, Véronique Satre2,4,5, Pierre F Ray2,3,5, Caroline Bosson3, Françoise Devillard4, Daphné Lehalle6, Valérie Malan7, Jeanne Amiel6, Maria Antonietta Mencarelli8, Margherita Baldassarri8,9, Alessandra Renieri8,9, Jill Clayton-Smith10, Gaëlle Vieville4, Julien Thevenon11, Florence Amblard4, François Berger1,2, Pierre-Simon Jouk2,4, Charles Coutton2,4,5. 1. UF Clinatec, Pôle Recherche, INSERM UMR 1205, CHU de Grenoble, Grenoble, France. 2. Université Grenoble-Alpes, Grenoble, France. 3. Département de Biochimie Toxicologie et Pharmacologie, Département de Biochimie Génétique et Moléculaire, Centre Hospitalier Universitaire de Grenoble, Grenoble, France. 4. Département de Génétique et Procréation, Hôpital Couple-Enfant, CHU de Grenoble, Grenoble, France. 5. Equipe "Genetics Epigenetics and Therapies of Infertility," Institut Albert Bonniot, INSERM U823, La Tronche, France. 6. Service de Génétique, INSERM U781, Hôpital Necker-Enfants Malades, Institut Imagine, University Sorbonne-Paris-Cité, Paris, France. 7. Service de Cytogénétique et UMR_S1163, IHU Imagine, Hôpital Necker-Enfants Malades, Paris, France. 8. Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy. 9. Medical Genetics, University of Siena, Siena, Italy. 10. Manchester Centre for Genomic Medicine, Central Manchester University Hospitals, Manchester Academic Health Sciences Centre, Manchester, UK. 11. Centre de Génétique et Centre de Référence "Anomalies du Développement et Syndromes Malformatifs," Hôpital d'Enfants, CHU Dijon, Dijon, France.
Abstract
PURPOSE: To determine whether duplication of the ARID1A gene is responsible for a new recognizable syndrome. METHODS: 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). RESULTS: 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. CONCLUSION: 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.
PURPOSE: To determine whether duplication of the ARID1A gene is responsible for a new recognizable syndrome. METHODS: 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). RESULTS: 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. CONCLUSION: 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.
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