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Novel promoters and coding first exons in DLG2 linked to developmental disorders and intellectual disability

Pascaline Létard 1 Séverine Drunat 2 Yoann Vial 3 Sarah Duerinckx Anais Ernault 2 Daniel Amram 4 Stéphanie Arpin 5 Marta Bertoli Tiffany Busa 6 Berten Ceulemans 7 Julie Desir 8 Martine Doco-Fenzy 9 Siham Chafai Elalaoui Koenraad Devriendt 10 Laurence Faivre 11 Christine Francannet 12 Geneviève Geneviève Cyril Gitiaux 13 Sophie Julia 14 Sébastien Lebon 15 Toni Lubala Michèle Mathieu-Dramard 16 Hélène Maurey 17 Julia Metreau 18 Sanaa Nasserereddine Mathilde Nizon 19 Geneviève Pierquin 20 Nathalie Pouvreau 4 Clothilde Rivier-Ringenbach 21 Massimiliano Rossi 22 Elise Schaefer 23 Yves Sznajer 24 Yusuf Tunca Sophie Guilmin Crepon 2 Corinne Alberti 25 Monique Elmaleh-Bergès 26 Brigitte Benzacken 27 Bernd Wollnick C Geoffrey Woods Anita Rauch 28 Vincent El Ghouzzi 1 Pierre Gressens 1 Alain Verloes 29 Sandrine Passemard 2 David Geneviève 30, 31 Julia Julia C. Geoffrey Woods S Mordel Stéphane Schaeffer 32 S. Dupas 33 Marie-Alice Laville Françoise Chapon 34 S. Allouche 35 Patrick Mordel 36 Quentin Dupas Claudio Reggiani Sandra Coppens Tayeb Sekhara Ivan Dimov Bruno Pichon Nicolas Lufin Marie-Claude Addor 37 Elga Fabia Belligni Maria Cristina Digilio 38 Flavio Faletra Giovanni Battista Ferrero Marion Gérard 39 Bertrand Isidor 19 Shelagh Joss 40 Florence Niel-Bütschi Maria Dolores Perrone Florence Petit 41 Alessandra Renieri 42 Serge Romana 43 Alexandra Topa Joris Robert Vermeesch 44 Tom Lenaerts 45 Georges Casimir Marc Abramowicz Gianluca Bontempi Catheline Vilain 46 Nicolas Deconinck 47 Guillaume Smits 48
1 PROTECT - Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies
2 AP-HP Hôpital universitaire Robert-Debré [Paris]
3 UNIROUEN UFR Santé - UNIROUEN - UFR Santé
4 Unité fonctionnelle de génétique clinique
5 Service de génétique [Tours]
6 Département de génétique médicale [Hôpital de la Timone - APHM]
7 UA - University of Antwerp
8 I.P.G. - Institut de Pathologie et Génétique [Gosselies]
9 Service de Génétique
10 Centre for Human Genetics
11 UNICANCER/CRLCC-CGFL - Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon]
12 Service de génétique médicale
13 IC UM3 (UMR 8104 / U1016) - Institut Cochin
14 Service de génétique médicale [Toulouse]
15 CHUV - Centre Hospitalier Universitaire Vaudois [Lausanne]
16 Service de génétique médicale
17 Service Neuropédiatrie
18 AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)
19 Service de génétique médicale - Unité de génétique clinique [Nantes]
20 Centre de Génétique Humaine
21 Service de pédiatre-Néonatologie
22 CRNL - Centre de recherche en neurosciences de Lyon
23 Service de Génétique
24 Medical Genetics
25 ECEVE (U1123 / UMR_S_1123) - Epidémiologie Clinique et Evaluation Economique Appliquées aux Populations Vulnérables
26 Service d'imagerie pédiatrique
27 Département de génétique
28 Allergy Unit - Department of Dermatology
29 Physiopathologie et neuroprotection des atteintes du cerveau en développement
30 Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier]
31 Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB)
32 Department of Biology [Utah]
33 LEGS - Laboratoire Evolution, Génomes et Spéciation
34 Hôpital Côte de Nacre [CHU Caen]
35 Service de biochimie [CHU Caen]
36 SEILIRM - Signalisation, électrophysiologie et imagerie des lésions d’ischémie-reperfusion myocardique
37 Département Génétique Médicale-Maternité
38 IRCCS Ospedale Pediatrico Bambino Gesù [Roma]
39 UL - Université de Lorraine
40 Center for Medical Genetics
41 JPArc - Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837
42 Medical Genetics
43 Laboratoire Histologie Embryologie Cytogénétique [CHU Necker]
44 Department of Human Genetics
45 AI-lab, Vakgroep Computerwetenschappen
46 ULB - Université libre de Bruxelles
47 Universiteit Gent [Ghent]
48 ULB - Hôpital Erasme [Bruxelles]
Abstract : Tissue-specific integrative omics has the potential to reveal new genic elements important for developmental disorders. METHODS: Two pediatric patients with global developmental delay and intellectual disability phenotype underwent array-CGH genetic testing, both showing a partial deletion of the DLG2 gene. From independent human and murine omics datasets, we combined copy number variations, histone modifications, developmental tissue-specific regulation, and protein data to explore the molecular mechanism at play. RESULTS: Integrating genomics, transcriptomics, and epigenomics data, we describe two novel DLG2 promoters and coding first exons expressed in human fetal brain. Their murine conservation and protein-level evidence allowed us to produce new DLG2 gene models for human and mouse. These new genic elements are deleted in 90% of 29 patients (public and in-house) showing partial deletion of the DLG2 gene. The patients' clinical characteristics expand the neurodevelopmental phenotypic spectrum linked to DLG2 gene disruption to cognitive and behavioral categories. CONCLUSIONS: While protein-coding genes are regarded as well known, our work shows that integration of multiple omics datasets can unveil novel coding elements. From a clinical perspective, our work demonstrates that two new DLG2 promoters and exons are crucial for the neurodevelopmental phenotypes associated with this gene. In addition, our work brings evidence for the lack of cross-annotation in human versus mouse reference genomes and nucleotide versus protein databases.
Keywords : Neurodevelopmental disorders Promoters Intellectual disability Next generation sequencing Functional genomics ATP6 deletion Complex V deficiency Mitochondrial disease NARP syndrome DLG2 primary microcephaly ASPM brain development centrosome brain imaging MCPH
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Journal articles
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https://hal-normandie-univ.archives-ouvertes.fr/hal-02268433
Contributor : Marion Gerard <>
Submitted on : Tuesday, August 20, 2019 - 10:22:58 PM
Last modification on : Thursday, January 14, 2021 - 11:10:03 AM

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COMUE-NORMANDIE | CGFL | CNRS | FNCLCC | UNIV-LORRAINE | ECEVE | UNIV-ST-ETIENNE | UNIV-LYON1 | UNIV-PARIS5 | BS | UNIV-MONTPELLIER | URCA | UNIV-NANTES | UNIROUEN | UNIV-AMU | UNIV-PARIS7 | UNICAEN | USPC | UDL | UNIV-PARIS | UP-SANTE | UNIV-LILLE

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Pascaline Létard, Séverine Drunat, Yoann Vial, Sarah Duerinckx, Anais Ernault, et al.. Novel promoters and coding first exons in DLG2 linked to developmental disorders and intellectual disability. Genome Medicine, BioMed Central, 2017, 9, pp.67. ⟨10.1186/s13073-017-0452-y⟩. ⟨hal-02268433⟩

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