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3 results on '"Laurence Duplomb-Jego"'

1. STAG1 mutations cause a novel cohesinopathy characterised by unspecific syndromic intellectual disability

Author

Julien Thevenon, Christiane Zweier, Hilde Olivié, Nicole Revencu, Aurélia Jacquette, Megan T. Cho, Anne-Laure Mosca-Boidron, Marjolein H. Willemsen, Laurence Faivre, Yannis Duffourd, Odile Boute-Benejean, Elaine H. Zackai, Carey McDougall, Amber Begtrup, Anita Rauch, Christel Thauvin-Robinet, Perrine Charles, Koen L.I. van Gassen, Thomas Smol, Laurence Duplomb-Jego, Daphné Lehalle, Amanda Clarkson, Orrin Devinsky, Catherine Vincent-Delorme, Paul Kuentz, Bénédicte Gérard, Patrick Callier, Karol Rubin, Jean-Baptiste Rivière, Sébastien Moutton, Deborah J. Shears, Ana Lisa Taylor Tavares, Ingrid Simonic, Paulien A. Terhal, Soo-Mi Park, Alice Masurel-Paulet, and Golder N. Wilson

Subjects
0301 basic medicine, Genetics, Mutation, Cohesin complex, Point mutation, Biology, medicine.disease, medicine.disease_cause, Bioinformatics, Frameshift mutation, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Intellectual disability, medicine, Journal Article, Missense mutation, Gene, 030217 neurology & neurosurgery, Genetics (clinical), Exome sequencing, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract

Item does not contain fulltext BACKGROUND: Cohesinopathies are rare neurodevelopmental disorders arising from a dysfunction in the cohesin pathway, which enables chromosome segregation and regulates gene transcription. So far, eight genes from this pathway have been reported in human disease. STAG1 belongs to the STAG subunit of the core cohesin complex, along with five other subunits. This work aimed to identify the phenotype ascribed to STAG1 mutations. METHODS: Among patients referred for intellectual disability (ID) in genetics departments worldwide, array-comparative genomic hybridisation (CGH), gene panel, whole-exome sequencing or whole-genome sequencing were performed following the local diagnostic standards. RESULTS: A mutation in STAG1 was identified in 17 individuals from 16 families, 9 males and 8 females aged 2-33 years. Four individuals harboured a small microdeletion encompassing STAG1; three individuals from two families had an intragenic STAG1 deletion. Six deletions were identified by array-CGH, one by whole-exome sequencing. Whole-exome sequencing found de novo heterozygous missense or frameshift STAG1 variants in eight patients, a panel of genes involved in ID identified a missense and a frameshift variant in two individuals. The 17 patients shared common facial features, with wide mouth and deep-set eyes. Four individuals had mild microcephaly, seven had epilepsy. CONCLUSIONS: We report an international series of 17 individuals from 16 families presenting with syndromic unspecific ID that could be attributed to a STAG1 deletion or point mutation. This first series reporting the phenotype ascribed to mutation in STAG1 highlights the importance of data sharing in the field of rare disorders.

Published
2017
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2. Application of whole-exome sequencing to unravel the molecular basis of undiagnosed syndromic congenital neutropenia with intellectual disability

Author

Jean Donadieu, Delphine Héron, Laurence Faivre, Salima El Chehadeh, Daphné Lehalle, Claire Briandet, Elodie Gautier, Julien Thevenon, Daniel Amram, Thibaud Jouan, Jean-Baptiste Rivière, Judith Melki, Laurence Duplomb-Jego, Frédéric Huet, Christine Bellanné-Chantelot, Christel Thauvin-Robinet, Ange-Line Bruel, Yannis Duffourd, Lucile Pinson, Isabelle Maystadt, Judith St-Onge, Sophia Julia, Alexandra Gauthier-Vasserot, Paul Kuentz, Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL), Génétique des Anomalies du Développement (GAD), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Dijon, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Immuno-hématologie pédiatrique (MaRIH), Laboratoire de géographie physique : Environnements Quaternaires et Actuels (LGP), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Centre de Génétique Humaine, Institut de Pathologie et de Génétique, Université de Namur [Namur] (UNamur), Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Unité fonctionnelle de génétique clinique, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Centre hospitalier universitaire de Toulouse-Purpan, Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] ( IHOPe ), Hospices Civils de Lyon ( HCL ), Génétique des Anomalies du Développement ( GAD ), Université de Bourgogne ( UB ) -IFR100 - Structure fédérative de recherche Santé-STIC, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Centre de Référence des Déficiences Intellectuelles de Causes Rares, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme ( GRC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Service d’oncologie hématologie pédiatrique [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Immuno-hématologie pédiatrique ( MaRIH ), Laboratoire de géographie physique ( LGP ), Université Panthéon-Sorbonne ( UP1 ) -Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Namur, Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Arnaud de Villeneuve, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Service de pédiatrie (CHU de Dijon), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), CHU Toulouse [Toulouse], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, Neutropenia, Adolescent, Neonatal onset, 03 medical and health sciences, 0302 clinical medicine, congenital neutropenia, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Intellectual Disability, Intellectual disability, Genetics, medicine, Congenital Bone Marrow Failure Syndromes, Humans, Exome, Child, Congenital Neutropenia, Genetic Association Studies, Genetics (clinical), Exome sequencing, Retrospective Studies, business.industry, High-Throughput Nucleotide Sequencing, Infant, Syndrome, medicine.disease, 3. Good health, Phenotype, 030104 developmental biology, CHD2, Child, Preschool, 030220 oncology & carcinogenesis, Cohort, Etiology, Female, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Biomarkers
Abstract

International audience; Neutropenia can be qualified as congenital when of neonatal onset or when associated with extra-hematopoietic manifestations. Overall, 30% of patients with congenital neutropenia (CN) remain without a molecular diagnosis after a multidisciplinary consultation and tedious diagnostic strategy. In the rare situations when neutropenia is identified and associated with intellectual disability (ID), there are few diagnostic hypotheses to test. This retrospective multicenter study reports on a clinically heterogeneous cohort of 10 unrelated patients with CN associated with ID and no molecular diagnosis prior to whole-exome sequencing (WES). WES provided a diagnostic yield of 40% (4/10). The results suggested that in many cases neutropenia and syndromic manifestations could not be assigned to the same molecular alteration. Three sub-groups of patients were highlighted: (i) severe, symptomatic chronic neutropenia, detected early in life, and related to a known mutation in the CN spectrum (ELANE); (ii) mild to moderate benign intermittent neutropenia, detected later, and associated with mutations in genes implicated in neurodevelopmental disorders (CHD2, HUWE1); and (iii) moderate to severe intermittent neutropenia as a probably undiagnosed feature of a newly reported syndrome (KAT6A). Unlike KAT6A, which seems to be associated with a syndromic form of CN, the other reported mutations may not explain the entire clinical picture. Although targeted gene sequencing can be discussed for the primary diagnosis of severe CN, we suggest that performing WES for the diagnosis of disorders associating CN with ID will not only provide the etiological diagnosis but will also pave the way towards personalized care and follow-up. (C) 2016 Wiley Periodicals, Inc., (C) 2016 John Wiley & Sons, Ltd

Published
2016
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3. Lysosomal Signaling Licenses Embryonic Stem Cell Differentiation via Inactivation of Tfe3

Author

Paul Kuentz, Magali Avila, Jean Baptiste Rivière, Pierre Vabres, Marietta Zinner, Julien Thevenon, Judith St-Onge, David Geneviève, Eveline S. J. M. de Bont, Florian Villegas, Floor A. M. Duijkers, Mieke M. van Haelst, Laurence Duplomb-Jego, Sébastien A. Smallwood, Silvana van Koningsbruggen, Daniel Olivieri, Nada Houcinat, Yannis Duffourd, Thibaud Jouan, Christel Thauvin-Robinet, Koen L.I. van Gassen, Daphné Lehalle, Melanie Rittirsch, Michael B. Stadler, Laurence Faivre, Daniel Hess, Klaske D. Lichtenbelt, Joerg Betschinger, Daniela Mayer, Friedrich Miescher Institute for Biomedical Research (FMI), Novartis Research Foundation, University of Basel (Unibas), FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Bourgogne Franche-Comté [COMUE] (UBFC), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL), Service de Dermatologie (CHU de Dijon), Beatrix Children's Hospital, Department of Clinical Genetics (Academic Medical Center, University of Amsterdam), VU University Medical Center [Amsterdam], Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), University Medical Center [Utrecht], Research Institute of the McGill University Hospital Centre, Human genetics, Cancer Center Amsterdam, Amsterdam Reproduction & Development (AR&D), Human Genetics, and ACS - Pulmonary hypertension & thrombosis

Subjects
Male, Transcription, Genetic, GTPase, GTP Phosphohydrolases, PATHWAY, Mice, 0302 clinical medicine, Neural Stem Cells, CRISPR, TUMOR-SUPPRESSOR, Cell Self Renewal, Phosphorylation, SPECIFICATION, developmental disorder, 0303 health sciences, Genome, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Cell Differentiation, Mouse Embryonic Stem Cells, Flcn, differentiation, Cell biology, medicine.anatomical_structure, mTOR, Molecular Medicine, Female, Signal transduction, Protein Binding, Signal Transduction, RECRUITMENT, Biology, 03 medical and health sciences, Rag GTPases, Lysosome, Genetics, medicine, Animals, Humans, Point Mutation, NAIVE PLURIPOTENCY, AMINO-ACID LEVELS, Transcription factor, Alleles, PI3K/AKT/mTOR pathway, 030304 developmental biology, COMPLEX, FOLLICULIN, Ragulator, Cell Biology, pluripotency, embryonic stem cell, Embryonic stem cell, Tfe3, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Cytoplasm, Lysosomes, 030217 neurology & neurosurgery
Abstract

International audience; Self-renewal and differentiation of pluripotent murine embryonic stem cells (ESCs) is regulated by extrinsic signaling pathways. It is less clear whether cellular metabolism instructs developmental progression. In an unbiased genome-wide CRISPR/Cas9 screen, we identified components of a conserved amino-acid-sensing pathway as critical drivers of ESC differentiation. Functional analysis revealed that lysosome activity, the Ragulator protein complex, and the tumor-suppressor protein Folliculin enable the Rag GTPases C and D to bind and seclude the bHLH transcription factor Tfe3 in the cytoplasm. In contrast, ectopic nuclear Tfe3 represses specific developmental and metabolic transcriptional programs that are associated with peri-implantation development. We show differentiation-specific and non-canonical regulation of Rag GTPase in ESCs and, importantly, identify point mutations in a Tfe3 domain required for cytoplasmic inactivation as potentially causal for a human developmental disorder. Our work reveals an instructive and biomedically relevant role of metabolic signaling in licensing embryonic cell fate transitions.

Published
2019
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