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1. Using multiomic integration to improve blood biomarkers of major depressive disorder: a case-control studyResearch in context

Author

Amazigh Mokhtari, El Chérif Ibrahim, Arnaud Gloaguen, Claire-Cécile Barrot, David Cohen, Margot Derouin, Hortense Vachon, Guillaume Charbonnier, Béatrice Loriod, Charles Decraene, Ipek Yalcin, Cynthia Marie-Claire, Bruno Etain, Raoul Belzeaux, Andrée Delahaye-Duriez, and Pierre-Eric Lutz

Subjects
Depression, Transcriptomic, microRNA, DNA methylation, Sex differences, Multiomic integration, Medicine, Medicine (General), R5-920
Abstract

Summary: Background: Major depressive disorder (MDD) is a leading cause of disability, with a twofold increase in prevalence in women compared to men. Over the last few years, identifying molecular biomarkers of MDD has proven challenging, reflecting interactions among multiple environmental and genetic factors. Recently, epigenetic processes have been proposed as mediators of such interactions, with the potential for biomarker development. Methods: We characterised gene expression and two mechanisms of epigenomic regulation, DNA methylation (DNAm) and microRNAs (miRNAs), in blood samples from a cohort of individuals with MDD and healthy controls (n = 169). Case-control comparisons were conducted for each omic layer. We also defined gene coexpression networks, followed by step-by-step annotations across omic layers. Third, we implemented an advanced multiomic integration strategy, with covariate correction and feature selection embedded in a cross-validation procedure. Performance of MDD prediction was systematically compared across 6 methods for dimensionality reduction, and for every combination of 1, 2 or 3 types of molecular data. Feature stability was further assessed by bootstrapping. Findings: Results showed that molecular and coexpression changes associated with MDD were highly sex-specific and that the performance of MDD prediction was greater when the female and male cohorts were analysed separately, rather than combined. Importantly, they also demonstrated that performance progressively increased with the number of molecular datasets considered. Interpretation: Informational gain from multiomic integration had already been documented in other medical fields. Our results pave the way toward similar advances in molecular psychiatry, and have practical implications for developing clinically useful MDD biomarkers. Funding: This work was supported by the Centre National de la Recherche Scientifique (contract UPR3212), the University of Strasbourg, the Université Sorbonne Paris Nord, the Université Paris Cité, the Fondation de France (FdF N° Engt:00081244 and 00148126; ECI, IY, RB, PEL), the French National Research Agency (ANR-18-CE37-0002, BE, CMC, ADD, PEL, ECI; ANR-18-CE17-0009, ADD; ANR-19-CE37-0010, PEL; ANR-21-RHUS-009, ADD, BE, CMC, CCB; ANR-22-PESN-0013, ADD), the Fondation pour la Recherche sur le Cerveau (FRC 2019, PEL), Fondation de France (2018, BE, CMC, ADD) and American Foundation for Suicide Prevention (AFSP YIG-1-102-19; PEL).

Published
2025
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2. Machine learning applications in drug development

Author

Clémence Réda, Emilie Kaufmann, and Andrée Delahaye-Duriez

Subjects
Drug discovery, Drug repurposing, Multi-armed bandit, Collaborative filtering, Bayesian optimization, Adaptive clinical trial, Biotechnology, TP248.13-248.65
Abstract

Due to the huge amount of biological and medical data available today, along with well-established machine learning algorithms, the design of largely automated drug development pipelines can now be envisioned. These pipelines may guide, or speed up, drug discovery; provide a better understanding of diseases and associated biological phenomena; help planning preclinical wet-lab experiments, and even future clinical trials. This automation of the drug development process might be key to the current issue of low productivity rate that pharmaceutical companies currently face. In this survey, we will particularly focus on two classes of methods: sequential learning and recommender systems, which are active biomedical fields of research.

Published
2020
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3. HOXC4 homeoprotein efficiently expands human hematopoietic stem cells and triggers similar molecular alterations as HOXB4

Author

Céline Auvray, Andrée Delahaye, Françoise Pflumio, Rima Haddad, Sophie Amsellem, Ayda Miri-Nezhad, Loïc Broix, Azzedine Yacia, Frédérique Bulle, Serge Fichelson, and Isabelle Vigon

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Background Expansion of hematopoietic stem cells represents an important objective for improving cell and gene therapy protocols. Retroviral transduction of the HoxB4 homeogene in mouse and human hematopoietic stem cells and hematopoietic progenitors is known to promote the cells’ expansion. A safer approach consists in transferring homeobox proteins into hematopoietic stem cells taking advantage of the natural ability of homeoproteins to cross cell membranes. Thus, HOXB4 protein transfer is operative for expanding human hematopoietic cells, but such expansion needs to be improved.Design and Methods To that aim, we evaluated the effects of HOXC4, a protein encoded by a HOXB4 paralog gene, by co-culturing HOXC4-producing stromal cells with human CD34+ hematopoietic cells. Numbers of progenitors and stem cells were assessed by in vitro cloning assays and injection into immuno-deficient mice, respectively. We also looked for activation or inhibition of target downstream gene expression.Results We show that the HOXC4 homeoprotein expands human hematopoietic immature cells by 3 to 6 times ex vivo and significantly improves the level of in vivo engraftment. Comparative transcriptome analysis of CD34+ cells subjected or not to HOXB4 or HOXC4 demonstrated that both homeoproteins regulate the same set of genes, some of which encode key hematopoietic factors and signaling molecules. Certain molecules identified herein are factors reported to be involved in stem cell fate or expansion in other models, such as MEF2C, EZH2, DBF4, DHX9, YPEL5 and Pumilio.Conclusions The present study may help to identify new HOX downstream key factors potentially involved in hematopoietic stem cell expansion or in leukemogenesis.

Published
2012
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7. Lessons from two series by physicians and caregivers’ self-reported data, and DNA methylation profile in DDX3X-Related Disorders

Author

David Geneviève, Valentin Ruault, Pauline Burger, Johanna Gradels-Hauguel, Nathalie Ruiz-Pallares, Xtraordinaire Association, Rami Abou Jamra, Alexandra Afenjar, Yves Alembik, Jean-Luc Alessandri, Arpin Stéphanie, Giulia Barcia, Šárka Bendová, Ange-Line Bruel, Perrine Charles, Nicolas Chatron, Maya Chopra, Solène Conrad, Valérie Cormier-Daire, Auriane Cospain, Christine Coubes, Juliette Coursimault, Andrée Delahaye-Duriez, Martine Doco-Fenzy, William Dufour, Benjamin Durand, Camille ENGEL, Laurence Faivre, Fanny Ferroul, Mélanie FRADIN, Hélène Frenkiel, Carlo Fusco, Livia Garavelli, Aurore Garde, Bénédicte Gérard, David Germanaud, Louise Goujon, Aurélie Gouronc, Emmanuelle Ginglinger, Alice Goldenberg, Miroslava Hancarova, Delphine Héron, Bertrand Isidor, Nolwenn Jean Marçais, Boris Keren, Margarete Koch-Hogrebe, Paul Kuentz, Victoria Lamure, Anne-Sophie Lebre, François Lecoquierre, Natacha Lehman, Gaetan Lesca, Stanislas Lyonnet, Delphine Martin, Cyril Mignot, Teresa Neuhann, Gaël Nicolas, Mathilde Nizon, Florence Petit, Christophe Philippe, Amélie Piton, Marzia Pollazzon, Darina Prchalova, Audrey Putoux, Marlène RIO, Sophie Rondeau, Massimiliano Rossi, Quentin Sabbagh, Pascale Saugier-Veber, Ariane Schmetz, Julie Steffann, Christel Thauvin-Robinet, Annick Toutain, Frédéric Tran-Mau-Them, Gabriele Trimarchi, Marie Vincent, Marketa Vlckova, Dagmar Wieczorek, Marjolaine Willems, kevin yauy, Michaela Zelinová, Alban Ziegler, Boris Chaumette, Bekim Sadikovic, and Jean-Louis Mandel

Abstract

We report two series of individuals with DDX3X variations, one (48 individuals) from physicians and one (44 individuals) from caregivers. These two series include several symptoms in common, with fairly similar distribution, which suggests that caregivers’ data are close to physicians’ data. For example, both series identified early childhood symptoms that were not previously described: feeding difficulties, mean walking age and age at first words. Each of the two datasets provide complementary knowledge. We confirmed that symptoms are similar to those in the literature and provide more details on feeding difficulties. Caregivers considered that the symptom attention-deficit/hyperactivity disorder was most worrisome. Both series also reported sleep disturbance. Recently, anxiety has been reported in individuals with DDX3X variants. We strongly suggest that attention-deficit/hyperactivity disorder, anxiety and sleep disorders need to be treated. In addition, we demonstrate preliminary evidence of a mild genome-wide DNA methylation profile in patients carrying mutations in DDX3X.

Published
2023
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8. ADGRL1 haploinsufficiency causes a variable spectrum of neurodevelopmental disorders in humans and alters synaptic activity and behavior in a mouse model

Author

Antonio Vitobello, Benoit Mazel, Vera G. Lelianova, Alice Zangrandi, Evelina Petitto, Jason Suckling, Vincenzo Salpietro, Robert Meyer, Miriam Elbracht, Ingo Kurth, Thomas Eggermann, Ouafa Benlaouer, Gurprit Lall, Alexander G. Tonevitsky, Daryl A. Scott, Katie M. Chan, Jill A. Rosenfeld, Sophie Nambot, Hana Safraou, Ange-Line Bruel, Anne-Sophie Denommé-Pichon, Frédéric Tran Mau-Them, Christophe Philippe, Yannis Duffourd, Hui Guo, Andrea K. Petersen, Leslie Granger, Amy Crunk, Allan Bayat, Pasquale Striano, Federico Zara, Marcello Scala, Quentin Thomas, Andrée Delahaye, Jean-Madeleine de Sainte Agathe, Julien Buratti, Serguei V. Kozlov, Laurence Faivre, Christel Thauvin-Robinet, and Yuri Ushkaryov

Subjects
Adult, Mice, Knockout, Receptors, Peptide, Autism Spectrum Disorder, Haploinsufficiency, Article, Receptors, G-Protein-Coupled, Disease Models, Animal, Mice, Neurodevelopmental Disorders, Intellectual Disability, Genetics, Animals, Humans, Genetics (clinical)
Abstract

ADGRL1/latrophilin-1, a well-characterized adhesion G protein-coupled receptor, has been implicated in synaptic development, maturation and activity. However, the role of ADGRL1 in human disease has been elusive. Here, we describe 10 individuals with variable neurodevelopmental features including developmental delay, intellectual disability, attention deficit hyperactivity and autism spectrum disorders, and epilepsy, all featuring heterozygous variants in ADGRL1. In vitro, human ADGRL1 variants expressed in neuroblastoma cells showed faulty ligand-induced regulation of intracellular Ca2+ influx, consistent with haploinsufficiency. In vivo, Adgrl1 was knocked out in mice and studied on two genetic backgrounds. On a non-permissive background, mice carrying a heterozygous Adgrl1 null allele exhibited neurological and developmental abnormalities while homozygous mice were non-viable. On a permissive background, the null allele also appeared at sub-Mendelian frequency, but many Adgrl1 null mice survived the gestation and reached adulthood. The Adgrl1-/- mice demonstrated stereotypic behaviors, sexual dysfunction, bimodal extremes of locomotion, augmented startle reflex and attenuated pre-pulse inhibition, which responded to risperidone. Ex vivo synaptic preparations displayed increased spontaneous exocytosis of dopamine, acetylcholine and glutamate, but Adgrl1-/- neurons formed synapses in vitro poorly. Overall, our findings demonstrate that ADGRL1 haploinsufficiency leads to consistent developmental, neurological and behavioral abnormalities in mice and humans.

Published
2022

9. Phenotypic spectrum and genomics of undiagnosed arthrogryposis multiplex congenital

Author

Ivo Gut, Sarah Grotto, Céline Bellesme, Arnold Munnich, Cyril Gitiaux, Jeanne Amiel, Chloé Quélin, Annie Laquerrière, Suonavy Khung, Hanitra Ranjatoelina-Randrianaivo, Luc Rigonnot, Christine Francannet, Loic Quevarec, Jérôme Bouligand, Fabienne Prieur, Alexandra Benachi, Valérie Cormier-Daire, Laurence Perrin, Judith Melki, Pierre-Simon Jouk, Flora Nolent, Tania Attié-Bitach, Delphine Héron, Marie-Line Jacquemont, Claire Beneteau, Fabien Guimiot, Laetitia Lambert, Sandra Mercier, Valérie Biancalana, Fanny Laffargue, Elise Boucher, Jean-Louis Bessereau, P. Landrieu, Annick Toutain, Alain Verloes, Alice Goldenberg, Philippe Latour, Dominique Martin-Coignard, Anne Guiochon-Mantel, Dan Mejlachowicz, Damien Sternberg, Haluk Topaloglu, Bruno Eymard, Géraldine Viot, Catherine Fallet-Bianco, Julien Saada, Isabelle Desguerre, Marie-Hélène Saint-Frison, Catherine Vincent-Delorme, Sophie Blesson, Radka Stoeva, Alexandre J. Vivanti, Martine Bucourt, Pascaline Letard, Jérome Maluenda, Laurence Loeuillet, Lionel Van Maldergem, Didier Lacombe, Marcel Tawk, Michèle Granier, Stanislas Lyonnet, Anne-Lise Delezoide, Andrée Delahaye-Duriez, André Mégarbané, Marie Gonzales, Florence Petit, Juliette Piard, Laurence Faivre, Helene Verhelst, Bettina Bessières, Sabine Sigaudy, Sandra Whalen, Valérie Layet, Yline Capri, Fanny Pelluard, Emanuela Abiusi, Klaus Dieterich, Marie Vincent, Marine Legendre, Dana Jaber, Romulus Grigorescu, Florent Marguet, Eric Bieth, Helge Amthor, Christine Barnerias, Estelle Colin, Laetitia Trestard, Mathilde Nizon, Jelena Martinovic, Daniel Amram, and Nicoletta Resta

Subjects
musculoskeletal diseases, Artrogriposi múltiple congènita, Settore BIO/18 - GENETICA, human genetics, neuromuscular diseases, Genomics, Biology, CONTRACTURES, CLASSIFICATION, diseases, symbols.namesake, Diagnòstic, Gene mapping, arthrogryposis multiplex congenita, Exome Sequencing, OF-FUNCTION MUTATIONS, Genetics, Medicine and Health Sciences, genomics, Humans, Genetics (clinical), Exome sequencing, Arthrogryposis, Sanger sequencing, Arthrogryposis multiplex congenita, Genetic heterogeneity, SPINAL MUSCULAR-ATROPHY, Proteins, nervous system malformations, DYSTROPHY, Disease gene identification, GENE, Human genetics, Pedigree, ETIOLOGY, Phenotype, symbols, neuromuscular, Genètica, Transcription Factors
Abstract

BackgroundArthrogryposis multiplex congenita (AMC) is characterised by congenital joint contractures in two or more body areas. AMC exhibits wide phenotypic and genetic heterogeneity. Our goals were to improve the genetic diagnosis rates of AMC, to evaluate the added value of whole exome sequencing (WES) compared with targeted exome sequencing (TES) and to identify new genes in 315 unrelated undiagnosed AMC families.MethodsSeveral genomic approaches were used including genetic mapping of disease loci in multiplex or consanguineous families, TES then WES. Sanger sequencing was performed to identify or validate variants.ResultsWe achieved disease gene identification in 52.7% of AMC index patients including nine recently identified genes (CNTNAP1, MAGEL2, ADGRG6, ADCY6, GLDN, LGI4, LMOD3, UNC50 and SCN1A). Moreover, we identified pathogenic variants in ASXL3 and STAC3 expanding the phenotypes associated with these genes. The most frequent cause of AMC was a primary involvement of skeletal muscle (40%) followed by brain (22%). The most frequent mode of inheritance is autosomal recessive (66.3% of patients). In sporadic patients born to non-consanguineous parents (n=60), de novo dominant autosomal or X linked variants were observed in 30 of them (50%).ConclusionNew genes recently identified in AMC represent 21% of causing genes in our cohort. A high proportion of de novo variants were observed indicating that this mechanism plays a prominent part in this developmental disease. Our data showed the added value of WES when compared with TES due to the larger clinical spectrum of some disease genes than initially described and the identification of novel genes.

Published
2022

10. Impact of Fetal Growth Restriction on the Neonatal Microglial Proteome in the Rat

Author

Olivier Baud, Valérie Faivre, Marie-Laure Possovre, Virginie Salnot, Marit Knoop, Daniel Vaiman, Marina Colella, Andrée Delahaye-Duriez, Johanna Bruce, Jérôme Mairesse, Manuela Zinni, François Guillonneau, and Julien Pansiot

Subjects
Senescence, proteome, microglia, Inflammation, brain development, Biology, medicine.disease_cause, Article, Rats, Sprague-Dawley, Immune system, Downregulation and upregulation, IUGR, hemic and lymphatic diseases, Diet, Protein-Restricted, medicine, Animals, Cluster Analysis, oxidative stress, TX341-641, chemistry.chemical_classification, Reactive oxygen species, Fetal Growth Retardation, Nutrition and Dietetics, Microglia, Nutrition. Foods and food supply, Body Weight, Cell biology, medicine.anatomical_structure, Animals, Newborn, chemistry, inflammation, Proteome, medicine.symptom, Oxidative stress, Food Science
Abstract

Microglial activation is a key modulator of brain vulnerability in response to intra-uterine growth restriction (IUGR). However, the consequences of IUGR on microglial development and the microglial proteome are still unknown. We used a model of IUGR induced by a gestational low-protein diet (LPD) in rats. Microglia, isolated from control and growth-restricted animals at P1 and P4, showed significant changes in the proteome between the two groups. The expression of protein sets associated with fetal growth, inflammation, and the immune response were significantly enriched in LPD microglia at P1 and P4. Interestingly, upregulation of protein sets associated with the oxidative stress response and reactive oxygen species production was observed at P4 but not P1. During development, inflammation-associated proteins were upregulated between P1 and P4 in both control and LPD microglia. By contrast, proteins associated with DNA repair and senescence pathways were upregulated in only LPD microglia. Similarly, protein sets involved in protein retrograde transport were significantly downregulated in only LPD microglia. Overall, these data demonstrate significant and multiple effects of LPD-induced IUGR on the developmental program of microglial cells, leading to an abnormal proteome within the first postnatal days.

Published
2021
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11. New evidence that biallelic loss of function in EEF1B2 gene leads to intellectual disability

Author

Lise Larcher, Julien Buratti, Brigitte Benzacken, Boris Keren, Bénédicte Héron‐Longe, Eva Pipiras, and Andrée Delahaye-Duriez

Subjects
Male, 0301 basic medicine, Protein subunit, Loss of Heterozygosity, 030105 genetics & heredity, Biology, Pathogenesis, Consanguinity, 03 medical and health sciences, Peptide Elongation Factor 1, Intellectual Disability, Intellectual disability, Genetics, medicine, Guanine Nucleotide Exchange Factors, Humans, Genetic Predisposition to Disease, Child, Gene, Genetics (clinical), Loss function, Siblings, Homozygote, EEF1B2, medicine.disease, Pedigree, 030104 developmental biology, Neurodevelopmental Disorders, Child, Preschool, Mutation, EEF1B2 Gene, Female, Guanine nucleotide exchange factor
Abstract

The guanine exchange factor subunit eEF1Bα encoded by the EEF1B2 gene belongs to the eukaryotic elongation translational machinery. Pathogen variants in genes of the translational machinery have been associated with several neurodevelopmental disorders. However, only one family of three siblings with intellectual disability (ID) has been reported so far with a homozygous variant in EEF1B2. Here, we report a second family with a novel homozygous loss of function (LoF) variant p.(Ser128*), carried by two siblings with moderate ID and seizures. Our findings confirm the role of EEF1B2 variants in the pathogenesis of autosomal-recessive ID, expand the variant spectrum and precisely describe the clinical consequences of the LoF of EEF1B2.

Published
2020
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14. Targeting Microglial Disturbances to Protect the Brain From Neurodevelopmental Disorders Associated With Prematurity

Author

Andrée Delahaye-Duriez, Pierre Gressens, Juliette Van Steenwinckel, Adrien Dufour, and Cindy Bokobza

Subjects
Brain development, Anti-Inflammatory Agents, Inflammation, Neuroprotection, Pathology and Forensic Medicine, Proinflammatory cytokine, Cellular and Molecular Neuroscience, Medicine, Humans, Microglia, business.industry, Infant, Newborn, Brain, Rodent model, General Medicine, Phenotype, medicine.anatomical_structure, nervous system, Neurology, Neurodevelopmental Disorders, Nanoparticles, Neurology (clinical), medicine.symptom, business, Neuroscience, Homeostasis, Infant, Premature
Abstract

Microglial activation during critical phases of brain development can result in short- and long-term consequences for neurological and psychiatric health. Several studies in humans and rodents have shown that microglial activation, leading to a transition from the homeostatic state toward a proinflammatory phenotype, has adverse effects on the developing brain and neurodevelopmental disorders. Targeting proinflammatory microglia may be an effective strategy for protecting the brain and attenuating neurodevelopmental disorders induced by inflammation. In this review we focus on the role of inflammation and the activation of immature microglia (pre-microglia) soon after birth in prematurity-associated neurodevelopmental disorders, and the specific features of pre-microglia during development. We also highlight the relevance of immunomodulatory strategies for regulating activated microglia in a rodent model of perinatal brain injury. An original neuroprotective approach involving a nanoparticle-based therapy and targeting microglia, with the aim of improving myelination and protecting the developing brain, is also addressed.

Published
2021

15. 16p13.11 microduplication in 45 new patients: refined clinical significance and genotype–phenotype correlations

Author

Aziza Lebbar, Sandra Chantot-Bastaraud, Catherine Yardin, Ghislaine Plessis, Patrick Edery, Damien Sanlaville, Laurence Faivre, Aline Receveur, Anne Claude Tabet, Solveig Heide, Laila El Khattabi, Patrick Callier, Christine Francannet, Alice Goldenberg, Eva Pipiras, Michèle Mathieu-Dramard, Chantal Missirian, Odile Boute-Benejean, Cécile Laroche, C. Francois-Fiquet, Pascal Garnier, Alice Masurel-Paulet, Nathalie Marle, Marion Gérard, Jean Michel Dupont, Alexandra Afenjar, Martine Doco Fenzy, Anne Moncla, Marie Pierre Cordier, Brigitte Benzacken, Jean-Hubert Caberg, Gaetan Lesca, Loïc de Pontual, Christine Ioos, Massimiliano Rossi, Nathalie Le Meur, Andrée Delahaye-Duriez, Joris Andrieux, Caroline Vincent-Delorme, Siham Chafai Elalaoui, Lesley Suiro, Philippe Vago, Anne-Laure Mosca-Boidron, Abdelhafid Natiq, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), [Institut Cochin] Département Développement, Reproduction et Cancer (DRC), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de génétique, CHU du Sart-Tilman, Laboratoire de Génétique Médicale, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), 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 Trousseau [APHP], Unité Fonctionnelle de Génétique Clinique [CHU Pitié Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Unité de Génétique Médicale, Hôtel-Dieu-CHU Clermont-Ferrand, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Laboratoire de cytogénétique (CHU de Dijon), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique médicale, CHU Amiens-Picardie, Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Jean Verdier [AP-HP], Handicaps génétiques de l'enfant (Inserm U393), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Raymond-Poincaré Hospital, Département de Génétique Médicale [INH Rabat], Institut National d'Hygiène, Rabat, Morocco, Service d'histologie, embryologie et cytogénétique [Béclère], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], Equipe de Recherche Médicale Appliquée (ERMA), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), BIO-INGENIERIE (XLIM-BIO-INGENIERIE), XLIM (XLIM), Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS)-Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS), Service de Pédiatrie médicale [CHU Limoges], CHU Limoges, Génétique Médicale, CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre Hospitalier Universitaire de Liège (CHU-Liège), Hôpital Jeanne de Flandre [Lille], Centre Hospitalier Universitaire de Reims (CHU Reims), IFR53, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Côte de Nacre [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), AP-HP Hôpital universitaire Robert-Debré [Paris], Hôpital Raymond Poincaré [AP-HP], Hôpital Maison Blanche, Hôpital Robert Debré, Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Centre de recherche en neurosciences de Lyon (CRNL), Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Université de Limoges (UNILIM)-CHU Limoges, and Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, 0301 basic medicine, Pediatrics, Autism Spectrum Disorder, Developmental Disabilities, Disease, 030105 genetics & heredity, Neurodevelopmental disorder, Risk Factors, Gene Duplication, Medicine, Child, Genetics (clinical), miR-484, 3. Good health, Phenotype, Cardiovascular Diseases, Autism spectrum disorder, Child, Preschool, Speech delay, Female, medicine.symptom, Microtubule-Associated Proteins, NDE1, Adult, medicine.medical_specialty, Adolescent, Genetic counseling, MYH11, [SDV.CAN]Life Sciences [q-bio]/Cancer, Context (language use), Young Adult, 03 medical and health sciences, Intellectual Disability, mental disorders, Genetics, Humans, Abnormalities, Multiple, Clinical significance, Genetic Association Studies, business.industry, Infant, medicine.disease, neurodevelopmental disorder, 16p13.11 duplication, MicroRNAs, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, business, Neurocognitive, Chromosomes, Human, Pair 16
Abstract

BackgroundThe clinical significance of 16p13.11 duplications remains controversial while frequently detected in patients with developmental delay (DD), intellectual deficiency (ID) or autism spectrum disorder (ASD). Previously reported patients were not or poorly characterised. The absence of consensual recommendations leads to interpretation discrepancy and makes genetic counselling challenging. This study aims to decipher the genotype–phenotype correlations to improve genetic counselling and patients’ medical care.MethodsWe retrospectively analysed data from 16 013 patients referred to 12 genetic centers for DD, ID or ASD, and who had a chromosomal microarray analysis. The referring geneticists of patients for whom a 16p13.11 duplication was detected were asked to complete a questionnaire for detailed clinical and genetic data for the patients and their parents.ResultsClinical features are mainly speech delay and learning disabilities followed by ASD. A significant risk of cardiovascular disease was noted. About 90% of the patients inherited the duplication from a parent. At least one out of four parents carrying the duplication displayed a similar phenotype to the propositus. Genotype–phenotype correlations show no impact of the size of the duplicated segment on the severity of the phenotype. However, NDE1 and miR-484 seem to have an essential role in the neurocognitive phenotype.ConclusionOur study shows that 16p13.11 microduplications are likely pathogenic when detected in the context of DD/ID/ASD and supports an essential role of NDE1 and miR-484 in the neurocognitive phenotype. Moreover, it suggests the need for cardiac evaluation and follow-up and a large study to evaluate the aortic disease risk.

Published
2018
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16. Decreased microglial Wnt/β-catenin signalling drives microglial pro-inflammatory activation in the developing brain

Author

Amélie Montané, Vincent Degos, Rebecca K. Holloway, Valérie C. Besson, Olivier Baud, David H. Rowitch, Pierre Gressens, A. David Edwards, Rahma Hassan-Abdi, Henrik Hagberg, Bobbi Fleiss, Nadia Soussi-Yanicostas, Sophie Lebon, Enrico Petretto, Gareth Ball, Tifenn Le Charpentier, Fabrice Chrétien, Andrée Delahaye-Duriez, Olivier Hennebert, Zsolt Csaba, Paul Aljabar, Anne-Laure Schang, Alka Saxena, Juliette Van Steenwinckel, Veronique E. Miron, Michelle L. Krishnan, Stéphanie Sigaut, Claire Leconte, Franck Verdonk, Cindy Bokobza, Leslie Schwendimann, Walter Birchmeier, Rowitch, David [0000-0002-0079-0060], Apollo - University of Cambridge Repository, Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), PremUp Foundation, Institut de Recherche pour le Développement (IRD)-CHI Créteil-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Paris (UP), Laboratoire de Chimie et Toxicologie Analytique et Cellulaire (EA 4463), Université Paris Descartes - Paris 5 (UPD5), King‘s College London, Service d'Anesthésie réanimation [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), UFR Santé, Médecine et Biologie Humaine (UFR SMBH), Université Sorbonne Paris Nord, Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Histopathologie humaine et Modèles animaux, Institut Pasteur [Paris], Conservatoire National des Arts et Métiers [CNAM] (CNAM), NIHR Biomedical Research Centre [London], Guy's and St Thomas' NHS Foundation Trust-King‘s College London, Queen's Medical Researche Institute, University of Edinburgh, Max Delbrueck Center for Molecular Medicine, Helmholtz-Gemeinschaft = Helmholtz Association, University of Cambridge [UK] (CAM), Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Pharmacologie de la circulation cérébrale (EA 4475), Duke-NUS Medical School [Singapore], University of Gothenburg (GU), Royal Melbourne Institute of Technology University (RMIT University), This study was supported by grants from Inserm, Université Paris Diderot, Université Sorbonne-Paris-Cité, Investissement d'Avenir (ANR-11-INBS-0011, NeurATRIS), ERA-NET Neuron (Micromet), DHU PROTECT, Association Robert Debré, PremUP, Fondation de France, Fondation pour la Recherche sur le Cerveau, Fondation des Gueules Cassées, Roger de Spoelberch Foundation, Grace de Monaco Foundation, Leducq Foundation, Action Medical Research, Cerebral Palsy Alliance Research Foundation Australia, Wellcome Trust (WSCR P32674) and The Swedish Research Council (2015-02493). We wish to acknowledge the support of the Department of Perinatal Imaging and Health, King’s College London. In addition, the authors acknowledge financial support from the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health., ANR-11-INBS-0011,NeurATRIS,Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences(2011), Soussi-Yanicostas, Nadia, Infrastructures - Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences - - NeurATRIS2011 - ANR-11-INBS-0011 - INBS - VALID, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut de Recherche pour le Développement (IRD)-CHI Créteil-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris-Saclay-Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Jean Verdier [AP-HP], Laboratoire de dynamique des systèmes neuroendocriniens, Service des Soins Intensifs [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Sorbonne Université, Zealand University Hospital, Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Computing [London], Biomedical Image Analysis Group [London] (BioMedIA), Imperial College London-Imperial College London, Physiopathologie, conséquences fonctionnelles et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-IFR2-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Cardiovascular and Metabolic Disorders, Imperial College London, Perinatal Center, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], neuroinflammation, Animals, Genetically Modified, [SCCO]Cognitive science, Mice, 0302 clinical medicine, Neuroinflammation, Zebrafish, [SDV.BDD]Life Sciences [q-bio]/Development Biology, innate immunity, Wnt Signaling Pathway, Cells, Cultured, Innate immunity, biology, Microglia, Inflammation/metabolism, neonatal encephalopathy, Wnt signaling pathway, Brain, Human brain, Neuroprotection, 3. Good health, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Blood-Brain Barrier, [SDV.IMM]Life Sciences [q-bio]/Immunology, neuroprotection, Signal transduction, Wnt Signaling Pathway/physiology, Blood-Brain Barrier/metabolism, [SDV.IMM] Life Sciences [q-bio]/Immunology, 3DNA, Neonatal encephalopathy, Microglia/metabolism, 03 medical and health sciences, [SDV.BDD] Life Sciences [q-bio]/Development Biology, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Brain/metabolism, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Inflammation, Innate immune system, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, Computational Biology, Original Articles, [SCCO] Cognitive science, biology.organism_classification, 030104 developmental biology, Neurology (clinical), Neuroscience, 030217 neurology & neurosurgery
Abstract

International audience; Microglia of the developing brain have unique functional properties but how their activation states are regulated is poorly understood. Inflammatory activation of microglia in the still-developing brain of preterm-born infants is associated with permanent neurological sequelae in 9 million infants every year. Investigating the regulators of microglial activation in the developing brain across models of neuroinflammation-mediated injury (mouse, zebrafish) and primary human and mouse microglia we found using analysis of genes and proteins that a reduction in Wnt/b-catenin signalling is necessary and sufficient to drive a microglial phenotype causing hypomyelination. We validated in a cohort of preterm-born infants that genomic variation in the Wnt pathway is associated with the levels of connectivity found in their brains. Using a Wnt agonist delivered by a blood-brain barrier penetrant microglia-specific targeting nanocarrier we prevented in our animal model the pro-inflammatory microglial activation, white matter injury and behavioural deficits. Collectively, these data validate that the Wnt pathway regulates microglial activation, is critical in the evolution of an important form of human brain injury and is a viable therapeutic target.

Published
2019
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18. Pontocerebellar hypoplasia with rhombencephalosynapsis and microlissencephaly expands the spectrum of PCH type 1B

Author

Annie Laquerrière, Pascale Saugier-Veber, Martine Bucourt, Andrée Delahaye, Florent Marguet, Thierry Frebourg, Pascaline Letard, Myriam Vezain, Bruno J. Gonzalez, Eva Pipiras, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Team 4 'NeoVasc' - INSERM U1245, Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Histologie-embryologie-cytogénétique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris 13 (UP13)-Hôpital Jean Verdier [AP-HP], and Service d'Anatomie et Cytologie Pathologique [CHU Rouen]

Subjects
0301 basic medicine, education.field_of_study, Pathology, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Population, Pontocerebellar hypoplasia, General Medicine, Spinal muscular atrophy, 030105 genetics & heredity, Biology, medicine.disease, Hypoplasia, 03 medical and health sciences, 030104 developmental biology, Atrophy, Agenesis, Genetics, medicine, Cerebellar atrophy, Global developmental delay, 10. No inequality, education, Genetics (clinical), ComputingMilieux_MISCELLANEOUS
Abstract

Rhombencephalosynapsis is a rare cerebellar malformation developing during embryogenesis defined by vermian agenesis or hypogenesis with fusion of the cerebellar hemispheres. It occurs either alone or in association with other cerebral and/or extracerebral anomalies. Its association with microlissencephaly is exceedingly rare and to date, only a heterozygous de novo missense variant in ADGRL2, a gene encoding Adhesion G-Protein-Coupled Receptor L2, has been identified. We report on two siblings of Roma origin presenting with severe growth retardation, fetal akinesia, microlissencephaly and small cerebellum with vermian agenesis. Neuropathological studies revealed extreme paucity in pontine transverse fibres, rudimentary olivary nuclei and rhombencephalosynapsis with vanishing spinal motoneurons in both fetuses. Comparative fetus-parent exome sequencing revealed in both fetuses a homozygous variant in exon 1 of the EXOSC3 gene encoding a core component of the RNA exosome, c.92G > C; p.(Gly31Ala). EXOSC3 accounts for 40%–75% of patients affected by ponto-cerebellar hypoplasia with spinal muscular atrophy (PCH1B). The c.92G > C variant is a founder mutation in the Roma population and has been reported in severe PCH1B. PCH1B is characterized by a broad phenotypic spectrum, ranging from mild phenotypes with spasticity, mild to moderate intellectual disability, pronounced distal muscular and cerebellar atrophy/hypoplasia, to severe phenotypes with profound global developmental delay, progressive microcephaly and atrophy of the cerebellar hemispheres. In PCH1B, the usual cerebellar lesions affect mainly the hemispheres with relative sparing of vermis that radically differs from rhombencephalosynapsis. This unusual foetal presentation expands the spectrum of PCH1B and highlights the diversity of rhombencephalosynapsis etiologies.

Published
2019
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19. Integrated systems-genetic analyses reveal a network target for delaying glioma progression

Author

Andrée Delahaye-Duriez, Julianna Stylianou, Kirill Shkura, Federico Roncaroli, Sarah R. Langley, Nelofer Syed, Albert J. Becker, Prashant K. Srivastava, Liisi Laaniste, Enrico Petretto, Qingyu Zeng, Marvin Johnson, Kevin O’Neill, Matthew Williams, Owen J. L. Rackham, Silvia Cases-Cunillera, and UCB Biopharma SPRL

Subjects
0301 basic medicine, NF-KAPPA-B, Gene regulatory network, Gene mutation, CHEMOPREVENTIVE AGENT RESVERATROL, 0302 clinical medicine, Medicine, Gene Regulatory Networks, TRANSCRIPTION FACTOR, Research Articles, LEVEL ANALYSIS, Brain Neoplasms, General Neuroscience, Astrocytoma, Glioma, GRADE GLIOMA, CANCER, Gene Expression Regulation, Neoplastic, Disease Progression, Functional genomics, Life Sciences & Biomedicine, Research Article, RC321-571, EXPRESSION, Clinical Neurology, Neurosciences. Biological psychiatry. Neuropsychiatry, 03 medical and health sciences, Cell Line, Tumor, Humans, CELL-CYCLE, RC346-429, neoplasms, Cell Proliferation, Science & Technology, COMPLEX, business.industry, Gene Expression Profiling, Neurosciences, FOXM1, medicine.disease, nervous system diseases, Gene expression profiling, 030104 developmental biology, Mutation, Cancer research, Neurology (clinical), Neurosciences & Neurology, Neurology. Diseases of the nervous system, business, 030217 neurology & neurosurgery, Anaplastic astrocytoma
Abstract

OBJECTIVE: To identify a convergent, multitarget proliferation characteristic for astrocytoma transformation that could be targeted for therapy discovery.METHODS: Using an integrated functional genomics approach, we prioritized networks associated with astrocytoma progression using the following criteria: differential co-expression between grade II and grade III IDH1-mutated and 1p/19q euploid astrocytomas, preferential enrichment for genetic risk to cancer, association with patient survival and sample-level genomic features. Drugs targeting the identified multitarget network characteristic for astrocytoma transformation were computationally predicted using drug transcriptional perturbation data and validated using primary human astrocytoma cells.RESULTS: A single network, M2, consisting of 177 genes, was associated with glioma progression on the basis of the above criteria. Functionally, M2 encoded physically interacting proteins regulating cell cycle processes and analysis of genome-wide gene-regulatory interactions using mutual information and DNA-protein interactions revealed the known regulators of cell cycle processes FoxM1, B-Myb, and E2F2 as key regulators of M2. These results suggest functional disruption of M2 via gene mutation or altered expression as a convergent pathway regulating astrocytoma transformation. By considering M2 as a multitarget drug target regulating astrocytoma transformation, we identified several drugs that are predicted to restore M2 expression in anaplastic astrocytoma toward its low-grade profile and of these, we validated the known antiproliferative drug resveratrol as down-regulating multiple nodes of M2 including at nanomolar concentrations achievable in human cerebrospinal fluid by oral dosing.INTERPRETATION: Our results identify M2 as a multitarget network characteristic for astrocytoma progression and encourage M2-based drug screening to identify new compounds for preventing glioma transformation.

Published
2019
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20. Cell Metabolic Alterations due to Mcph1 Mutation in Microcephaly

Author

Nathalie, Journiac, Javier, Gilabert-Juan, Sara, Cipriani, Paule, Benit, Xiaoqian, Liu, Sandrine, Jacquier, Valérie, Faivre, Andrée, Delahaye-Duriez, Zsolt, Csaba, Tristan, Hourcade, Eliza, Melinte, Sophie, Lebon, Céline, Violle-Poirsier, Jean-François, Oury, Homa, Adle-Biassette, Zhao-Qi, Wang, Shyamala, Mani, Pierre, Rustin, Pierre, Gressens, and Jeannette, Nardelli

Subjects
Male, Neurons, Cell Survival, Neurogenesis, Voltage-Dependent Anion Channel 1, Cell Cycle Proteins, Cell Differentiation, Nerve Tissue Proteins, Mitochondria, Mice, Inbred C57BL, Mitochondrial Proteins, Cytoskeletal Proteins, Mice, HEK293 Cells, Mutation, Microcephaly, Animals, Humans, Female, HSP70 Heat-Shock Proteins, Neuroglia, Cell Proliferation
Abstract

A distinctive feature of neocortical development is the highly coordinated production of different progenitor cell subtypes, which are critical for ensuring adequate neurogenic outcome and the development of normal neocortical size. To further understand the mechanisms that underlie neocortical growth, we focused our studies on the microcephaly gene Mcph1, and we report here that Mcph1 (1) exerts its functions in rapidly dividing apical radial glial cells (aRGCs) during mouse neocortical development stages that precede indirect neurogenesis; (2) is expressed at mitochondria; and (3) controls the proper proliferation and survival of RGCs, potentially through crosstalk with cellular metabolic pathways involving the stimulation of mitochondrial activity via VDAC1/GRP75 and AKT/HK2/VDAC1 and glutaminolysis via ATF4/PCK2. We currently report the description of a MCPH-gene implication in the interplay between bioenergetic pathways and neocortical growth, thus pointing to alterations of cellular metabolic pathways, in particular glutaminolysis, as a possible cause of microcephalic pathogenesis.

Published
2019

21. Identification de cibles thérapeutiques et repositionnement de médicaments par analyses de réseaux géniques

Author

Andrée Delahaye-Duriez, Clémence Réda, Pierre Gressens, Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Paris, NeuroDiderot, Inserm U1141, F-75019 Paris, France 48 boulevard Sérurier, 75019 Paris, Centre for the Developing Brain [London], and King‘s College London-St Thomas' Hospital [London]

Subjects
Regulation of gene expression, 0303 health sciences, Drug discovery, [SDV]Life Sciences [q-bio], Gene regulatory network, General Medicine, Computational biology, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract

International audience; No abstract available

Published
2019
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22. NR4A2 haploinsufficiency is associated with intellectual disability and autism spectrum disorder

Author

Jean Xavier, Cyril Mignot, Anne-Claude Tabet, C. Dupont, Andrée Delahaye-Duriez, Eva Pipiras, Boris Keren, A. Maruani, Brigitte Benzacken, M. Heulin, E. Charles, J. Lévy, S. Grotto, Alain Verloes, Damien Haye, Service de dermatologie (CHRU de Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Institute for System and Robotics [Lisbonne] (ISR), University of Lisbon, Unité fonctionnelle de génétique clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Pathogènes Hydriques Santé Environnement (PHySE ), Hydrosciences Montpellier (HSM), Institut de Recherche pour le Développement (IRD)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut de Recherche pour le Développement (IRD)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Universidade de Lisboa (ULISBOA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Institut national des sciences de l'Univers (INSU - CNRS)-Institut de Recherche pour le Développement (IRD)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Institut de Recherche pour le Développement (IRD)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Universidade de Lisboa = University of Lisbon (ULISBOA)

Subjects
Male, 0301 basic medicine, Adolescent, Autism Spectrum Disorder, Cellular homeostasis, Glycerolphosphate Dehydrogenase, Haploinsufficiency, medicine.disease_cause, 03 medical and health sciences, Exon, [SCCO]Cognitive science, Neurodevelopmental disorder, Intellectual Disability, Nuclear Receptor Subfamily 4, Group A, Member 2, Intellectual disability, Genetics, Humans, Medicine, Genetic Predisposition to Disease, Child, 10. No inequality, Genetic Association Studies, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, business.industry, Exons, medicine.disease, 030104 developmental biology, Autism spectrum disorder, Autism, Female, business, Carcinogenesis
Abstract

NR4A2, a member of the nuclear receptor superfamily, is involved in modulation of target gene transcription, regulating several developmental processes such as regulation of cellular homeostasis, neuronal development, inflammation and carcinogenesis. 2q24.1 deletions are extremely rare, and only 1 patient with a de novo deletion encompassing only NR4A2 gene was reported so far. We report 3 additional patients with a de novo deletion encompassing NR4A2: 2 patients have deletions encompassing only NR4A2 gene and 1 patient has a deletion including NR4A2 and the first exon of GPD2. Our patients presented a neurodevelopmental disorder including language impairment, developmental delay, intellectual disability and/or autism spectrum disorder. We suggest that NR4A2 haploinsufficiency is implicated in neurodevelopmental disorder with high penetrance.

Published
2018
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23. Loss of the Wnt/β-catenin pathway in microglia of the developing brain drives pro-inflammatory activation leading to white matter injury

Author

Stéphanie Sigaut, Valérie C. Besson, Franck Verdonk, Alka Saxena, A. Montane, Alexander D. Edwards, Claire Leconte, Bobbi Fleiss, David H. Rowitch, C. Bokobza, Henrik Hagberg, Rebecca K. Holloway, Vincent Degos, Enrico Petretto, Veronique E. Miron, Leslie Schwendimann, Gareth Ball, Andrée Delahaye-Duriez, Anne-Laure Schang, J. Van Steenwinckel, Michelle L. Krishnan, Pierre Gressens, Rahma Hassan-Abdi, Nadia Soussi-Yanicostas, Walter Birchmeier, Fabrice Chrétien, T. Le Charpentier, Sophie Lebon, Paul Aljabar, and O. Hennebert

Subjects
Cancer Research, 0303 health sciences, Microglia, biology, Encephalopathy, Wnt signaling pathway, Human brain, medicine.disease, biology.organism_classification, Oligodendrocyte, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Catenin, medicine, Zebrafish, Neuroscience, 030217 neurology & neurosurgery, Neuroinflammation, 030304 developmental biology
Abstract

Microglia-mediated neuroinflammation is key in numerous brain diseases including encephalopathy of the preterm born infant. Microglia of the still-developing brain have unique properties but little is known of how they regulate their inflammatory activation. This is important information as every year 9 million preterm born infants acquire persisting neurological injuries associated with encephalopathy and we lack strategies to prevent and treat these injuries. Our study of activation state regulators in immature brain microglia found a robust down-regulation of Wnt/β-catenin pathway receptors, ligands and intracellular signalling members in pro-inflammatory microglia. We undertook our studies initially in a mouse model of microglia-mediated encephalopathy including the clinical hallmarks of oligodendrocyte injury and hypomyelination. We purified microglia from this model and applied a genome-wide transcriptomics analysis validated with quantitative profiling. We then verified that down-regulation of the Wnt/β-catenin signalling cascade is sufficient and necessary to drive microglia into an oligodendrocyte-damaging phenotype using multiple pharmacological and genetic approaches in vitro and in vivo in mice and in humans and zebrafish. We also demonstrated that genomic variance in the WNT/β-catenin pathway is associated with the anatomical connectivity phenotype of the human preterm born infant. This integrated analysis of genomics and connectivity, as a surrogate for oligodendrocyte function/myelination, is agnostic to cell type. However, this data indicates that the WNT pathway is relevant to human brain injury and specifically that WNT variants may be useful clinically for injury stratification and prognosis. Finally, we performed a translational experiment using a BBB penetrant microglia-specific targeting 3DNA nanocarrier to deliver a Wnt agonist specifically and directly to microglia in vivo. Increasing the activity of the Wnt/β-catenin pathway specifically in microglia in our model of microglia-mediated encephalopathy was able to reduce microglial pro-inflammatory activation, prevent the typical hypomyelination and also prevent the long-term memory deficit associated with this hypomyelination. In summary, the canonical Wnt/β-catenin pathway regulates microglial activation and up-regulation of this pathway could be a viable neurotherapeutic strategy.

Published
2018
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24. A systems-level framework for drug discovery identifies Csf1R as an anti-epileptic drug target

Author

Kirill Shkura, Seon-Ah Chong, Gaëlle Gillet, Pierre Gressens, James Keaney, Jacques Behmoaras, Andrée Delahaye-Duriez, Catherine Vandenplas, Isabelle Niespodziany, Bénédicte Danis, Patrik Foerch, Marvin Johnson, Liisi Laaniste, Karine Leclercq, Manuela Mazzuferi, Prashant K. Srivastava, Frederic Vanclef, Juliette Van Steenwinckel, Julien Gasser, Enrico Petretto, Irena Kadiu, Patrice Godard, Alvaro Cardenas, Jonathan van Eyll, Georges Mairet-Coello, Rafal M. Kaminski, Commission of the European Communities, UCB Biopharma SPRL, Imperial College Healthcare NHS Trust- BRC Funding, and Medical Research Council (MRC)

Subjects
0301 basic medicine, Computer science, General Physics and Astronomy, Disease, Epileptogenesis, DISEASE, Epilepsy, Mice, 0302 clinical medicine, DRIVERS, Drug Discovery, TEMPORAL-LOBE EPILEPSY, NETWORK, EEG, Molecular Targeted Therapy, lcsh:Science, PILOCARPINE MODEL, health care economics and organizations, GENE-EXPRESSION, Regulation of gene expression, Multidisciplinary, Drug discovery, Systems Biology, Pilocarpine, High-Throughput Nucleotide Sequencing, Current Literature in Basic Science, 3. Good health, Multidisciplinary Sciences, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor, Science & Technology - Other Topics, Anticonvulsants, Causal reasoning, Systems biology, Science, education, Computational biology, Muscarinic Agonists, behavioral disciplines and activities, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, medicine, Animals, Humans, Computer Simulation, CELL, Genetic Association Studies, Science & Technology, Sequence Analysis, RNA, Gene Expression Profiling, General Chemistry, medicine.disease, Gene expression profiling, Disease Models, Animal, 030104 developmental biology, OPINION, Epilepsy, Temporal Lobe, Gene Expression Regulation, SEIZURES, lcsh:Q, 030217 neurology & neurosurgery
Abstract

Srivastava PK, van Eyll J, Godard P, Mazzuferi M, Delahaye-Duriez A, Steenwinckel JV, et al. A systems-level framework for drug discovery identifies Csf1R as an anti-epileptic drug target. Nat Commun. 2018;9(1):3561. doi:10.1038/s41467-018-06008-4.The identification of drug targets is highly challenging, particularly for diseases of the brain. To address this problem, we developed and experimentally validated a general computational framework for drug target discovery that combines gene regulatory information with causal reasoning (“Causal Reasoning Analytical Framework for Target discovery”-CRAFT). Using a systems genetics approach and starting from gene expression data from the target tissue, CRAFT provides a predictive framework for identifying cell membrane receptors with a direction-specified influence over disease-related gene expression profiles. As proof of concept, we applied CRAFT to epilepsy and predicted the tyrosine kinase receptor Csf1R as a potential therapeutic target. The predicted effect of Csf1R blockade in attenuating epilepsy seizures was validated in 3 preclinical models of epilepsy. These results highlight CRAFT as a systems-level framework for target discovery and suggest Csf1R blockade as a novel therapeutic strategy in epilepsy. The CRAFT is applicable to disease settings other than epilepsy.

Published
2018
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25. A series of 38 novel germline and somatic mutations ofNIPBLin Cornelia de Lange syndrome

Author

Hervé Testard, Martine Doco-Fenzy, Alice Goldenberg, Fabienne Prieur, Caroline Michot, Marcia Henry, Sandrine Marlin, Sophie Blesson, Clarisse Baumann, Valérie Cormier-Daire, Philippe Loget, Sylvie Odent, Marlène Rio, Anne-Lise Delezoide, Andrée Delahaye-Duriez, Jean-Paul Bonnefont, Anne Dieux-Coeslier, Audrey Putoux, Marie-Pierre Cordier-Alex, Ghislaine Plessis, Valérie Layet, Albert David, Mathilde Nizon, Bettina Bessières, Jelena Martinovic, Laurent Pasquier, Anne Bazin, and Laurence Faivre

Subjects
0301 basic medicine, Genetics, Sanger sequencing, Mutation, Microcephaly, Cornelia de Lange Syndrome, Genetic counseling, Buccal swab, NIPBL, Biology, medicine.disease_cause, medicine.disease, Germline, 3. Good health, 03 medical and health sciences, symbols.namesake, 030104 developmental biology, medicine, symbols, Genetics (clinical)
Abstract

Cornelia de Lange syndrome is a multisystemic developmental disorder mainly related to de novo heterozygous NIPBL mutation. Recently, NIPBL somatic mosaicism has been highlighted through buccal cell DNA study in some patients with a negative molecular analysis on leukocyte DNA. Here, we present a series of 38 patients with a Cornelia de Lange syndrome related to an heterozygous NIPBL mutation identified by Sanger sequencing. The diagnosis was based on the following criteria: 1) intrauterine growth retardation and postnatal short stature, 2) feeding difficulties and/or gastro-oesophageal reflux, 3) microcephaly, 4) intellectual disability and 5) characteristic facial features. We identified 37 novel NIPBL mutations including 34 in leukocytes and three in buccal cells only. All mutations shown to have arisen de novo when parent blood samples were available. The present series confirms the difficulty in predicting the phenotype according to the NIPBL mutation. Until now, somatic mosaicism has been observed for twenty cases which does not seem to be consistently associated with a milder phenotype. Besides, several reports support a postzygotic event for those cases. Considering these elements, we recommend a first-line buccal cell DNA analysis in order to improve gene testing sensitivity in Cornelia de Lange syndrome and genetic counseling

Published
2016
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26. A Systems-Level Framework for Drug Discovery Identifies Csf1R As A Novel Anti-Epileptic Drug Target

Author

Bénédicte Danis, Catherine Vandenplas, Manuela Mazzuferi, Andrée Delahaye-Duriez, Liisi Laaniste, Prashant K. Srivastava, Patrik Foerch, Enrico Petretto, Marvin Johnson, Patrice Godard, Rafal M. Kaminski, Karine Leclercq, Kirill Shkura, Frederic Vanclef, Jonathan van Eyll, and Georges Mairet-Coello

Subjects
Drug, 0303 health sciences, Drug discovery, media_common.quotation_subject, Systems biology, Drug target, Computational biology, Disease, Biology, Bioinformatics, medicine.disease, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, medicine, Causal reasoning, Functional genomics, 030217 neurology & neurosurgery, 030304 developmental biology, media_common
Abstract

The identification of mechanistically novel drug targets is highly challenging, particularly for diseases of the central nervous system. To address this problem we developed and experimentally validated a new computational approach to drug target identification that combines gene-regulatory information with a causal reasoning framework (“causal reasoning analytical framework for target discovery” – CRAFT). Starting from gene expression data, CRAFT provides a predictive functional genomics framework for identifying membrane receptors with a direction-specified influence over network expression. As proof-of-concept we applied CRAFT to epilepsy, and predicted the tyrosine kinase receptor Csf1R as a novel therapeutic target for epilepsy. The predicted therapeutic effect of Csf1R blockade was validated in two pre-clinical models of epilepsy using a small molecule inhibitor of Csf1R. These results suggest Csf1R blockade as a novel therapeutic strategy in epilepsy, and highlight CRAFT as a systems-level framework for predicting mechanistically new drugs and targets. CRAFT is applicable to disease settings other than epilepsy.

Published
2017
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27. WWOX-related encephalopathies: delineation of the phenotypical spectrum and emerging genotype-phenotype correlation

Author

Nicolas Lebrun, Thierry Bienvenu, Stéphane Auvin, Aissa Moustaïne, Lila Allou, Jean-Louis Guéant, Laurent Pasquier, Philippe Jonveaux, Andrée Delahaye-Duriez, Eva Pipiras, Anne-Isabelle Vermersch, Bénédicte Héron, Cyril Mignot, Laetitia Lambert, Aline Saunier, Christophe Philippe, Marie-Laure Moutard, Marie-Christine Nougues, Jeremie Lefranc, Virginie Roth, Catherine Barrey, Boris Keren, Mylène Valduga, Laurence Olivier-Faivre, Sandra Chantot-Bastaraud, Delphine Héron, Service de génétique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Unité de Génétique Clinique [CHRU Nancy], Service de Médecine Néonatale [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ) -Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), CHU Pontchaillou [Rennes], CLAD Ouest, Centre Hospitalier Universitaire [Rennes], Laboratoire de Biochimie et Génétique Moléculaire, CHU Cochin [AP-HP], Hôpital Jean Verdier, CHRU de Brest - Département de Pédiatrie ( CHU BREST Pédiatrie ), Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Service de Génétique Médicale [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Nutrition-Génétique et Exposition aux Risques Environnementaux ( NGERE ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lorraine ( UL ), Service de neuropédiatrie [Debré], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré, Hôpital Saint Camille, Service de Génétique et d'Embryologie Médicales [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Service de Neuropédiatrie [CHU Trousseau], Service de neurophysiologie [CHU Trousseau], Génétique des Anomalies du Développement ( GAD ), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne ( UB ), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHRU de Brest - Département de Pédiatrie (CHU BREST Pédiatrie), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Service de génétique et embryologie médicales [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Génétique des Anomalies du Développement (GAD), and IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB)

Subjects
WWOX, Microcephaly, [SDV]Life Sciences [q-bio], Nonsense mutation, Mutation, Missense, Biology, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Humans, Spinocerebellar Ataxias, Missense mutation, Allele, Genetics (clinical), infantile, 030304 developmental biology, Comparative Genomic Hybridization, 0303 health sciences, [ SDV ] Life Sciences [q-bio], Tumor Suppressor Proteins, Chromosomal fragile site, High-Throughput Nucleotide Sequencing, genotype/phenotype correlations, medicine.disease, Null allele, 3. Good health, Phenotype, WW Domain-Containing Oxidoreductase, Codon, Nonsense, intellectual disability, Spinocerebellar ataxia, Oxidoreductases, Spasms, Infantile, high throughput data mining, 030217 neurology & neurosurgery
Abstract

International audience; BACKGROUND:Homozygous mutations in WWOX were reported in eight individuals of two families with autosomal recessive spinocerebellar ataxia type 12 and in two siblings with infantile epileptic encephalopathy (IEE), including one who deceased prior to DNA sampling.METHODS:By combining array comparative genomic hybridisation, targeted Sanger sequencing and next generation sequencing, we identified five further patients from four families with IEE due to biallelic alterations of WWOX.RESULTS:We identified eight deleterious WWOX alleles consisting in four deletions, a four base-pair frameshifting deletion, one missense and two nonsense mutations. Genotype-phenotype correlation emerges from the seven reported families. The phenotype in four patients carrying two predicted null alleles was characterised by (1) little if any psychomotor acquisitions, poor spontaneous motility and absent eye contact from birth, (2) pharmacoresistant epilepsy starting in the 1st weeks of life, (3) possible retinal degeneration, acquired microcephaly and premature death. This contrasted with the less severe autosomal recessive spinocerebellar ataxia type 12 phenotype due to hypomorphic alleles. In line with this correlation, the phenotype in two siblings carrying a null allele and a missense mutation was intermediate.CONCLUSIONS:Our results obtained by a combination of different molecular techniques undoubtedly incriminate WWOX as a gene for recessive IEE and illustrate the usefulness of high throughput data mining for the identification of genes for rare autosomal recessive disorders. The structure of the WWOX locus encompassing the FRA16D fragile site might explain why constitutive deletions are recurrently reported in genetic databases, suggesting that WWOX-related encephalopathies, although likely rare, may not be exceptional.

Published
2014
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28. Molecular findings and clinical data in a cohort of 150 patients with anophthalmia/microphthalmia

Author

Marie-Line Jacquemont, Christel Thauvin-Robinet, Didier Lacombe, Josseline Kaplan, Odile Boute-Benejean, Bertrand Isidor, Dominique Martin-Coignard, Fabienne Giuliano, Chloé Quélin, J.-L. Alessandri, Lucile Pinson, Sabine Sigaudy, H. Dollfus, Adeline Vigouroux, Michèle Mathieu-Dramard, Odile Boespflug-Tanguy, Brigitte Gilbert-Dussardier, Alexandre Causse, Marie Gonzales, Sylvie Odent, Andrée Delahaye, Nicolas Chassaing, Muriel Holder-Espinasse, P Calvas, Bénédicte Duban-Bedu, Annick Toutain, and Olivier Picone

Subjects
Genetics, Anophthalmia, Genetic heterogeneity, Genetic counseling, Biology, medicine.disease, Microphthalmia, eye diseases, 3. Good health, Testis determining factor, Multiplex polymerase chain reaction, medicine, Homeobox, sense organs, Gene, Genetics (clinical)
Abstract

Anophthalmia and microphthalmia (AM) are the most severe malformations of the eye, corresponding respectively to reduced size or absent ocular globe. Wide genetic heterogeneity has been reported and different genes have been demonstrated to be causative of syndromic and non-syndromic forms of AM. We screened seven AM genes [GDF6 (growth differentiation factor 6), FOXE3 (forkhead box E3), OTX2 (orthodenticle protein homolog 2), PAX6 (paired box 6), RAX (retina and anterior neural fold homeobox), SOX2 (SRY sex determining region Y-box 2), and VSX2 (visual system homeobox 2 gene)] in a cohort of 150 patients with isolated or syndromic AM. The causative genetic defect was identified in 21% of the patients (32/150). Point mutations were identified by direct sequencing of these genes in 25 patients (13 in SOX2, 4 in RAX, 3 in OTX2, 2 in FOXE3, 1 in VSX2, 1 in PAX6, and 1 in GDF6). In addition eight gene deletions (five SOX2, two OTX2 and one RAX) were identified using a semi-quantitative multiplex polymerase chain reaction (PCR) [quantitative multiplex PCR amplification of short fluorescent fragments (QMPSF)]. The causative genetic defect was identified in 21% of the patients. This result contributes to our knowledge of the molecular basis of AM, and will facilitate accurate genetic counselling.

Published
2013
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29. Clinical and Molecular Findings in 39 Patients with KBG Syndrome Caused by Deletion or Mutation of ANKRD11

Author

Aurélia Jacquette, Alice Goldenberg, Thierry Frebourg, Julien Thevenon, David Geneviève, Anne-Marie Guerrot, Andrée Delahaye-Duriez, Yline Capri, Bruno Leheup, François Lecoquierre, Florence Riccardi, Tiffany Busa, Laurent Villard, Pierre Cacciagli, Vincent Gatinois, Julien Mancini, Chantal Missirian, Lionel Van Maldergem, Massimiliano Rossi, Laurence Perrin, Catherine Vincent-Delorme, Pascale Saugier-Veber, Philippe Khau Van Kien, Gwenaël Nadeau, Annick Toutain, Alain Verloes, Sandrine Marlin, Rolph Pfundt, Elise Schaefer, Arthur Sorlin, Vincent Michaud, Christel Thauvin-Robinet, Philippe Parent, Cyril Mignot, Charles Coutton, Nicole Philip, Véronique Satre, Aude Tessier, Service de génétique [Rouen], CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Génétique Médicale et Génomique Fonctionnelle ( GMGF ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Department of Human Genetics, Département de génétique, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), Institut d'oncologie/développement Albert Bonniot de Grenoble ( INSERM U823 ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpital Jean Verdier, Génétique du cancer et des maladies neuropsychiatriques ( GMFC ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), CHU Rouen, Cellules souches mésenchymateuses, environnement articulaire et immunothérapies de la polyarthrite rhumatoide, Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Centre Hospitalier Régional Universitaire de Nîmes ( CHRU Nîmes ), Service de Génétique Médicale [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), CHU Trousseau [APHP], Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), École Supérieure des Géomètres et Topographes ( ESGT CNAM ), Conservatoire National des Arts et Métiers [CNAM] ( CNAM ), Laboratoire de Géodésie et de Géomatique ( L2G ESGT CNAM ), Conservatoire National des Arts et Métiers [CNAM] ( CNAM ) -Conservatoire National des Arts et Métiers [CNAM] ( CNAM ) -Conservatoire National des Arts et Métiers [CNAM] ( CNAM ), Service de Cytogénétique, Centre hospitalier de Valence, Centre de Référence des Déficiences Intellectuelles de Causes Rares, Centre Interdisciplinaire de Nanoscience de Marseille ( CINaM ), Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de recherche en neurosciences de Lyon ( CRNL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service de génétique [Tours], Hôpital Bretonneau-CHRU Tours, Service de Génétique, Hôpital de Hautepierre [Strasbourg], 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 ), Laboratoire Chrono-environnement ( LCE ), Université Bourgogne Franche-Comté ( UBFC ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Franche-Comté ( UFC ), AGeing and IMagery ( AGIM ), Université Pierre Mendès France - Grenoble 2 ( UPMF ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -École pratique des hautes études ( EPHE ) -Centre National de la Recherche Scientifique ( CNRS ), Service de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP), Centre de Maladies Rares, Anomalies du Développement Nord de France-CH Arras - CHRU Lille, Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale ( SESSTIM ), Institut de Recherche pour le Développement ( IRD ) -Aix Marseille Université ( AMU ) -ORS PACA-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Paoli Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Biostatistique et technologies de l'information et de la communication (BioSTIC) - [Hôpital de la Timone - APHM] ( BiosTIC ), Assistance Publique - Hôpitaux de Marseille ( APHM ) -Aix Marseille Université ( AMU ) -Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale ( SESSTIM ), Institut de Recherche pour le Développement ( IRD ) -Aix Marseille Université ( AMU ) -ORS PACA-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut de Recherche pour le Développement ( IRD ) -Aix Marseille Université ( AMU ) -ORS PACA-Institut National de la Santé et de la Recherche Médicale ( INSERM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Radboud University Medical Center [Nijmegen], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU de Bordeaux Pellegrin [Bordeaux], Centre Interdisciplinaire de Nanoscience de Marseille (CINaM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), AGeing and IMagery (AGIM), Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Joseph Fourier - Grenoble 1 (UJF)-Université Pierre Mendès France - Grenoble 2 (UPMF), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U912 INSERM - Aix Marseille Univ - IRD), Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Institut Paoli-Calmettes, Biostatistique et technologies de l'information et de la communication (BioSTIC) - [Hôpital de la Timone - APHM] (BiosTIC ), Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Gall, Valérie, Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE), Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), and Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)

Subjects
Male, 0301 basic medicine, 030105 genetics & heredity, medicine.disease_cause, Bioinformatics, Intellectual disability, Child, Genetics (clinical), Genetics, Comparative Genomic Hybridization, Mutation, Middle Aged, KBG syndrome, Phenotype, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Child, Preschool, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, Chromosome Deletion, medicine.symptom, Haploinsufficiency, Adult, Adolescent, Biology, Malignancy, Short stature, ANKRD11, Young Adult, 03 medical and health sciences, Intellectual Disability, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Humans, Precocious puberty, Abnormalities, Multiple, long-term prognosis, Alleles, Genetic Association Studies, Aged, Retrospective Studies, Bone Diseases, Developmental, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Tooth Abnormalities, 16q24.3 deletion, Point mutation, Facies, Infant, medicine.disease, haploinsufficiency, Repressor Proteins, Amino Acid Substitution, Autism, Chromosomes, Human, Pair 16
Abstract

Item does not contain fulltext KBG syndrome, due to ANKRD11 alteration is characterized by developmental delay, short stature, dysmorphic facial features, and skeletal anomalies. We report a clinical and molecular study of 39 patients affected by KBG syndrome. Among them, 19 were diagnosed after the detection of a 16q24.3 deletion encompassing the ANKRD11 gene by array CGH. In the 20 remaining patients, the clinical suspicion was confirmed by the identification of an ANKRD11 mutation by direct sequencing. We present arguments to modulate the previously reported diagnostic criteria. Macrodontia should no longer be considered a mandatory feature. KBG syndrome is compatible with autonomous life in adulthood. Autism is less frequent than previously reported. We also describe new clinical findings with a potential impact on the follow-up of patients, such as precocious puberty and a case of malignancy. Most deletions remove the 5'end or the entire coding region but never extend toward 16q telomere suggesting that distal 16q deletion could be lethal. Although ANKRD11 appears to be a major gene associated with intellectual disability, KBG syndrome remains under-diagnosed. NGS-based approaches for sequencing will improve the detection of point mutations in this gene. Broad knowledge of the clinical phenotype is essential for a correct interpretation of the molecular results. (c) 2016 Wiley Periodicals, Inc.

Published
2016
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30. Haploinsufficiency ofSOX5at 12p12.1 is associated with developmental delays with prominent language delay, behavior problems, and mild dysmorphic features

Author

Michael E. Talkowski, Blake C. Ballif, Roger A. Schultz, Patricia I. Bader, Susan Sell, Zheng Fan, James F. Gusella, Debra J Keelean-Fuller, Suneeta Madan-Khetarpal, Loren Mackay-Loder, Deborah Terespolsky, Urvashi Surti, Jill Pouncey, Santhosh Girirajan, Marilyn C. Jones, Bénédicte Héron‐Longe, Ian Blumenthal, Kenneth N. Rosenbaum, Maria Descartes, Jill A. Rosenfeld, Cynthia C. Morton, Evan E. Eichler, Gwen M. Glew, Alain Verloes, Amy Shealy, Sandrine Passemard, Brigitte Benzacken, Cathy A. Stevens, Eva Pipiras, Nicholas J. Neill, Roger L. Ladda, Rocio Moran, Lisa G. Shaffer, John B. Moeschler, Allen N. Lamb, Judith A. Martin, Stephanie E. Vallee, Kent E. Opheim, Juliann Mcconnell, Bertrand Isidor, Andrée Delahaye, Cédric Le Caignec, and Shawnia Ryan

Subjects
Adult, Male, Adolescent, Developmental Disabilities, Haploinsufficiency, Biology, Article, Exon, Intellectual disability, Genetics, medicine, Humans, Language Development Disorders, Child, Gene, Genetics (clinical), Chromosomes, Human, Pair 12, Mental Disorders, Breakpoint, Body Dysmorphic Disorders, medicine.disease, Phenotype, Case-Control Studies, Child, Preschool, Body dysmorphic disorder, Speech delay, Female, medicine.symptom, SOXD Transcription Factors
Abstract

SOX5 encodes a transcription factor involved in the regulation of chondrogenesis and the development of the nervous system. Despite its important developmental roles, SOX5 disruption has yet to be associated with human disease. We report one individual with a reciprocal translocation breakpoint within SOX5, eight individuals with intragenic SOX5 deletions (four are apparently de novo and one inherited from an affected parent), and seven individuals with larger 12p12 deletions encompassing SOX5. Common features in these subjects include prominent speech delay, intellectual disability, behavior abnormalities, and dysmorphic features. The phenotypic impact of the deletions may depend on the location of the deletion and, consequently, which of the three major SOX5 protein isoforms are affected. One intragenic deletion, involving only untranslated exons, was present in a more mildly affected subject, was inherited from a healthy parent and grandparent, and is similar to a deletion found in a control cohort. Therefore, some intragenic SOX5 deletions may have minimal phenotypic effect. Based on the location of the deletions in the subjects compared to the controls, the de novo nature of most of these deletions, and the phenotypic similarities among cases, SOX5 appears to be a dosage-sensitive, developmentally important gene.

Published
2012
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31. Intégration des données de RNAseq sur cellule unique du cerveau

Author

Andrée Delahaye-Duriez, Enrico Petretto, Marvin Johnson, and Brigitte Benzacken

Subjects
0301 basic medicine, 03 medical and health sciences, 030104 developmental biology, Anatomy
Abstract

Introduction Le cerveau des mammiferes possede un nombre extraordinaire de cellules. On distingue differents types cellulaires dans le systeme nerveux central. Les cellules d’une meme categorie, ou d’un meme type, en plus de se ressembler, ont aussi des profils d’expression similaires. Recemment, l’etude des profils d’expression chez la souris, par sequencage a tres haut debit (« RNAseq ») sur cellule unique (« single-cell RNAseq »), a permis d’etablir une delineation tres fine des differents types cellulaires du cerveau des mammiferes [1] , [2] . Le but de l’etude presentee ici est d’exploiter ces donnees pour analyser un reseau de genes impliques dans les formes rares et communes d’epilepsie, le reseau M30 [3] . Materiels et methodes Les donnees de « single-cell RNAseq » de cerveau murin (n = 3005 [1], n = 1424 [2] ) ont ete re-exploitees. Nous avons utilise le test exact de Fisher (FET) pour tester l’enrichissement du reseau M30 en genes marqueurs de chaque type cellulaire. Les outils crees pour ces analyses sont disponibles dans un package R, appele BrainCell ( https://github.com/adelahay/BrainCell ). Resultats Le reseau M30 est significativement enrichi en genes marqueurs des interneurones (FET p-value = 1,65 × 10−8, OR = 4,37) et des neurones pyramidaux (FET p-value = 7,71 × 10−4, OR = 3,07). Cet enrichissement mixte est coherent avec le profil d’expression des genes orthologues murins du reseau M30 observe a partir des donnees de « single-cell RNAseq » de l’institut Allen Brain [2] . Discussion et conclusion La microanatomie complexe du cerveau revelee par l’etude des ARN sur cellule unique est portee dans des jeux de donnees en acces libre dont l’exploitation ne fait que debuter. L’integration de ces donnees montre ici que le reseau de genes M30, associe aux formes rares et communes d’epilepsie, est fortement exprime a la fois, dans les neurones excitateurs et inhibiteurs.

Published
2017
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32. What can we learn from old microdeletion syndromes using array-CGH screening?

Author

Nathalie Marle, Muriel Holder-Espinasse, C. Ragon, P. Callier, Anne Dieux-Coeslier, Anne-Laure Mosca-Boidron, Philippe Jonveaux, Joris Andrieux, Catherine Vincent-Delorme, Muriel Payet, Brigitte Benzacken, Francine Mugneret, E Questiaux, Ghislaine Plessis, Eva Pipiras, C. Thauvin-Robinet, Alice Masurel-Paulet, Sonia Bouquillon, Andrée Delahaye, C Bonnet, Sylvie Manouvrier-Hanu, M Berri, and Laurence Faivre

Subjects
Adult, Adolescent, Genotype, Chromosomes, Human, Pair 22, Karyotype, Biology, Bioinformatics, Intellectual Disability, Variable phenotype, Intellectual disability, Genetics, medicine, Humans, Abnormalities, Multiple, Genetics (clinical), Comparative Genomic Hybridization, medicine.disease, Phenotype, Child, Preschool, Chromosome Deletion, Chromosomes, Human, Pair 7, Modifier Genes, Comparative genomic hybridization
Abstract

Most microdeletion syndromes identified before the implementation of array-comparative genomic hybridization (array-CGH) were presumed to be well-defined clinical entities. However, the introduction of whole-genome screening led not only to the description of new syndromes but also to the recognition of a broader spectrum of features for well-known syndromes. Here, we report on 10 patients presenting with mental retardation associated with atypical features not suggestive of a known microdeletion and a normal standard karyotype. Array-CGH analyses revealed five microdeletions in the DiGeorge region, three microdeletions in the Williams-Beuren region and two microdeletions in the Smith-Magenis region. Reevaluation in these patients confirmed that the diagnosis remained difficult on clinical grounds and emphasized that well-known genomic disorders can have a phenotype that is heterogeneous and more variable than originally thought. The widespread use of array-CGH shows that such patients may be more readily achieved on the basis of genotype rather than phenotype.

Published
2011
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33. Les approches de génomique intégrative identifient un réseau de gènes pour le développement de médicaments anti-épileptiques

Author

Enrico Petretto, Bénédicte Danis, Sarah R. Langley, Manuela Mazzuferi, Prashant K. Srivastava, Kay L. Richards, Patrik Foerch, Marvin Johnson, Steven Petrou, Kirill Shkura, Elena V. Gazina, Rafal M. Kaminski, and Andrée Delahaye-Duriez

Subjects
0301 basic medicine, 03 medical and health sciences, 030104 developmental biology, Anatomy
Abstract

Introduction/Objectifs L’epilepsie est une maladie neurologique grave qui se caracterise par une recurrence non provoquee de crises convulsives. La biologie des systemes et les analyses de reseaux de genes constituent des approches puissantes pour etudier les voies moleculaires impliquees dans l’epilepsie. Elles ont aussi deja permis de pointer de nouvelles cibles therapeutiques. Materiels/Patients et methodes Des donnees en acces libre issues de plusieurs types d’etudes ont ete re-analysees en utilisant des approches de genomique integrative basees sur l’analyse des reseaux de genes et de proteines. La nouvelle exploitation de ces donnees a permis l’identification du reseau M30. Le reseau M30 se compose de 320 genes largement exprimes dans le cerveau humain qui codent principalement pour des proteines qui sont impliquees dans des processus synaptiques. Resultats L’alteration fonctionnelle de M30 par des variations genetiques rares ou communes, et la diminution de son expression semblent constituer un mecanisme convergent influencant la susceptibilite a l’epilepsie et aux crises d’epilepsie en general. En tirant profit des changements d’expression induits par des medicaments rapportes pour 1300 composes therapeutiques, nous avons pu selectionner les medicaments dont l’effet sur l’expression de M30 est d’inverser la diminution d’expression observee dans les cerveaux epileptiques. Les meilleurs resultats ont ete obtenus pour l’acide valproique (anti-epileptique connu), apportant une nouvelle preuve de concept au paradigme de reversion de la signature transcriptionnelle comme strategie therapeutique. Conclusions Au total, nos resultats suggerent qu’en ciblant le reseau M30 on pourrait identifier de nouvelles molecules anti-epileptiques et developper de nouvelles strategies therapeutiques contre l’epilepsie [1] .

Published
2018
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34. Further delineation of the 17p13.3 microdeletion involving YWHAE but distal to PAFAH1B1: Four additional patients

Author

Séverine Drunat, Patrick Edery, Laurence Perrin, Alain Verloes, Audrey Labalme, Sandrine Passemard, Azzedine Aboura, Manuel Schiff, D Sanlaville, Andrée Delahaye, Sylvie Manouvrier-Hanu, Brigitte Benzacken, Sonia Bouquillon, Joris Andrieux, Catherine Vincent-Delorme, and Monique Elmaleh-Bergès

Subjects
Male, Pathology, medicine.medical_specialty, Lissencephaly, Classical Lissencephalies and Subcortical Band Heterotopias, Haploinsufficiency, Young Adult, PAFAH1B1, Ductus arteriosus, Genetics, medicine, Humans, Abnormalities, Multiple, Child, YWHAE, Genetics (clinical), Coloboma, business.industry, Macrocephaly, General Medicine, medicine.disease, Microcornea, medicine.anatomical_structure, 14-3-3 Proteins, Child, Preschool, 1-Alkyl-2-acetylglycerophosphocholine Esterase, Cancer research, Female, Chromosome Deletion, medicine.symptom, business, Microtubule-Associated Proteins, Chromosomes, Human, Pair 17
Abstract

Background The 17p13.3 deletion syndrome (or Miller-Dieker syndrome, MDS, MIM 247200) is characterized by lissencephaly, mental retardation and facial dysmorphism. The phenotype is attributed to haploinsufficiency of two genes present in the minimal critical region of MDS: PAFAH1B1 (formerly referred to as LIS1) and YWHAE. Whereas isolated PAFAH1B1 deletion causes lissencephaly, YWHAE is a candidate for the dysmorphic phenotype associated with MDS. Objective We describe clinical, neuroradiological and molecular data in four patients with a 17p13.3 deletion distal to PAFAH1B1 involving YWHAE. Results All patients presented with mild or moderate developmental delay and pre and/or post-natal growth retardation. Patients A, B and C had neuro-imaging anomalies: leucoencephalopathy with macrocephaly (patients A and C), Chiari type 1 malformation (patient A) and paraventricular cysts (patient C). Patient B had patent ductus arteriosus and pulmonary arterial hypertension. Patient C had unilateral club foot. Patient D had enlarged Virchow Robin spaces, microcornea, and chorioretinal and lens coloboma. Array-CGH revealed de novo terminal 17p13.3 deletions for patient A and B, and showed interstitial 17p13.3 deletions of 1.4 Mb for patient C and of 0.5 Mb for patient D. In all patients, PAFAH1B1 was not deleted. Conclusion Our patients confirm that 17p deletion distal to PAFAH1B1 have a distinctive phenotype : mild mental retardation, moderate to severe growth restriction, white matter abnormalities and developmental defects including Chiari type 1 malformation and coloboma. Our patients contribute to the delineation and clinical characterization of 17p13.3 deletion distal to PAFAH1B1 and highlight the role of the region containing YWHAE in brain and eye development and in somatic growth.

Published
2010
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35. Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease

Author

Bénédicte Danis, Alessia Visconti, Owen J. L. Rackham, Alexander Grote, Christoph Helmstaedter, Blair H. Smith, Gail Davies, Caroline Hayward, Anaïs Katz, Kirill Shkura, Sandosh Padmanabhan, Rafal M. Kaminski, Aida Moreno-Moral, Andrée Delahaye-Duriez, David J. Porteous, Tiziana Rossetti, Albert J. Becker, W. David Hill, Lynne J. Hocking, Mario Falchi, Leonardo Bottolo, Ian J. Deary, Patrik Foerch, Marvin Johnson, Prashant K. Srivastava, David C. Liewald, John M. Starr, Sarah R. Langley, Manuela Mazzuferi, Maxime Rotival, Enrico Petretto, Doug Speed, Slavé Petrovski, Sarah E. Harris, Imperial College Healthcare NHS Trust- BRC Funding, Medical Research Council (MRC), and UCB PHARMA SA

Subjects
0301 basic medicine, INTELLECTUAL DISABILITY, Developmental Disabilities, Gene regulatory network, Gene Expression, Genome-wide association study, Disease, Biology, Hippocampus, Nervous System, SET ANALYSIS, 03 medical and health sciences, Cognition, Genetic variation, Intellectual disability, medicine, Animals, Humans, EPILEPTIC ENCEPHALOPATHIES, HUMAN INTELLIGENCE, Gene Regulatory Networks, GENOME-WIDE ASSOCIATION, Exome, Gene, Brain Chemistry, Science & Technology, Neurology & Neurosurgery, General Neuroscience, GENERATION SCOTLAND, TEST BATTERIES, Neurosciences, Genetic Variation, 1702 Cognitive Science, medicine.disease, HUMAN BRAIN, SCOTTISH FAMILY HEALTH, 030104 developmental biology, Epilepsy, Temporal Lobe, DE-NOVO MUTATIONS, Synapses, Neurosciences & Neurology, 1109 Neurosciences, Neuroscience, Life Sciences & Biomedicine, Genome-Wide Association Study
Abstract

Genetic determinants of cognition are poorly characterized, and their relationship to genes that confer risk for neurodevelopmental disease is unclear. Here we performed a systems-level analysis of genome-wide gene expression data to infer gene-regulatory networks conserved across species and brain regions. Two of these networks, M1 and M3, showed replicable enrichment for common genetic variants underlying healthy human cognitive abilities, including memory. Using exome sequence data from 6,871 trios, we found that M3 genes were also enriched for mutations ascertained from patients with neurodevelopmental disease generally, and intellectual disability and epileptic encephalopathy in particular. M3 consists of 150 genes whose expression is tightly developmentally regulated, but which are collectively poorly annotated for known functional pathways. These results illustrate how systems-level analyses can reveal previously unappreciated relationships between neurodevelopmental disease–associated genes in the developed human brain, and provide empirical support for a convergent gene-regulatory network influencing cognition and neurodevelopmental disease.

Published
2016
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36. Apport de la CGH-array au diagnostic prénatal d’anomalies génomiques chez des fœtus présentant des signes malformatifs, avec un caryotype apparemment équilibré

Author

L. Lohman, Michèle Uzan, A. Aboura, Brigitte Benzacken, S. Kanafani, Andrée Delahaye, Eva Pipiras, J.-F. Oury, C. Dupont, and A.-C. Tabet

Subjects
Biomedical Engineering, Biophysics
Abstract

Resume Objectif Certains fœtus presentent des signes evocateurs d’anomalie chromosomique (polymalformations, retard de croissance, hyper clarte nucale…), avec un caryotype apparemment equilibre. L’etude des chromosomes selon les techniques de cytogenetique classique ne permet pas la mise en evidence de remaniements desequilibres du genome dont la taille est inferieure a 5 megabases (Mb), telles que les microdeletions des regions telomeriques ou interstitielles. La comparative genomic hybridization array (CGH-array) permet la mise en evidence de remaniements genomiques de petite taille, en analysant un grand nombre de fragments d’ADN du genome. Nous proposons d’utiliser cette methode, pour etablir une correlation phenotype–genotype de plusieurs fœtus presentant un syndrome malformatif sans anomalie cytogenetique. Methode Le principe de la technique est comparable a la CGH classique. Le remplacement des chromosomes par une serie de clones d’ADN specifiques de ces chromosomes offre un avantage significatif concernant la resolution qui est a la hauteur du nombre de clones utilises. La technique de CGH-array est realisee sur puces ADN, (BAC), Genosystem®, selon leurs instructions. Les resultats anormaux ont ete verifies par Fish. Resultats Trois desequilibres chromosomiques ont ete identifies et caracterises precisement (une tetrasomie 12p, une deletion du bras long d’un chromosome 7 dans la region Sonic Hedgehog et une deletion terminale d’un chromosome 7, par cytogenetique moleculaire. Discussion et conclusion Le but de cette etude est d’etendre cette methodologie, chez tous les fœtus ayant des signes d’appel echographiques tres evocateurs d’anomalie chromosomique et dont le caryotype conventionnel est normal ou apparemment equilibre.

Published
2007
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37. Complex nature of apparently balanced chromosomal rearrangements in patients with autism spectrum disorder

Author

Céline Dupont, Richard Delorme, Sandrine Passemard, Laurence Perrin, Gudrun Nygren, Delphine Héron, Marion Leboyer, Azzedine Aboura, Françoise Devillard, Anne-Claude Tabet, Christopher Gillberg, Marion Pilorge, Catalina Betancur, Brigitte Benzacken, Aurélia Jacquette, Jean-Pierre Siffroi, Mary Coleman, Andrée Delahaye, Pierre Bitoun, Elsa Delaby, Alain Verloes, Marion Gérard, Département de génétique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Psychiatrie de l'Enfant et de l'Adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Gillberg Neuropsychiatry Centre [Göteborg, Sueden], Institute of Neuroscience and Physiology [Göteborg]-University of Gothenburg (GU), Pôle Couple-Enfant, Département de Génétique et Procréation, Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Neurologie, Hôpital Robert Debré, Groupe de recherche clinique 'déficience intellectuelle et autisme', Université Pierre et Marie Curie - Paris 6 (UPMC), Unité fonctionnelle de neurogénétique moléculaire et cellulaire, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de génétique et embryologie médicales [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), Unité de Cytogénétiqué, Hôpital Jean-Verdier, Service de Pédiatrie [Jean Verdier], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Foundation for Autism Research, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, AP HP, Reprod Biol Unit CECOS, Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This research was supported by Fondation de France, INSERM, and Institut de France., Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, Gillberg Neuropsychiatry Centre, University of Gothenburg (GU), CHU de Grenoble, Hôpital Couple-Enfant, Département de Génétique et Procréation, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique [Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP]-Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Service de Génétique et d'Embryologie Médicales [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Jean Verdier [Bondy], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Centre Hospitalier Universitaire Jean Verdier, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Betancur, Catalina

Subjects
de novo, CNV, translocation, autism spectrum disorder, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, Bioinformatics, duplication Wolf-Hirschhorn region, Autism Diagnostic Observation Schedule, inversion, Developmental Neuroscience, Dysmorphic feature, balanced chromosomal rearrangement, mental disorders, Gene duplication, Intellectual disability, medicine, copy number variant, Copy-number variation, deletion, Molecular Biology, Genetics, RFX3, SNP microarray, [SDV.GEN]Life Sciences [q-bio]/Genetics, 2q37 deletion syndrome, Research, 7q21.3q22.1 deletion, 18p11.22p11.31 deletion, medicine.disease, Human genetics, 3. Good health, karyotype, Psychiatry and Mental health, duplication, Autism spectrum disorder, Developmental Biology, SNP array
Abstract

Background:\ud Apparently balanced chromosomal rearrangements can be associated with an abnormal phenotype, including intellectual disability and autism spectrum disorder (ASD). Genome-wide microarrays reveal cryptic genomic imbalances, related or not to the breakpoints, in 25% to 50% of patients with an abnormal phenotype carrying a microscopically balanced chromosomal rearrangement. Here we performed microarray analysis of 18 patients with ASD carrying balanced chromosomal abnormalities to identify submicroscopic imbalances implicated in abnormal neurodevelopment.\ud \ud Methods:\ud Eighteen patients with ASD carrying apparently balanced chromosomal abnormalities were screened using single nucleotide polymorphism (SNP) arrays. Nine rearrangements were de novo, seven inherited, and two of unknown inheritance. Genomic imbalances were confirmed by fluorescence in situ hybridization and quantitative PCR.\ud \ud Results:\ud We detected clinically significant de novo copy number variants in four patients (22%), including three with de novo rearrangements and one with an inherited abnormality. The sizes ranged from 3.3 to 4.9 Mb; three were related to the breakpoint regions and one occurred elsewhere. We report a patient with a duplication of the Wolf-Hirschhorn syndrome critical region, contributing to the delineation of this rare genomic disorder. The patient has a chromosome 4p inverted duplication deletion, with a 0.5 Mb deletion of terminal 4p and a 4.2 Mb duplication of 4p16.2p16.3. The other cases included an apparently balanced de novo translocation t(5;18)(q12;p11.2) with a 4.2 Mb deletion at the 18p breakpoint, a subject with de novo pericentric inversion inv(11)(p14q23.2) in whom the array revealed a de novo 4.9 Mb deletion in 7q21.3q22.1, and a patient with a maternal inv(2)(q14.2q37.3) with a de novo 3.3 Mb terminal 2q deletion and a 4.2 Mb duplication at the proximal breakpoint. In addition, we identified a rare de novo deletion of unknown significance on a chromosome unrelated to the initial rearrangement, disrupting a single gene, RFX3.\ud \ud Conclusions: \ud These findings underscore the utility of SNP arrays for investigating apparently balanced chromosomal abnormalities in subjects with ASD or related neurodevelopmental disorders in both clinical and research settings.

Published
2015
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38. Subject Index Vol. 21, 2006

Author

Petronella Hupuczi, Lucia Haakova, P. De la Fuente, Hana Viskova, Triantafyllos Tafas, Andrée Delahaye, Mark I. Evans, Paul Thornton, Joseph P. Bruner, Nikolaos A. Papadopulos, Omer Kandemir, Hélio Antonio Guimarães Filho, J.M. Puente, Sebastião Marques Zanforlin Filho, István Sziller, James Tepperberg, N. Scott Adzick, Jan Kvasnicka, Edgar Biemer, Matthias Foehn, Gábor Viktor Szabó, Brigitte Benzacken, George E. Davis, Mark P. Johnson, William H. Peranteau, Jean-Philippe Wolf, Arupa Ganguly, Serdar Şen, G.A. Rau, Luciano Marcondes Machado Nardozza, Evangelos Paraskevaidis, Julia Henke, Serdar Kasakyan, B. Hollwitz, R. Hass, Cyril Eboué, Zsanett Szigeti, J. Schauer, Michael Sharp, Ömer Faruk Demir, Laszlo Kovacs, Ulrike Schillinger, Charles A. Stanley, Susanne Klotz, I. Staboulidou, Lori J. Howell, Catherine Delorme-Vincent, Noel Tulipan, Moncef Benkhalifa, Andreas Raith, Ioanna Bouba, Ioannis Georgiou, Stéphanie Aicardi, D. Escribano, Patrick Bailleul, Antonio Fernandes Moron, Eva Pipiras, Elisabeth Hatzi, Petros Tsipouras, Corinne Jeanne-Pasquier, Edward Araujo Júnior, Z. Zizka, J. Arbués, Michel Dreyfus, Michael W. Kilpatrick, Leandros Lazaros, Louise Devisme, A. Galindo, Bahar Başkan, M. Klimek, Barbara Rigó, Zoltán Papp, Raymund E. Horch, Laura Steinmuller, Tomas Fait, Michel Herlicoviez, Pavel Calda, Claudio Rodrigues Pires, A. Scharf, Luc Durin, and Müberra Koçak

Subjects
Embryology, Index (economics), business.industry, Pediatrics, Perinatology and Child Health, Statistics, Obstetrics and Gynecology, Medicine, Radiology, Nuclear Medicine and imaging, Subject (documents), General Medicine, business
Published
2006
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39. Contents Vol. 21, 2006

Author

Elisabeth Hatzi, Michael Sharp, Michel Herlicoviez, Andreas Raith, Ömer Faruk Demir, Moncef Benkhalifa, Omer Kandemir, Edward Araujo Júnior, Z. Zizka, Ioannis Georgiou, Gábor Viktor Szabó, Petros Tsipouras, Triantafyllos Tafas, Barbara Rigó, Susanne Klotz, Zoltán Papp, Pavel Calda, Stéphanie Aicardi, Laura Steinmuller, Serdar Şen, Michael W. Kilpatrick, A. Galindo, Luciano Marcondes Machado Nardozza, Eva Pipiras, N. Scott Adzick, Matthias Foehn, Catherine Delorme-Vincent, Noel Tulipan, Joseph P. Bruner, D. Escribano, István Sziller, Bahar Başkan, Ioanna Bouba, George E. Davis, Tomas Fait, Leandros Lazaros, Müberra Koçak, Arupa Ganguly, Jean-Philippe Wolf, Claudio Rodrigues Pires, Cyril Eboué, Jan Kvasnicka, Louise Devisme, J. Schauer, A. Scharf, Hélio Antonio Guimarães Filho, J.M. Puente, Luc Durin, Corinne Jeanne-Pasquier, Laszlo Kovacs, Julia Henke, Nikolaos A. Papadopulos, P. De la Fuente, B. Hollwitz, J. Arbués, Zsanett Szigeti, Ulrike Schillinger, Michel Dreyfus, M. Klimek, Patrick Bailleul, Serdar Kasakyan, Antonio Fernandes Moron, G.A. Rau, Raymund E. Horch, Petronella Hupuczi, I. Staboulidou, Hana Viskova, Andrée Delahaye, Brigitte Benzacken, Sebastião Marques Zanforlin Filho, Evangelos Paraskevaidis, Charles A. Stanley, Paul Thornton, Lucia Haakova, James Tepperberg, Edgar Biemer, Lori J. Howell, Mark I. Evans, Mark P. Johnson, William H. Peranteau, and R. Hass

Subjects
Embryology, Traditional medicine, business.industry, Pediatrics, Perinatology and Child Health, Obstetrics and Gynecology, Medicine, Radiology, Nuclear Medicine and imaging, General Medicine, business
Published
2006
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40. Retrospective Diagnosis of Pallister-Killian Syndrome by CGH Array

Author

Catherine Delorme-Vincent, Eva Pipiras, Brigitte Benzacken, Moncef Benkhalifa, Serdar Kasakyan, Andrée Delahaye, Jean-Philippe Wolf, and Louise Devisme

Subjects
Embryology, Pathology, medicine.medical_specialty, Aneuploidy, Prenatal diagnosis, Pallister–Killian syndrome, Ulnar–mammary syndrome, Humans, Medicine, Abnormalities, Multiple, Radiology, Nuclear Medicine and imaging, Craniofacial, Oligonucleotide Array Sequence Analysis, Chromosomes, Human, Pair 12, Mosaicism, business.industry, Infant, Newborn, Cytogenetics, Obstetrics and Gynecology, Syndrome, General Medicine, medicine.disease, Karyotyping, Pediatrics, Perinatology and Child Health, Tetrasomy, Female, business, Comparative genomic hybridization
Abstract

Objective and Methods: We report a girl presenting with a polymalformation syndrome. Despite a normal karyotype on peripheral lymphocytes and the unavailability of cultured fibroblasts, a tetrasomy 12p was identified on pulmonary DNA extracted from a postmortem biopsy, by use of comparative genomic hybridization (CGH) and confirmed by CGH array. The clinical picture of our patient was consistent, but not specific of the diagnosis of Pallister-Killian syndrome. She presented with the association of antenatal polyhydramnios, craniofacial dysmorphic features, skeletal abnormalities, and a congenital cardiopathy. Conclusion: We discuss the usefulness of CGH and CGH array in prenatal and constitutional cytogenetics.

Published
2006
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41. Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1

Author

Christelle Dubourg, Joris Andrieux, Stanislas Lyonnet, Pietro Palumbo, Chantal Missirian, Alice Masurel, Brigitte Benzacken, Alain Verloes, Nathalie Marle, Anne Lise Delezoide, Clarisse Baumann, Aimé Ravel, Valérie Malan, Anne Claude Tabet, Laila El Khattabi, Muriel Holder-Espinasse, Serge Romana, Mylène Valduga, Laurence Faivre, Anne Moncla, Hélène Dessuant, Sylvie Jaillard, Jean Michel Dupont, Sonia Bouquillon, Alexandre Moerman, Séverine Drunat, Fabien Guimiot, Hubert Journel, Bruno Delobel, Massimo Carella, Sylvie Odent, Florence Demurger, Céline Dupont, Eva Pipiras, Andrée Delahaye, Marie Vermelle, Orazio Palumbo, Service de Biologie du Développement, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré, Service Histologie-embryologie-cytogénétique, Université Paris 13 ( UP13 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Jean Verdier, Laboratoire de Génétique Clinique, Hôpital Jeanne de Flandre [Lille]-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Département de Génétique Médicale, Systèmes de Référence Temps Espace ( SYRTE ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Observatoire de Paris-Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), Centre de Génétique Chromosomique, Hôpital Saint Vincent de Paul-GHICL, Service de Cytogénétique et de Biologie Cellulaire, Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Département de génétique, Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ) -Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), 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 ), Service de génétique clinique, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Service de Génétique Médicale [CHU Necker], CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service de génétique, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Département de génétique médicale [Hôpital de la Timone - APHM], Institut National de la Santé et de la Recherche Médicale ( INSERM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) -Aix Marseille Université ( AMU ), Service de Génétique clinique, Laboratoire de Génétique Chromosomique, Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Centre de Référence ' Anomalies du Développement et Syndromes Malformatifs Sud - Est PACA ', Universita degli studi di Napoli 'Parthenope' [Napoli], INSERM EMI0210 ( EMI0210 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire Histologie Embryologie Cytogénétique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Instituto di Ricovero e Cura a Carattere Scientifico, Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), AP HP, Reprod Biol Unit CECOS, Centre Hospitalier Universitaire Jean Verdier, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Jeanne de Flandre [Lille]-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Systèmes de Référence Temps Espace (SYRTE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Università degli Studi di Napoli 'Parthenope' = University of Naples (PARTHENOPE), INSERM EMI0210 (EMI0210), Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris 13 (UP13)-Hôpital Jean Verdier [AP-HP], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Jean Verdier [Bondy], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), PSL Research University (PSL)-PSL Research University (PSL)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], and Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)

Subjects
Adult, Male, Adolescent, [SDV]Life Sciences [q-bio], Penetrance, Bioinformatics, Polymorphism, Single Nucleotide, Article, Pregnancy, GRIK2, Basic Helix-Loop-Helix Transcription Factors, Genetics, Humans, SNP, Obesity, Child, Gene, Genetic Association Studies, Genetics (clinical), Comparative Genomic Hybridization, biology, [ SDV ] Life Sciences [q-bio], Infant, Phenotype, Repressor Proteins, Child, Preschool, Aborted Fetus, SIM1, biology.protein, Chromosomes, Human, Pair 6, Female, Haploinsufficiency, Prader-Willi Syndrome, Comparative genomic hybridization
Abstract

International audience; 6q16 deletions have been described in patients with a Prader-Willi-like (PWS-like) phenotype. Recent studies have shown that certain rare single-minded 1 (SIM1) loss-of-function variants were associated with a high intra-familial risk for obesity with or without features of PWS-like syndrome. Although SIM1 seems to have a key role in the phenotype of patients carrying 6q16 deletions, some data support a contribution of other genes, such as GRIK2, to explain associated behavioural problems. We describe 15 new patients in whom de novo 6q16 deletions were characterised by comparative genomic hybridisation or single-nucleotide polymorphism (SNP) array analysis, including the first patient with fetopathological data. This fetus showed dysmorphic facial features, cerebellar and cerebral migration defects with neuronal heterotopias, and fusion of brain nuclei. The size of the deletion in the 14 living patients ranged from 1.73 to 7.84 Mb, and the fetus had the largest deletion (14 Mb). Genotype-phenotype correlations confirmed the major role for SIM1 haploinsufficiency in obesity and the PWS-like phenotype. Nevertheless, only 8 of 13 patients with SIM1 deletion exhibited obesity, in agreement with incomplete penetrance of SIM1 haploinsufficiency. This study in the largest series reported to date confirms that the PWS-like phenotype is strongly linked to 6q16.2q16.3 deletions and varies considerably in its clinical expression. The possible involvement of other genes in the 6q16.2q16.3-deletion phenotype is discussed.

Published
2014
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42. Cerebral small-vessel disease associated with COL4A1 and COL4A2 gene duplications

Author

Andrée Delahaye, Brigitte Benzacken, Dimitri Renard, Elisabeth Tournier-Lasserve, Manuele Mine, Eva Pipiras, and Pierre Labauge

Subjects
Adult, Collagen Type IV, medicine.medical_specialty, DNA Mutational Analysis, Fibrinogen, Gastroenterology, Fibrin, chemistry.chemical_compound, Internal medicine, Gene Duplication, medicine, Factor V Leiden, Humans, cardiovascular diseases, medicine.diagnostic_test, biology, Cholesterol, business.industry, Antithrombin, Brain, Middle Aged, medicine.disease, Magnetic Resonance Imaging, chemistry, Cerebral Small Vessel Diseases, biology.protein, Disease Progression, Female, Neurology (clinical), Liver function tests, business, Protein C, medicine.drug, Lipoprotein
Abstract

A nonsmoking woman, aged 44 years, presented with transient right-sided hemiparesis. CT showed leukoencephalopathy without infarction (figure). Blood pressure was normal. Blood count, plasma glucose levels, C-reactive protein, renal/liver function tests, cardiac enzymes, atrial natriuretic factor, HIV/syphilis/hepatitis B and C serology, and lactic acid levels were normal. Low-density lipoprotein (LDL) cholesterol levels were slightly elevated (1.25 g/L). Screening tests for prothrombotic disorders (serum fibrinogen, D-dimer, fibrin degradation products, antithrombin III level, protein C and S level, factor V Leiden, prothrombin gene mutation, antiphospholipid antibodies) were normal. Carotid duplex scanning, transthoracic echocardiography, and 24-hour Holter ECG were normal. Acetylsalicylic acid 160 mg once daily was started.

Published
2014

43. P159: Variants in cohesin release factors WAPL, PDS5A, and PDS5B define a new class of cohesinopathies

Author

Philip Boone, Kamli Faour, Kiana Mohajeri, John Lemanski, Bimal Jana, Jack Fu, Jennifer Kerkhof, Haley McConkey, Ryan Collins, Diane Lucente, Celine de Esch, Mariana Moysés-Oliveira, Alexander Nuttle, Aloysius Domingo, Serkan Erdin, Maris Hanley, Amy Watt, Eric Surette, Gloria Lima, Laura Smith, Monica Salani, Rachita Yadav, Ricardo Harripaul, Kathryn O’Keefe, Nicholas Burt, Matthew Larson, Riya Bhavsar, Benjamin Currall, Susan Sell, Roger Ladda, LaDonna Immken, Catherine Buchanan, Bo Yuan, Sally Lynch, Christian Gilissen, Rolph Pfundt, Charlotte Ockeloen, Tjitske Kleefstra, Els Vanhoutte, Margje Sinnema, Sander Stegmann, Servi Stevens, Maria Iascone, Silvia Maitz, Benjamin Cogne, Cedric Le Caignec, Marie Vincent, Mathilde Nizon, Alison Male, Pankaj Agrawal, Michelle Thompson, Pernille Torring, Charlotte Brasch-Andersen, Laurence Faivre, Ange-Line Bruel, Bertrand Isidor, Christophe Philippe, Manuela Morleo, Monica Wojcik, Casie Genetti, Siddharth Srivastava, Sonia Ballal, Sophia Schließke, Rami Abou Jamra, Andree Delahaye, Lydia von Wintzingerode, Viktoria Bothe, Marine Houlier, Timothy Stout, Gaber Bergant, Borut Peterlin, Oana Moldovan, Núria Martínez-Gil, Emanuela Argilli, Elliott Sherr, Tamar Harel, Hallel Rosenberg-Fogler, Jill Rosenfeld, Ingrid Wentzensen, Dominik Westphal, Korbinian Riedhammer, Laura Orec, James Gusella, Bekim Sadikovic, Derek Tai, and Michael Talkowski

Subjects
Genetics, QH426-470, Medicine
Published
2023
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44. MEFV analysis is of particularly weak diagnostic value for recurrent fevers in Western European Caucasian patients

Author

Stéphane Moutereau, Serge Amselem, G. Grateau, Andrée Delahaye, Dimitri Tchernitchko, C. Lacombe, Cécile Cazeneuve, and Marie Legendre

Subjects
medicine.medical_specialty, Pathology, DNA Mutational Analysis, Immunology, Familial Mediterranean fever, Pyrin domain, White People, Rheumatology, Internal medicine, Humans, Immunology and Allergy, Medicine, Pharmacology (medical), Genetic Testing, Allele, Genetic testing, medicine.diagnostic_test, business.industry, Pyrin, MEFV, medicine.disease, Familial Mediterranean Fever, Europe, Cytoskeletal Proteins, Phenotype, Recurrent fever, Clinical diagnosis, Mutation, business
Abstract

Objective Familial Mediterranean fever (FMF) is an autosomal-recessive disorder characterized by recurrent attacks of fever, with abdominal, thoracic, or articular pain. FMF is particularly common in Mediterranean populations, while other populations are rarely affected. MEFV gene analysis provides the only objective diagnostic criterion for FMF. However, the spectrum of MEFV mutations, which was first established in classically affected populations, remains insufficiently studied in other populations. The purpose of this study was to assess involvement of MEFV in the phenotype of western European Caucasian patients with a clinical diagnosis of FMF. Methods Mutation analysis was performed in 208 Caucasian patients from western Europe, by screening for the most common MEFV mutations in exons 2, 3, 5, and 10, and by sequencing the promoter region and the whole MEFV coding sequence in 21 of these patients. Results None of the patients carried 2 mutated alleles. Only 2 patients carried 1 mutated allele. Conclusion FMF-like syndromes in western European Caucasian populations cannot be explained by MEFV mutations. These results should be helpful in avoiding laborious and costly MEFV molecular analyses that, at the population level, seem to be of poor diagnostic value in the case of western European Caucasian patients, and rather should prompt a search for other causes in those patients.

Published
2005
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45. Mutations in the C-terminus of CDKL5: proceed with caution

Author

Svetlana Gataullina, Thierry Bienvenu, Juliette Nectoux, Andrée Delahaye, Bertrand Diebold, and Chloé Delépine

Subjects
DNA Mutational Analysis, CDKL5, Mutation, Missense, Short Report, Rett syndrome, Biology, Protein Serine-Threonine Kinases, Bioinformatics, medicine.disease_cause, Exon, Genetic variation, Genetics, medicine, Rett Syndrome, Missense mutation, Humans, Atypical Rett syndrome, Genetic Predisposition to Disease, Child, Gene, Genetics (clinical), Genetic Association Studies, Mutation, Base Sequence, medicine.disease, Molecular Diagnostic Techniques, Child, Preschool, Female
Abstract

Mutations in the cyclin-dependent kinase-like 5 (CDKL5) gene have been described in girls with Rett-like features and early-onset epileptic encephalopathy including infantile spasms. Milder phenotypes have been associated with sequence variations in the 3′-end of the CDKL5 gene. Identification of novel CDKL5 transcripts coding isoforms characterized by an altered C-terminal region strongly questions the eventual pathogenicity of sequence variations located in the 3′-end of the gene. We investigated a group of 30 female patients with a clinically heterogeneous phenotype ranging from nonspecific intellectual disability to a severe neonatal encephalopathy and identified two heterozygous CDKL5 missense mutations, the previously reported p.Val999Met and the novel mutation p.Pro944Thr. However, these mutations have also been detected in their healthy father. Considering our results and all data from the literature, we suggest that genetic variations beyond the codon 938 in human CDKL5115 protein may have minor or no significance. It is probable that screening of exons 19–21 of the CDKL5 gene is not useful in practical molecular diagnosis of atypical Rett syndrome.

Published
2013

46. ARHGEF26/SGEF controls fovea formation, immunity, neurodevelopment and arteriosclerosis

Author

Eva Pipiras, P Bitoun, Andrée Delahaye, and Brigitte Benzacken

Subjects
Pathology, medicine.medical_specialty, Retina, genetic structures, biology, Photophobia, ABCA4, General Medicine, Arteriosclerosis, Macular dystrophy, Fundus (eye), Corpus callosum, medicine.disease, eye diseases, Hypoplasia, Ophthalmology, medicine.anatomical_structure, biology.protein, medicine, sense organs, medicine.symptom
Abstract

Purpose Identify cause of congenital syndrome with macular dystrophy, absent fovea in consanguineous family 6 yo girl with congenital nystagmus,low vision after informed consent. Methods Family had complete ophthalmologic, neurologic examination, brain MRI, genetic tests, array CGH, lipid profiles, vascular Doppler US.Mouse,human fetal ISH Results Proband had congenital nystagmus and corpus callosum agenesis.Vision was 20/200 w/o photophobia,night blindness. Fundus showed macular atrophy, normal vessels w/o pigment, small papilla. ERG, OP were normal, absent pattern VEP points to macular bundle defect.OCT showed absent fovea, thin retina (102 µm OD and 92 OS) interruption of the photoreceptor layer. MRI showed hippocampi hypoplasia. ABCA4 testing was negative as 18 ARRP genes. Parents have normal vision,ERG,VEP,OCT, angio and brain MRI. Array CGH showed 114kb homozygous 3q23 deletion up to 6th intron of SGEF gene in 3 sibs. Sister had absent fovea on OCT, low vision and macular dystrophy, brother had decreased foveal function on multifocal ERG with normal vision. Girls have repeated infections: EBV hepatitis,dental abcesses..Well parents harbor same heterozygous deletion. Mouse antibody In situ hybridisatio mapped to retina.Human Fetal brain cortex ISH wss positive. SGEF controls leukocyte trans-endothelial migration,1st phase of atherosclerosis. Mother with high cholesterol 212mg/dl and hyper-triglyceridemia had normal cervical arteries doppler US normal examination w/o atherosclerosis at 42yo Conclusion Data suggests ARHGEF26/SGEF gene controls arteriosclerosis, macular cone development, immune function, axon midline crossing with recessive inheritance. Deletion possibly has protective effect against arteriosclerosis

Published
2012
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47. Recurrent mutations in the CDKL5 gene: Genotype-phenotype relationships

Author

Thierry Bienvenu, Emilie Caietta, Nadia Bahi-Buisson, Mathieu Milh, Hélène Maurey, Anne Moncla, Flore Zufferey, Bertrand Diebold, Nathalie Villeneuve, Aurélia Jacquette, Gert Matthijs, Andrée Delahaye, and Hilde Van Esch

Subjects
Microcephaly, Encephalopathy, CDKL5, Rett syndrome, Protein Serine-Threonine Kinases, Biology, medicine.disease_cause, Bioinformatics, Frameshift mutation, Adenosine Triphosphate, X Chromosome Inactivation, Intellectual Disability, Genotype, Rett Syndrome, Genetics, medicine, Humans, Missense mutation, Protein Interaction Domains and Motifs, Genetic Association Studies, Genetics (clinical), Mutation, Binding Sites, Infant, Newborn, Infant, medicine.disease, Phenotype, Female, Spasms, Infantile
Abstract

Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) have been described in epileptic encephalopathies in females with infantile spasms with features that overlap with Rett syndrome. With more than 80 reported patients, the phenotype of CDKL5-related encephalopathy is well-defined. The main features consist of seizures starting before 6 months of age, severe intellectual disability with absent speech and hand stereotypies and deceleration of head growth, which resembles Rett syndrome. However, some clinical discrepancies suggested the influence of genetics and/or environmental factors. No genotype-phenotype correlation has been defined and thus there is a need to examine individual mutations. In this study, we analyzed eight recurrent CDKL5 mutations to test whether the clinical phenotype of patients with the same mutation is similar and whether patients with specific CDKL5 mutations have a milder phenotype than those with other CDKL5 mutations. Patients bearing missense mutations in the ATP binding site such as the p.Ala40Val mutation typically walked unaided, had normocephaly, better hand use ability, and less frequent refractory epilepsy when compared to girls with other CDKL5 mutations. In contrast, patients with mutations in the kinase domain (such as p.Arg59X, p.Arg134X, p.Arg178Trp/Pro/Gln, or c.145 + 2T > C) and frameshift mutations in the C-terminal region (such as c.2635_2636delCT) had a more severe phenotype with infantile spasms, refractory epileptic encephalopathy, absolute microcephaly, and inability to walk. It is important for clinicians to have this information when such patients are diagnosed. © 2012 Wiley Periodicals, Inc. ispartof: American Journal of Medical Genetics A vol:158 issue:7 pages:1612-1619 ispartof: location:United States status: published

Published
2012

48. Chromosomal microarray analysis in ocular developmental anomalies

Author

Andrée Delahaye, Brigitte Benzacken, and Eva Pipiras

Subjects
Chromosome Aberrations, Pathology, medicine.medical_specialty, genetic structures, Microarray, DNA Copy Number Variations, Microarray analysis techniques, High-Throughput Nucleotide Sequencing, Biology, Eye, eye diseases, Human genetics, Pathology and Forensic Medicine, Genetics, medicine, Molecular Medicine, Chromosomes, Human, Humans, sense organs, Copy-number variation, Eye Abnormalities, Molecular Biology, Oligonucleotide Array Sequence Analysis
Abstract

Ocular developmental anomalies (ODAs) are structural defects of the eye with vari-ous severities, caused by the disruption of the complex process of ocular morpho-genesis. Although the reported prevalence at birth varies greatly, congenital eye mal-formations are rare; they are estimated to occur in four to six per 10,000 neonates in European registries

Published
2012

49. HOXC4 homeoprotein efficiently expands human hematopoietic stem cells and triggers similar molecular alterations as HOXB4

Author

Sophie Amsellem, Loïc Broix, Isabelle Vigon, Rima Haddad, Françoise Pflumio, Andrée Delahaye, Frederique Bulle, Céline Auvray, Ayda Miri-Nezhad, Serge Fichelson, Azzedine Yacia, and Inserm U1016, Institut Cochin, Paris, France, 22 Rue Méchain, 75014 Paris, France, CNRS UMR8104, Paris, France, Université Paris Descartes, Sorbonne-Paris-Cité, Paris, France, Laboratoire de Recherche d'Hémobiologie Cochin, Hôpital Cochin, Paris, France.

Subjects
[SDV.BIO]Life Sciences [q-bio]/Biotechnology, [SDV]Life Sciences [q-bio], CD34, Stem cell factor, Mice, SCID, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biology, Stem cell marker, CXCR4, 03 medical and health sciences, Mice, 0302 clinical medicine, Cancer stem cell, Mice, Inbred NOD, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], medicine, Animals, Humans, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Cell Proliferation, Homeodomain Proteins, 0303 health sciences, Hematopoietic stem cell, Hematology, Hematopoietic Stem Cells, Molecular biology, Coculture Techniques, Cell biology, medicine.anatomical_structure, HEK293 Cells, 030220 oncology & carcinogenesis, Stem cell, Original Articles and Brief Reports, Adult stem cell, Transcription Factors
Abstract

Background Expansion of hematopoietic stem cells represents an important objective for improving cell and gene therapy protocols. Retroviral transduction of the HoxB4 homeogene in mouse and human hematopoietic stem cells and hematopoietic progenitors is known to promote the cells’ expansion. A safer approach consists in transferring homeobox proteins into hematopoietic stem cells taking advantage of the natural ability of homeoproteins to cross cell membranes. Thus, HOXB4 protein transfer is operative for expanding human hematopoietic cells, but such expansion needs to be improved. Design and Methods To that aim, we evaluated the effects of HOXC4, a protein encoded by a HOXB4 paralog gene, by co-culturing HOXC4-producing stromal cells with human CD34+ hematopoietic cells. Numbers of progenitors and stem cells were assessed by in vitro cloning assays and injection into immuno-deficient mice, respectively. We also looked for activation or inhibition of target downstream gene expression. Results We show that the HOXC4 homeoprotein expands human hematopoietic immature cells by 3 to 6 times ex vivo and significantly improves the level of in vivo engraftment. Comparative transcriptome analysis of CD34+ cells subjected or not to HOXB4 or HOXC4 demonstrated that both homeoproteins regulate the same set of genes, some of which encode key hematopoietic factors and signaling molecules. Certain molecules identified herein are factors reported to be involved in stem cell fate or expansion in other models, such as MEF2C, EZH2, DBF4, DHX9, YPEL5 and Pumilio. Conclusions The present study may help to identify new HOX downstream key factors potentially involved in hematopoietic stem cell expansion or in leukemogenesis.

Published
2012
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50. Genomic imbalances detected by array-CGH in patients with syndromal ocular developmental anomalies

Author

Anne-Claude Tabet, Marion Gérard-Blanluet, Brigitte Benzacken, Jacques Elion, Nicolas Chassaing, Eva Pipiras, Serge Amselem, Pierre Bitoun, Céline Dupont, Sandrine Passemard, Annick Toutain, Alain Verloes, Samuel Quentin, Marie Legendre, Laurence Faivre, Andrée Delahaye, Frédérique Gatelais, Sophie Kaltenbach, Séverine Drunat, Pierre Gressens, Azzedine Aboura, Couvet, Sandrine, Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), AP-HP. Nord - Université Paris Cité, Université Paris Cité (UPCité), Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Faculté de Médecine Paris-Diderot [Paris], Université Paris Diderot - Paris 7 (UPD7), CHU d'Angers [Département Urgences], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Physiopathologie des maladies génétiques d'expression pédiatrique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratoire Histologie Embryologie Cytogénétique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hopital Saint-Louis [AP-HP] (AP-HP), Pharmacogénétique et abords thérapeutiques des maladies héréditaires, and Université des Antilles et de la Guyane (UAG)-Université Paris Diderot - Paris 7 (UPD7)-IFR2-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Adult, Male, Adolescent, ocular developmental anomaly, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Genetic counseling, [SDV]Life Sciences [q-bio], Gene Dosage, 16p11.2 deletion, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Bioinformatics, Gene dosage, Genome, Article, Genetics, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, YWHAE, Copy-number variation, Eye Abnormalities, Child, Gene, Genetics (clinical), Chromosome Aberrations, Comparative Genomic Hybridization, Otx Transcription Factors, Microarray analysis techniques, Genome, Human, Forkhead Transcription Factors, Syndrome, [SDV] Life Sciences [q-bio], [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, array-CGH, Human genome, FOXC1, Female, Comparative genomic hybridization, OTX2
Abstract

International audience; In 65 patients, who had unexplained ocular developmental anomalies (ODAs) with at least one other birth defect and/or intellectual disability, we performed oligonucleotide comparative genome hybridisation-based microarray analysis (array-CGH; 105A or 180K, Agilent Technologies). In four patients, array-CGH identified clinically relevant deletions encompassing a gene known to be involved in ocular development (FOXC1 or OTX2). In four other patients, we found three pathogenic deletions not classically associated with abnormal ocular morphogenesis, namely, del(17)(p13.3p13.3), del(10)(p14p15.3), and del(16)(p11.2p11.2). We also detected copy number variations of uncertain pathogenicity in two other patients. Rearranged segments ranged in size from 0.04 to 5.68 Mb. These results show that array-CGH provides a high diagnostic yield (15%) in patients with syndromal ODAs and can identify previously unknown chromosomal regions associated with these conditions. In addition to their importance for diagnosis and genetic counselling, these data may help identify genes involved in ocular development.

Published
2012
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