Descriptor: "MESH: Abnormalities, Multiple" / Topic: mesh: female - Searchworks@Jio Institute Digital Library Search Results

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24 results on '"MESH: Abnormalities, Multiple"'

1. Recurrence of an early postzygotic rescue of an inherited unbalanced translocation resulting in mosaic segmental uniparental isodisomy of chromosome 11q in siblings

Author: Alice Goldenberg, Gaël Nicolas, Maud Blanluet, Sandra Chantot-Bastaraud, Gabriella Vera, Boris Keren, Géraldine Joly-Helas, Thierry Frebourg, Didier Hannequin, Jean-Pierre Siffroi, Kévin Cassinari, Nathalie Le Meur, Bertrand Mace, Pascal Chambon, Couvet, Sandrine, UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-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), UF de Génétique chromosomique [CHU Trousseau], CHU Trousseau [APHP], Service de Génétique médicale [CHU Pitié-Salpêtrière], and CHU Pitié-Salpêtrière [AP-HP]
Subjects: MESH: Abnormalities, Multiple, MESH: Chromosome Deletion, [SDV]Life Sciences [q-bio], MESH: Chromosomes, Human, Pair 2, Chromosomal translocation, Chromosomal rearrangement, postzygotic, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, MESH: Cervical Vertebrae, Germline, MESH: Intellectual Disability, MESH: Uniparental Disomy, Gene duplication, Genetics, medicine, MESH: In Situ Hybridization, Fluorescence, Genetics (clinical), MESH: Humans, medicine.diagnostic_test, MESH: Genetic Predisposition to Disease, MESH: Scoliosis, Chromosome, Karyotype, MESH: Male, MESH: Translocation, Genetic, MESH: Siblings, [SDV] Life Sciences [q-bio], MESH: Karyotyping, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Uniparental Isodisomy, rescue, unbalanced translocation, MESH: Chromosome Banding, MESH: Chromosomes, mosaic, MESH: Mosaicism, MESH: Kyphosis, MESH: Chromosomes, Human, Pair 11, MESH: Female, Fluorescence in situ hybridization
Abstract: Balanced translocations are associated with a risk of transmission of unbalanced chromosomal rearrangements in the offspring. Such inherited chromosomal abnormalities are typically non-mosaic as they are present in the germline. We report the recurrence in two siblings of a mosaicism for a chromosomal rearrangement inherited from their asymptomatic father who carried a balanced t(2;11)(q35;q25) translocation. Both siblings exhibited a similar phenotype including intellectual disability, dysmorphic features, kyphoscoliosis, and cervical spinal stenosis. Karyotyping, fluorescence in situ hybridization and SNP array analysis of blood lymphocytes of both siblings identified two cell lines: one carrying a 2q35q37.3 duplication and a 11q25qter deletion (~90% cells), and one carrying an 11q uniparental isodisomy of maternal origin (~10% cells). We hypothesize that these mosaics were related to a postzygotic rescue mechanism which unexpectedly recurred in both siblings.
Published: 2021

2. Severe central apnea secondary to cerebellar dysplasia in a child: look past Joubert syndrome

Author: Guillaume Aubertin, Chiara Sileo, Diana Rodriguez, Harriet Corvol, Stéphanie Valence, Nicole Beydon, Jessica Taytard, Plamen Bokov, Service de Pneumologie pédiatrique [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Radiologie [CHU Trousseau], 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), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Service de physiologie, unité fonctionnelle d’explorations respiratoires [CHU Trousseau], Neurophysiologie Respiratoire Expérimentale et Clinique (UMRS 1158), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Mucoviscidose: physiopathologie et phénogénomique [CRSA], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), and Gestionnaire, Hal Sorbonne Université
Subjects: MESH: Kidney Diseases, Cystic, Pulmonary and Respiratory Medicine, Pediatrics, medicine.medical_specialty, MESH: Abnormalities, Multiple, Central sleep apnea, Cerebellar dysplasia, Central apnea, Case Reports, Polysomnography, Tachypnea, central sleep apnea, Joubert syndrome, MESH: Magnetic Resonance Imaging, children, MESH: Child, Female patient, medicine, MESH: Syndrome, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, MESH: Humans, medicine.diagnostic_test, business.industry, MESH: Retina, medicine.disease, MESH: Eye Abnormalities, Sleep in non-human animals, MESH: Cerebellum, respiratory tract diseases, 3. Good health, Neurology, MESH: Sleep Apnea, Central, cerebellar dysplasia, Neurology (clinical), medicine.symptom, business, MESH: Female, tachypnea, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: We report the case of a female patient aged 12 years referred to our pediatric sleep unit with a history of central sleep apnea associated with transient episodes of tachypnea on polysomnography recordings. The patient was otherwise healthy, with no personal or family medical history, and had a normal physical and neuropsychological examination. Brain magnetic resonance imaging showed signs of cerebellar vermis dysplasia but without the classical features of the molar tooth sign. The rest of the workup (genetic tests, blood tests, cardiac investigations) was normal except for an increased peripheral chemosensitivity to carbon dioxide and oxygen. The patient was successfully treated with bilevel positive airway pressure. This case report highlights the importance of performing brain magnetic resonance imaging in patients with central sleep apnea to study the cerebellum, beyond the brainstem area. Cerebellar malformations can be found even in the absence of any other neurological condition. CITATION: Taytard J, Valence S, Sileo C, et al. Severe central apnea secondary to cerebellar dysplasia in a child: look past Joubert syndrome. J Clin Sleep Med. 2020;16(12):2113–2116.
Published: 2020

3. Early-infantile onset epilepsy and developmental delay caused by bi-allelic GAD1 variants

Author: Neuray, C., Maroofian, R., Scala, M., Sultan, T., Pai, G. S., Mojarrad, M., Khashab, H. E., Deholl, L., Yue, W., Alsaif, H. S., Zanetti, M. N., Bello, O., Person, R., Eslahi, A., Khazaei, Z., Feizabadi, M. H., Efthymiou, S., El-Bassyouni, H. T., Soliman, D. R., Tekes, S., Ozer, L., Baltaci, V., Khan, S., Beetz, C., Amr, K. S., Salpietro, V., Jamshidi, Y., Alkuraya, F. S., Houlden, H., Groppa, S., Karashova, B. M., Nachbauer, W., Boesch, S., Arning, L., Timmann, D., Cormand, B., Perez-Duenas, B., Synaps, Group, Di Rosa, G., Aguennouz, M., Goraya, J. S., Mine, J., Avdjieva, D., Kathom, H., Tincheva, R., Banu, S., Pineda-Marfa, M., Veggiotti, P., Ferrari, M. D., Verrotti, A., Marseglia, G., Savasta, S., Garcia-Silva, M., Ruiz, A. M., Garavaglia, B., Borgione, E., Portaro, S., Sanchez, B. M., Boles, R., Papacostas, S., Vikelis, M., Papanicolaou, E. Z., Dardiotis, E., Maqbool, S., Ibrahim, S., Kirmani, S., Rana, N. N., Atawneh, O., Koutsis, G., Breza, M., Mangano, S., Scuderi, C., Morello, G., Stojkovic, T., Zollo, M., Heimer, G., Dauvilliers, Y. A., Striano, P., Al-Khawaja, I., Al-Mutairi, F., Sherifa, H., Neuray C., Maroofian R., Scala M., Sultan T., Pai G.S., Mojarrad M., Khashab H.E., deHoll L., Yue W., Alsaif H.S., Zanetti M.N., Bello O., Person R., Eslahi A., Khazaei Z., Feizabadi M.H., Efthymiou S., El-Bassyouni H.T., Soliman D.R., Tekes S., Ozer L., Baltaci V., Khan S., Beetz C., Amr K.S., Salpietro V., Jamshidi Y., Alkuraya F.S., Houlden H., Mangano S., Dicle Üniversitesi, Tıp Fakültesi, Temel Tıp Bilimleri Bölümü, Tıbbi Biyoloji Ana Bilim Dalı, Tekeş, Selahattin, University College of London [London] (UCL), Paracelsus Medizinische Privatuniversität = Paracelsus Medical University (PMU), University of Genoa (UNIGE), IRCCS Istituto Giannina Gaslini [Genoa, Italy], Children's Hospital [Lahore], Institute of Child Health [Lahore], Medical University of South Carolina [Charleston] (MUSC), Mashhad University of Medical Sciences, Ain Shams University (ASU), University of Oxford [Oxford], GeneDx [Gaithersburg, MD, USA], Khorasan Razavi Agricultural and Natural Resources Research and Education Center, National Research Centre [Cairo, Egypt], Benha University (BU), Dicle University, CENTOGENE AG, University of London [London], King Faisal Specialist Hospital [Riyadh, Saudi Arabia] (Research Centre), and SYNaPS Study Group: Stanislav Groppa, Blagovesta Marinova Karashova, Wolfgang Nachbauer, Sylvia Boesch, Larissa Arning, Dagmar Timmann, Bru Cormand, Belen Pérez-Dueñas, Gabriella Di Rosa, Jatinder S Goraya, Tipu Sultan, Jun Mine, Daniela Avdjieva, Hadil Kathom, Radka Tincheva, Selina Banu, Mercedes Pineda-Marfa, Pierangelo Veggiotti, Michel D Ferrari, Alberto Verrotti, Giangluigi Marseglia, Salvatore Savasta, Mayte García-Silva, Alfons Macaya Ruiz, Barbara Garavaglia, Eugenia Borgione, Simona Portaro, Benigno Monteagudo Sanchez, Richard Boles, Savvas Papacostas, Michail Vikelis, Eleni Zamba Papanicolaou, Efthymios Dardiotis, Shazia Maqbool, Shahnaz Ibrahim, Salman Kirmani, Nuzhat Noureen Rana, Osama Atawneh, George Koutsis, Marianthi Breza, Salvatore Mangano, Carmela Scuderi, Eugenia Borgione, Giovanna Morello, Tanya Stojkovic, Massimi Zollo, Gali Heimer, Yves A Dauvilliers, Pasquale Striano, Issam Al-Khawaja, Fuad Al-Mutairi, Hamed Sherifa
Subjects: Male, 0301 basic medicine, Glutamate decarboxylase, Malalties cerebrals, Neurotransmissors, Neurodevelopmental delay, Epilepsy, 0302 clinical medicine, MESH: Child, Age of Onset, Child, cleft palate, GAD1, AcademicSubjects/SCI01870, Glutamate Decarboxylase, Glutamate receptor, Muscle weakness, purl.org/becyt/ford/3.1 [https], Neurotransmitters, MESH: Infant, Hypotonia, muscle weakne, Cleft palate, MESH: Epilepsy, Child, Preschool, Muscle Hypotonia, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], purl.org/becyt/ford/3 [https], Female, Brain diseases, Abnormalities, medicine.symptom, Multiple, medicine.drug, epilepsy, muscle weakness, neurodevelopmental delay, MESH: Glutamate Decarboxylase, medicine.medical_specialty, MESH: Abnormalities, Multiple, MESH: Mutation, MESH: Age of Onset, Biology, Inhibitory postsynaptic potential, GAD1, cleft palate, epilepsy, muscle weakness, neurodevelopmental delay, gamma-Aminobutyric acid, 03 medical and health sciences, Excitatory synapse, Internal medicine, medicine, Humans, Abnormalities, Multiple, Preschool, Alleles, MESH: Neurodevelopmental Disorders, MESH: Humans, MESH: Muscle Hypotonia, MESH: Alleles, MESH: Child, Preschool, Infant, medicine.disease, MESH: Male, Epilèpsia, Editor's Choice, 030104 developmental biology, Endocrinology, Neurodevelopmental Disorders, Mutation, AcademicSubjects/MED00310, Neurology (clinical), MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery, Reports
Abstract: Mice lacking GAD1 show neonatal mortality, but the human phenotype associated with GAD1 disruption is poorly characterized. Neuray et al. describe six patients with biallelic GAD1 mutations, presenting with early-infantile onset epilepsy, neurodevelopmental delay, muscle weakness and non-CNS manifestations., Gamma-aminobutyric acid (GABA) and glutamate are the most abundant amino acid neurotransmitters in the brain. GABA, an inhibitory neurotransmitter, is synthesized by glutamic acid decarboxylase (GAD). Its predominant isoform GAD67, contributes up to ∼90% of base-level GABA in the CNS, and is encoded by the GAD1 gene. Disruption of GAD1 results in an imbalance of inhibitory and excitatory neurotransmitters, and as Gad1−/− mice die neonatally of severe cleft palate, it has not been possible to determine any potential neurological dysfunction. Furthermore, little is known about the consequence of GAD1 disruption in humans. Here we present six affected individuals from six unrelated families, carrying bi-allelic GAD1 variants, presenting with developmental and epileptic encephalopathy, characterized by early-infantile onset epilepsy and hypotonia with additional variable non-CNS manifestations such as skeletal abnormalities, dysmorphic features and cleft palate. Our findings highlight an important role for GAD1 in seizure induction, neuronal and extraneuronal development, and introduce GAD1 as a new gene associated with developmental and epileptic encephalopathy.
Published: 2020

4. Growth charts in Kabuki syndrome 1

Author: Claire Jeandel, Caroline Michot, Odile Boute, Mario Abaji, Stanislas Lyonnet, Julie Reversat, Lucile Pinson, Sandrine Akouete, Bertrand Isidor, Marie-Ange Delrue, Valérie Cormier-Daire, Isabelle Touitou, Pierre Sarda, Bérénice Doray, Tiffany Busa, Anne Moncla, Véra Georgescu, Alice Goldenberg, Damien Sanlaville, Cyril Amouroux, Elodie Sanchez, Mélanie Fradin, Guilaine Boursier, Didier Lacombe, Mouna Barat-Houari, Annick Toutain, Brigitte Gilbert-Dussardier, David Geneviève, Fabienne Giuliano, Kim Hanh Le Quan Sang, Joelle Roume, Marianne Till, Yves Alembick, Nicole Philip, Elise Schaefer, Marjolaine Willems, Claire Duflos, Aurélia Jacquette, Eudeline Alix, Sébastien Moutton, Adeline Bonnard, Vincent Gatinois, Marie-Pierre Cordier, Clarisse Baumann, Martine Le Merrer, Marie-Line Jacquemont, Lydie Burglen, Valentin Ruault, Laurence Faivre, Carole Corsini, Sylvie Manouvrier, Svetlana Gorokhova, Anna Pelet, Delphine Héron, Sylvie Odent, Jeanne Amiel, Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Département d'Information Médicale [CHRU Montpellier], 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), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Laboratoire de Cytogénétique Constitutionnelle [Hospices civils de Lyon], Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, 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), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Hôpital Robert Debré Paris, Hôpital Robert Debré, Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), 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), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Hôpital d'Enfants [CHU Dijon], Hôpital du Bocage, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de génétique clinique [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Service Génétique Médicale [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Dpt génétique médicale [CHU Nice], Centre Hospitalier Universitaire de Nice (CHU Nice), Département de génétique [CHU Rouen] (Centre Normandie de Génomique et de Médecine Personnalisée), CHU Rouen, Normandie Université (NU)-Normandie Université (NU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital saint Pierre, GH Sud Réunion, Centre de référence des maladies endocriniennes rares de la croissance et du développement [CHU Pitié-Salpêtrière], Département Pédiatrie [CHRU Montpellier], Pôle Femme Mère Enfant [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de recherche en neurosciences de Lyon (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), centre hospitalier intercommunal de Poissy/Saint-Germain-en-Laye - CHIPS [Poissy], Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Département génétique méd, mal rares et médecine personnalisée [CHRU de Montpellier], Pôle Biologie-Pathologie [CHRU Montpellier], Salvy-Córdoba, Nathalie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, 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), and Centre hospitalier intercommunal de Poissy/Saint-Germain-en-Laye - CHIPS [Poissy]
Subjects: Male, MESH: Neoplasm Proteins, CHILDREN, Growth, MESH: Growth Charts, Body Mass Index, MALFORMATION, Parental target size, MESH: Child, KDM6A, Growth Charts, Child, Specific curves, Genetics (clinical), 2. Zero hunger, Genetics & Heredity, Histone Demethylases, 0303 health sciences, education.field_of_study, 030305 genetics & heredity, Increase size, Circumference, MESH: Hematologic Diseases, Adult height, 3. Good health, Neoplasm Proteins, DNA-Binding Proteins, Vestibular Diseases, Child, Preschool, Cohort, MLL2, Female, MESH: Vestibular Diseases, Life Sciences & Biomedicine, MESH: Face, growth hormone deficiency, MESH: Abnormalities, Multiple, MESH: Mutation, Adolescent, growth, Population, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Growth hormone deficiency, MESH: Body Mass Index, 03 medical and health sciences, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, EARS, MESH: Body Height, MESH: Histone Demethylases, Genetics, medicine, Humans, Abnormalities, Multiple, education, 030304 developmental biology, MESH: Adolescent, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Science & Technology, Kabuki syndrome, MESH: Humans, business.industry, MUTATIONS, Body Weight, MESH: Child, Preschool, specific curves, MAKE-UP-SYNDROME, medicine.disease, Hematologic Diseases, Body Height, MESH: Male, MESH: Body Weight, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, parental target size, Face, Mutation, business, Body mass index, MESH: Female, MESH: DNA-Binding Proteins, Demography
Abstract: Kabuki syndrome (KS, KS1: OMIM 147920 and KS2: OMIM 300867) is caused by pathogenic variations in KMT2D or KDM6A. KS is characterized by multiple congenital anomalies and neurodevelopmental disorders. Growth restriction is frequently reported. Here we aimed to create specific growth charts for individuals with KS1, identify parameters used for size prognosis and investigate the impact of growth hormone therapy on adult height. Growth parameters and parental size were obtained for 95 KS1 individuals (41 females). Growth charts for height, weight, body mass index (BMI) and occipitofrontal circumference were generated in standard deviation values for the first time in KS1. Statural growth of KS1 individuals was compared to parental target size. According to the charts, height, weight, BMI, and occipitofrontal circumference were lower for KS1 individuals than the normative French population. For males and females, the mean growth of KS1 individuals was -2 and -1.8 SD of their parental target size, respectively. Growth hormone therapy did not increase size beyond the predicted size. This study, from the largest cohort available, proposes growth charts for widespread use in the management of KS1, especially for size prognosis and screening of other diseases responsible for growth impairment beyond a calculated specific target size. ispartof: AMERICAN JOURNAL OF MEDICAL GENETICS PART A vol:182 issue:3 pages:446-453 ispartof: location:United States status: published
Published: 2019

5. Mutations in the BAF-complex subunit DPF2 associated with Coffin-Siris syndrome

Author: Andrew O.M. Wilkie, Georgia Vasileiou, Bernt Popp, Yun Li, Maren Wenzel, Marion Gérard, Susan Tomkins, Jenny Morton, Megan T. Cho, André Reis, Astrid Weber, George E. Hoganson, Beate Albrecht, Felix B. Engel, Arif B. Ekici, Maria-Renée Plona, Janine Altmüller, Christian Thiel, Christian Büttner, Jill Clayton-Smith, Karen Low, Dagmar Wieczorek, Deciphering Developmental Disorders Study, Bernd Wollnik, Eduardo Calpena, Nuria C. Bramswig, Sabine Endele, Hermann-Josef Lüdecke, Silvia Vergarajauregui, Tim M. Strom, Institute of Human Genetics, University Erlangen-Nuremberg, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), 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), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Normandie Université (NU)-Normandie Université (NU), Institut für Humangenetik, Regional Genetic Service, St Mary's Hospital, Manchester, West Midlands Regional Genetics Laboratory and Clinical Genetics Unit, Birmingham Women's Hospital, Max Planck Institute for Plant Breeding Research (MPIPZ), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), University Medicine Goettingen, Department of Pediatrics [Chicago, IL, USA] (College of Medicine), University of Illinois [Chicago] (UIC), University of Illinois System-University of Illinois System, GeneDx [Gaithersburg, MD, USA], JRC Institute for Energy and Transport (IET), European Commission - Joint Research Centre [Petten], Institut für Humangenetik [Essen], Universitätsklinikum Essen, Technical University of Munich (TUM), Institute of Human Genetics, University Hospital Erlangen, Institute of Human Genetics [Erlangen, Allemagne], Université de Lorraine (UL), Institute of Human Genetics [Cologne], Universitätsklinikum Köln (Uniklinik Köln)-University of Cologne, University Medical Center Göttingen (UMG), Institute of Human Genetics - Institut für Humangenetik [Essen], Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen)-Universitat Duisberg-Essen, Technische Universität München [München] (TUM)-German Research Center for Environmental Health-Helmholtz-Zentrum München (HZM), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester], Birmingham Women's and Children's NHS Foundation Trust, University Hospitals Bristol, Liverpool Women's NHS Foundation Trust, Genetikum, Cologne Center for Genomics [Cologne] (CCG), University of Cologne, Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), University of Illinois College of Medicine, University of Illinois System, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), and University of Oxford [Oxford]
Subjects: 0301 basic medicine, Male, Medizin, PHD finger, MESH: Amino Acid Sequence, Histones, 0302 clinical medicine, MESH: Child, Chlorocebus aethiops, MESH: Hand Deformities, Congenital, Missense mutation, Coffin-Siris syndrome, histone modification, MESH: Animals, BAF complex, nuclear aggregates, Child, Genetics (clinical), Genetics, MESH: Histones, MESH: Protein Subunits, DNA-Binding Proteins, MESH: COS Cells, Histone, Phenotype, DPF2, MESH: Facies, intellectual disability, Child, Preschool, MESH: HEK293 Cells, COS Cells, Female, MESH: Neck, Hand Deformities, Congenital, MESH: Face, MESH: Abnormalities, Multiple, MESH: Mutation, Adolescent, Protein subunit, Micrognathism, dominant negative, autism spectrum disorder, Biology, MESH: Micrognathism, MESH: Phenotype, Frameshift mutation, MESH: Intellectual Disability, 03 medical and health sciences, Report, medicine, Animals, Humans, Abnormalities, Multiple, Amino Acid Sequence, Gene, Coffin–Siris syndrome, MESH: Adolescent, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Coarse facial features, MESH: Child, Preschool, Facies, medicine.disease, MESH: Cercopithecus aethiops, MESH: Male, Protein Subunits, Autism Spectrum Disorder, Baf Complex, Coffin-siris Syndrome, Dominant Negative, Dpf2, Histone Modification, Intellectual Disability, Nail Hypoplasia, Nuclear Aggregates, Phd Finger, 030104 developmental biology, HEK293 Cells, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Face, Mutation, biology.protein, nail hypoplasia, MESH: Female, 030217 neurology & neurosurgery, Neck, MESH: DNA-Binding Proteins, Transcription Factors
Abstract: International audience; Variants affecting the function of different subunits of the BAF chromatin-remodelling complex lead to various neurodevelopmental syndromes, including Coffin-Siris syndrome. Furthermore, variants in proteins containing PHD fingers, motifs recognizing specific histone tail modifications, have been associated with several neurological and developmental-delay disorders. Here, we report eight heterozygous de novo variants (one frameshift, two splice site, and five missense) in the gene encoding the BAF complex subunit double plant homeodomain finger 2 (DPF2). Affected individuals share common clinical features described in individuals with Coffin-Siris syndrome, including coarse facial features, global developmental delay, intellectual disability, speech impairment, and hypoplasia of fingernails and toenails. All variants occur within the highly conserved PHD1 and PHD2 motifs. Moreover, missense variants are situated close to zinc binding sites and are predicted to disrupt these sites. Pull-down assays of recombinant proteins and histone peptides revealed that a subset of the identified missense variants abolish or impaire DPF2 binding to unmodified and modified H3 histone tails. These results suggest an impairment of PHD finger structural integrity and cohesion and most likely an aberrant recognition of histone modifications. Furthermore, the overexpression of these variants in HEK293 and COS7 cell lines was associated with the formation of nuclear aggregates and the recruitment of both wild-type DPF2 and BRG1 to these aggregates. Expression analysis of truncating variants found in the affected individuals indicated that the aberrant transcripts escape nonsense-mediated decay. Altogether, we provide compelling evidence that de novo variants in DPF2 cause Coffin-Siris syndrome and propose a dominant-negative mechanism of pathogenicity.
Published: 2018

6. The scalp hair collar and tuft signs: A retrospective multicenter study of 78 patients with a systematic review of the literature

Author: C. Eschard, Jean-Philippe Lacour, Nausicaa Malissen, Juliette Mazereeuw-Hautier, Thomas Hubiche, Stéphanie Mallet, Emmanuel Mahé, Sébastien Barbarot, Valérie Rigau, Didier Bessis, Sylvie Fraitag, Ludovic Martin, Guillaume Captier, Nathalie Milla, C. Abasq, A. Phan, Marie-Christine Picot, Hassan El Fertit, Emmanuelle Bourrat, M. Marque, Christine Chiaverini, Olivia Boccara, Michèle Bigorre, Eve Puzenat, Nicolas Leboucq, Patrice Plantin, Pierre Vabres, F. Boralevi, Pathogénèse et contrôle des infections chroniques (PCCI), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Département de dermatologie [CHU de Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de chirurgie pédiatrique [Hôpital Lapeyronie-Arnaud de Villeneuve], Hôpital Lapeyronie [Montpellier] (CHU), Service de Dermatologie [Nice], Hôpital Archet 2 [Nice] (CHU), Service de dermatologie (Dermato - BREST), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service de dermatologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Département de Neuroradiologie[Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), Service de dermatologie et pathologies vasculaires [CH Argenteuil], Centre Hospitalier Victor Dupouy, Service de dermatologie, vénéreologie et cancérologie cutanée [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service de Dermatologie [CHU Angers] (PXE - le PseudoXanthome Elastique), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Centre de référence des maladies rares de la peau et des muqueuses d’origine génétique [CHU Toulouse] (CRMRP), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service de Dermatologie, Centre Hospitalier Sud, Hospices Civils, Lyon, Service de dermatologie et vénérologie [Hôpital Laënnec, site de Quimper], CH Cornouaille, Département d'information médicale [Montpellier], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service de Dermatologie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Biothérapies des maladies génétiques et cancers, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Dermatologie pédiatrique - Bordeaux, CHU Bordeaux [Bordeaux], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier )-Université de Montpellier (UM), Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), centre de référence des maladies rares de la peau, and CHU Toulouse [Toulouse]
Subjects: Male, Multimodal Imaging, MESH: Magnetic Resonance Imaging, 030207 dermatology & venereal diseases, paraganglioma, sebaceous nevus, 0302 clinical medicine, Meninges, Paraganglioma, MESH: Neuroimaging, Prospective Studies, meningocele, Ultrasonography, Doppler, Color, False Negative Reactions, MESH: False Negative Reactions, Neural Plate, cephalocele, medicine.diagnostic_test, hair tuft, membranous aplasia cutis, MESH: Infant, Newborn, MESH: Multimodal Imaging, Brain, MESH: Choristoma, MESH: Infant, Magnetic Resonance Imaging, 3. Good health, medicine.anatomical_structure, MESH: Skull, Female, Radiology, MESH: Hair, sinus pericranii, MESH: Tomography, X-Ray Computed, medicine.medical_specialty, MESH: Abnormalities, Multiple, MESH: Neural Plate, MESH: Meninges, Neuroimaging, Dermatology, MESH: Ultrasonography, Doppler, Color, Choristoma, MESH: Scalp, Veins, 03 medical and health sciences, MESH: Brain, medicine, Nevus, Humans, Abnormalities, Multiple, False Positive Reactions, Sinus pericranii, Retrospective Studies, Cephalocele, hair collar, MESH: Humans, Scalp, MESH: Veins, MESH: False Positive Reactions, business.industry, Skull, Infant, Newborn, Infant, Magnetic resonance imaging, MESH: Retrospective Studies, Neurovascular bundle, medicine.disease, MESH: Male, MESH: Prospective Studies, Surgery, smooth muscle cell nevus, business, Tomography, X-Ray Computed, MESH: Female, 030217 neurology & neurosurgery, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology, Hair
Abstract: International audience; BACKGROUND:Hair collar sign (HCS) and hair tuft of the scalp (HTS) are cutaneous signs of an underlying neuroectodermal defect, but most available data are based on case reports.OBJECTIVE:We sought to define the clinical spectrum of HCS and HTS, clarify the risk for underlying neurovascular anomalies, and provide imaging recommendations.METHODS:A 10-year multicenter retrospective and prospective analysis of clinical, radiologic, and histopathologic features of HCS and HTS in pediatric patients was performed.RESULTS:Of the 78 patients included in the study, 56 underwent cranial and brain imaging. Twenty-three of the 56 patients (41%) had abnormal findings, including the following: (1) cranial/bone defect (30.4%), with direct communication with the central nervous system in 28.6%; (2) venous malformations (25%); or (3) central nervous system abnormalities (12.5%). Meningeal heterotopia in 34.6% (9/26) was the most common neuroectodermal association. Sinus pericranii, paraganglioma, and combined nevus were also identified.LIMITATIONS:The partial retrospective design and predominant recruitment from the dermatology department are limitations of this study.CONCLUSIONS:Infants with HCS or HTS are at high risk for underlying neurovascular anomalies. Magnetic resonance imaging scans should be performed in order to refer the infant to the appropriate specialist for management.Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.
Published: 2016

7. TRα receptor mutations extend the spectrum of syndromes of reduced sensitivity to thyroid hormone

Author: Frédéric Flamant, Jean-Louis Wémeau, Stéphanie Espiard, Virginie Vlaeminck-Guillem, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Centre Hospitalier Universitaire de Lille (CHU de Lille), Institut de Génomique Fonctionnelle de Lyon (IGFL), École normale supérieure - Lyon (ENS Lyon)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Recherche Agronomique (INRA)-École normale supérieure - Lyon (ENS Lyon), École normale supérieure de Lyon (ENS de Lyon)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, [SDV]Life Sciences [q-bio], Thyrotropin, MESH: Triiodothyronine, MESH: Genotype, MESH: Child, MESH: Codon, Nonsense, MESH: Dwarfism, Age of Onset, Child, Frameshift Mutation, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Genes, Dominant, MESH: Thyroid Hormone Resistance Syndrome, MESH: Middle Aged, Triiodothyronine, Thyroid, MESH: Frameshift Mutation, General Medicine, Middle Aged, Congenital hypothyroidism, MESH: Hyperlipoproteinemia Type II, medicine.anatomical_structure, Phenotype, Thyroid hormone receptor alpha, MESH: Young Adult, Codon, Nonsense, MESH: Thyrotropin, MESH: Psychomotor Disorders, Female, medicine.symptom, Psychomotor disorder, Thyroid Hormone Receptors alpha, Adult, Thyroid Hormone Resistance Syndrome, medicine.medical_specialty, Thyroid Hormones, MESH: Abnormalities, Multiple, Adolescent, Genotype, MESH: Age of Onset, MESH: Thyroid Hormone Receptors alpha, Mutation, Missense, Dwarfism, MESH: Phenotype, Short stature, MESH: Bradycardia, Hyperlipoproteinemia Type II, Young Adult, MESH: Thyroid Hormones, Internal medicine, medicine, Bradycardia, Humans, Point Mutation, [INFO]Computer Science [cs], Abnormalities, Multiple, MESH: Point Mutation, MESH: Adolescent, MESH: Mutation, Missense, MESH: Humans, Thyroid hormone receptor, business.industry, MESH: Adult, medicine.disease, MESH: Male, Endocrinology, Psychomotor Disorders, MESH: Genes, Dominant, business, MESH: Female, Hormone
Abstract: International audience; Since 2012, eight different abnormalities have been described in the THRA gene (encoding the TRα1 thyroid hormone receptor) of 14 patients from 9 families. These mutations induce a clinical phenotype (resistance to thyroid hormone type α) associating symptoms of untreated mild congenital hypothyroidism and a near-normal range of free and total thyroid hormones and TSH (the T4/T3 ratio is nevertheless usually low). The phenotype can diversely include short stature (due to growth retardation), dysmorphic syndrome (face and limb extremities), psychoneuromotor disorders, constipation and bradycardia. The identified genetic abnormalities are located within the ligand-binding domain and result in defective T3 binding, an abnormally strong interaction with corepressors and a dominant negative activity against still functional receptors. The identification of patients with consistent phenotypes and the underlying mutations are warranted to better delineate the spectrum of the syndromes of reduced sensitivity to thyroid hormone.
Published: 2015

8. A Homozygous PDE6D Mutation in Joubert Syndrome Impairs Targeting of Farnesylated INPP5E Protein to the Primary Cilium

Author: Tania Attié-Bitach, Sophie Saunier, Mandy Kwong, Nadia Elkhartoufi, Enza Maria Valente, Isabelle Perrault, Joseph G. Gleeson, Alessia Micalizzi, Stéphanie Le Corre, Marta Romani, Julie Litzler, Lydie Burglen, Iain A. Drummond, Kevin J. Wright, Avinash Abhyankar, Julien Saada, Jean-Laurent Casanova, Stanislas Lyonnet, Nathalie Boddaert, Nicolas Chassaing, Arnold Munnich, Jeanne Amiel, Peter K. Jackson, Emilie Filhol, Michel Vekemans, Ferechté Encha-Ravazi, Wolfgang Baehr, Sophie Thomas, 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), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Genentech, Inc., Genentech, Inc. [San Francisco], Massachusetts General Hospital [Boston], Mendel Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo] (IRCCS), Universita degli Studi di Messina, Rockefeller University [New York], AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], CHU Necker - Enfants Malades [AP-HP], Génétique Humaine des Maladies Infectieuses (Inserm U980), Service de radiologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Utah, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité différenciation épidermique et auto-immunité rhumatoïde (UDEAR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse], Howard Hughes Medical Institute (HHMI), University of California [San Diego] (UC San Diego), University of California, and Harvard Medical School [Boston] (HMS)
Subjects: Male, Models, Molecular, Proteomics, MESH: Sequence Analysis, DNA, MESH: Cilia / metabolism, MESH: Cerebellar Diseases / genetics, Mutant, INPP5E, Ciliopathies, MESH: Phosphoric Monoester Hydrolases / metabolism, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Cerebellum, MESH: Cyclic Nucleotide Phosphodiesterases, Type 6 / genetics, Exome, MESH: Animals, Eye Abnormalities, Genetics (clinical), Exome sequencing, Zebrafish, Genetics, 0303 health sciences, MESH: Exome, MESH: Protein Prenylation, Splice site mutation, ADP-Ribosylation Factors, MESH: ADP-Ribosylation Factors / metabolism, Cilium, MESH: Proteomics, Homozygote, MESH: Genetic Predisposition to Disease, MESH: Kidney Diseases, Cystic / genetics, prenylation, Kidney Diseases, Cystic, Pedigree, Female, MESH: Models, Molecular, MESH: Homozygote, MESH: Abnormalities, Multiple, MESH: Zebrafish Proteins / metabolism, PDE6D, MESH: Pedigree, Protein Prenylation, Biology, MESH: Retina / metabolism, MESH: Zebrafish / abnormalities, Joubert syndrome, Article, Retina, MESH: Zebrafish / genetics, 03 medical and health sciences, MESH: Cyclic Nucleotide Phosphodiesterases, Type 6 / metabolism, primary cilia, MESH: Cerebellar Diseases / metabolism, Cerebellar Diseases, medicine, Animals, Humans, Abnormalities, Multiple, Genetic Predisposition to Disease, MESH: Retina / abnormalities, MESH: Eye Abnormalities / metabolism, Cilia, 030304 developmental biology, Cyclic Nucleotide Phosphodiesterases, Type 6, MESH: Humans, Sequence Analysis, DNA, Zebrafish Proteins, medicine.disease, MESH: Cerebellum / abnormalities, Phosphoric Monoester Hydrolases, MESH: Male, MESH: Phosphoric Monoester Hydrolases / genetics, MESH: Eye Abnormalities / genetics, Protein prenylation, MESH: Zebrafish Proteins / genetics, MESH: Female, 030217 neurology & neurosurgery, MESH: Kidney Diseases, Cystic / metabolism
Abstract: International audience; Joubert syndrome (JS) is characterized by a distinctive cerebellar structural defect, namely the << molar tooth sign >>. JS is genetically heterogeneous, involving 20 genes identified to date, which are all required for cilia biogenesis and/or function. In a consanguineous family with JS associated with optic nerve coloboma, kidney hypoplasia, and polydactyly, combined exome sequencing and mapping identified a homozygous splice-site mutation in PDE6D, encoding a prenyl-binding protein. We found that pde6d depletion in zebrafish leads to renal and retinal developmental anomalies and wild-type but not mutant PDE6D is able to rescue this phenotype. Proteomic analysis identified INPP5E, whose mutations also lead to JS or mental retardation, obesity, congenital retinal dystrophy, and micropenis syndromes, as novel prenyl-dependent cargo of PDE6D. Mutant PDE6D shows reduced binding to INPP5E, which fails to localize to primary cilia in patient fibroblasts and tissues. Furthermore, mutant PDE6D is unable to bind to GTP-bound ARL3, which acts as a cargo-release factor for PDE6D-bound INPP5E. Altogether, these results indicate that PDE6D is required for INPP5E ciliary targeting and suggest a broader role for PDE6D in targeting other prenylated proteins to the cilia. This study identifies PDE6D as a novel JS disease gene and provides the first evidence of prenyl-binding-dependent trafficking in ciliopathies.
Published: 2014

9. Involvement of ITIH5, a candidate gene for congenital uterovaginal aplasia (Mayer-Rokitansky-Küster-Hauser syndrome), in female genital tract development

Author: Jean Lévêque, Daniel Guerrier, Karine Morcel, Stéphane Deschamps, Isabelle Pellerin, Francis Omilli, Tanguy Watrin, Frédérique Jaffre, Service de Gynécologie et Obstétrique [Rennes] = Gynaecology [Rennes], CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), 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 ), and Le Corre, Morgane
Subjects: Candidate gene, 46, XX Disorders of Sex Development, Mouse, Uterus, [SDV.GEN] Life Sciences [q-bio]/Genetics, Kidney, Mice, 0302 clinical medicine, MESH: Reverse Transcriptase Polymerase Chain Reaction, Mayer-Rokitansky-Kuster-Hauser Syndrome, MESH: Animals, Mullerian Ducts, In Situ Hybridization, ComputingMilieux_MISCELLANEOUS, 030219 obstetrics & reproductive medicine, Reverse Transcriptase Polymerase Chain Reaction, Aplasia, Genitalia, Female, Extracellular matrix, MESH: Proteinase Inhibitory Proteins, Secretory, medicine.anatomical_structure, Somites, 030220 oncology & carcinogenesis, Vagina, MESH: Uterus, Female, MESH: Spine, MESH: Mullerian Ducts, Gene isoform, medicine.medical_specialty, MESH: Abnormalities, Multiple, Blotting, Western, Proteinase Inhibitory Proteins, Secretory, Biology, Article, Congenital Abnormalities, MRKH syndrome, Andrology, MESH: Somites, 03 medical and health sciences, MESH: In Situ Hybridization, Internal medicine, Genetics, medicine, Gene family, Animals, ITIH5, MESH: Blotting, Western, Abnormalities, Multiple, Molecular Biology, Gene, MESH: Mice, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Kidney, medicine.disease, Spine, Disease Models, Animal, Endocrinology, MESH: Vagina, Congenital uterovaginal aplasia, MESH: Disease Models, Animal, MESH: Genitalia, Female, MESH: Female
Abstract: The ITI (inter-trypsine inhibitor) gene family includes five genes (ITIH1 to ITIH5) that encode proteins involved in the dynamics of the extracellular matrix (ECM). ITIH5 was found inactivated by partial deletion in a case of congenital uterovaginal aplasia, a human rare disease also called Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome. The aim of the present study was to analyze the expression of ITIH5 in the uterus in adult life and during embryogenesis in order to establish the involvement of this gene in both normal and pathological conditions of uterus development. This was achieved in mice by reverse transcription-quantitative PCR, whole-mount hybridization, and Western blot analysis. Itih5 expression was much stronger in female genital tract primordia (Mullerian ducts) and derivatives than elsewhere in the body. This gene was strongly expressed during pregnancy and development of the female genital tract, indicating that the encoded protein probably had an important function in the uterus during these periods. Two different specific isoforms of the protein were detected in Mullerian derivatives during embryogenesis and in adults. Although ITIH genes are expected to be predominantly expressed in the liver, ITIH5 is mainly expressed in the uterus during development and adult life. This tends to indicate an additional and specific role of this gene in the female reproductive tract, and furthermore reinforces ITIH5 as a putative candidate gene for MRKH syndrome.
Published: 2012

10. Diagnosis of fetal urinary tract malformations: prenatal management and postnatal outcome

Author: Ryckewaert-D'Halluin, Amélie, Le Bouar, Gwenaelle, Odent, Sylvie, Milon, Joëlle, D'Hervé, Dominique, Lucas, Josette, Rouget, Florence, Loget, Philippe, Poulain, Patrice, Le Gall, Edouard, Taque, Sophie, Service de médecine de l'enfant et de l'adolescent [CHU Rennes], CHU Pontchaillou [Rennes], Service de Gynécologie et Obstétrique [Rennes] = Gynaecology [Rennes], Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Clinique mutualiste La Sagesse, Service de Cytogénétique et de Biologie Cellulaire, Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], De Villemeur, Hervé, Service de médecine de l'enfant et de l'adolescent, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Service de Génétique Clinique, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-hôpital Sud, and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes]
Subjects: Adult, Male, MESH: Abnormalities, Multiple, Abnormal Karyotype, MESH: Amniotic Fluid, Gestational Age, MESH: Prognosis, prenatal renal function, MESH: Pregnancy, Pregnancy, MESH: Gestational Age, Prenatal Diagnosis, [SDV.BDD] Life Sciences [q-bio]/Development Biology, MESH: Urinary Tract, Humans, Abnormalities, Multiple, MESH: Prenatal Diagnosis, Urinary Tract, fetal prognosis, MESH: Prenatal Care, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Retrospective Studies, Ultrasonography, MESH: Humans, MESH: Child, Preschool, Pregnancy Outcome, MESH: Retrospective Studies, MESH: Adult, Prenatal Care, MESH: Pregnancy Outcome, Amniotic Fluid, Prognosis, MESH: Male, Fetal Diseases, MESH: Fetal Diseases, Child, Preschool, Female, MESH: Abnormal Karyotype, fetal urinary tract malformations, MESH: Female
Abstract: International audience; OBJECTIVE: To evaluate prenatal management and to define the criteria of gravity for accurate assessment of the renal and overall prognosis of fetuses presenting malformations of the urinary tract. METHODS: We carried out a retrospective study of 127 cases of urinary tract malformation. We carried out descriptive statistical and univariate analyses as a function of severity criteria and the outcome of pregnancy. RESULTS: One-third of fetuses presented associated extrarenal malformations and 10% of the karyotypes were abnormal. There were more abortions in case of decrease in amniotic fluid volume (p < 0.001), extent of renal damage (p < 0.05), presence of associated extrarenal malformations (p < 0.05), early diagnosis of the malformation (p < 0.001) and presence of chromosomal syndrome (p = 0.01). In our study, there was an excellent correlation between prenatal data and pathological findings for the fetus following abortions for medical reasons or obtained during the surveillance of live-born children. Fetal biochemistry made very little contribution. CONCLUSION: In cases of urinary tract malformation, this work confirms the need for regular and frequent ultrasound scans, checking for the echographic factors indicative of gravity and for adapted karyotyping. It also demonstrates that pluridisciplinary management is necessary for the prenatal evaluation of renal and overall fetal prognosis.
Published: 2011

11. Utero-vaginal aplasia (Mayer-Rokitansky-Küster-Hauser syndrome) associated with deletions in known DiGeorge or DiGeorge-like loci

Author: Karine Morcel, Tanguy Watrin, Véronique David, Cédric Le Caignec, Lucie Rochard, Claude Bendavid, Bernard-Jean Paniel, Isabelle Pellerin, Christèle Dubourg, Daniel Guerrier, Sylvie Odent, Laurent Pasquier, Philippe Loget, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Service de Gynécologie et Obstétrique [Rennes] = Gynaecology [Rennes], CHU Pontchaillou [Rennes], Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Service de Génétique Médicale, Institut du thorax, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de génétique moléculaire et génomique médicale [CHU Rennes], Service de pathologie, hôpital Sud, Service de Gynécologie-Obstétrique, CHI Créteil, This work was supported by the CNRS and by grants from 'Rennes Métropole', 'Conseil Régional de Bretagne', and 'La Fondation Langlois'. D. Guerrier is a permanent researcher at the 'Institut National de la Recherche Médicale (INSERM)'., Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Clinique, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-hôpital Sud, Laboratoire de Génétique Moléculaire et Hormonologie, Hôpital Pontchaillou, and De Villemeur, Hervé
Subjects: Proband, 46, XX Disorders of Sex Development, lcsh:Medicine, [SDV.GEN] Life Sciences [q-bio]/Genetics, Kidney, MESH: Aborted Fetus, Cohort Studies, MURCS association, MESH: Pregnancy, Pregnancy, DiGeorge syndrome, Genetics(clinical), Pharmacology (medical), Mayer-Rokitansky-Kuster-Hauser Syndrome, Mullerian Ducts, MESH: Cohort Studies, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Genetics (clinical), Oligonucleotide Array Sequence Analysis, Sequence Deletion, Medicine(all), Genetics, 0303 health sciences, MESH: 46, XX Disorders of Sex Development, 030305 genetics & heredity, MESH: DNA, Karyotype, General Medicine, Aplasia, MESH: Sequence Deletion, 3. Good health, Somites, MESH: Young Adult, Aborted Fetus, Vagina, MESH: Uterus, Female, MESH: Abnormalities, Multiple, Genetic counseling, Biology, Congenital Abnormalities, Young Adult, 03 medical and health sciences, [SDV.BDD] Life Sciences [q-bio]/Development Biology, DiGeorge Syndrome, medicine, Humans, MESH: Chromosome Aberrations, Abnormalities, Multiple, Multiplex ligation-dependent probe amplification, 030304 developmental biology, Chromosome Aberrations, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: DiGeorge Syndrome, Research, Uterus, lcsh:R, DNA, medicine.disease, Spine, MESH: Vagina, MESH: Oligonucleotide Array Sequence Analysis, MESH: Female
Abstract: Background Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is characterized by congenital aplasia of the uterus and the upper part of the vagina in women showing normal development of secondary sexual characteristics and a normal 46, XX karyotype. The uterovaginal aplasia is either isolated (type I) or more frequently associated with other malformations (type II or Müllerian Renal Cervico-thoracic Somite (MURCS) association), some of which belong to the malformation spectrum of DiGeorge phenotype (DGS). Its etiology remains poorly understood. Thus the phenotypic manifestations of MRKH and DGS overlap suggesting a possible genetic link. This would potentially have clinical consequences. Methods We searched DiGeorge critical chromosomal regions for chromosomal anomalies in a cohort of 57 subjects with uterovaginal aplasia (55 women and 2 aborted fetuses). For this candidate locus approach, we used a multiplex ligation-dependent probe amplification (MLPA) assay based on a kit designed for investigation of the chromosomal regions known to be involved in DGS. The deletions detected were validated by Duplex PCR/liquid chromatography (DP/LC) and/or array-CGH analysis. Results We found deletions in four probands within the four chromosomal loci 4q34-qter, 8p23.1, 10p14 and 22q11.2 implicated in almost all cases of DGS syndrome. Conclusion Uterovaginal aplasia appears to be an additional feature of the broad spectrum of the DGS phenotype. The DiGeorge critical chromosomal regions may be candidate loci for a subset of MRKH syndrome (MURCS association) individuals. However, the genes mapping at the sites of these deletions involved in uterovaginal anomalies remain to be determined. These findings have consequences for clinical investigations, the care of patients and their relatives, and genetic counseling.
Published: 2011

12. Microdeletion at chromosome 4q21 defines a new emerging syndrome with marked growth restriction, mental retardation and absent or severely delayed speech

Author: Bonnet, F., Andrieux, A, Béri-Dexheimer, D, Leheup, L, Boute, B, Manouvrier, M, Delobel, D, Copin, C., Receveur, A., Mathieu, M., Thiriez, G., Le Caignec, L, David, D, de Blois, M, Malan, M, Philippe, P., Cormier-Daire, D, Colleaux, Laurence, Flori, F, Dollfus, D, Pelletier, P, Thauvin-Robinet, C., Masurel-Paulet, P, Faivre, F, Tardieu, M., Bahi-Buisson, N., Callier, P., Mugneret, F., Edery, P., Jonveaux, P., Sanlaville, D., Andrieux, J., Beri-Dexheimer, M., Leheup, B., Boute, O., Manouvrier, S., Delobel, B., Copin, H., Le Caignec, C., David, A., de Blois, C., Malan, V., Philippe, A., Cormier-Daire, V., Flori, E., Dollfus, H., Pelletier, V., Masurel-Paulet, A., Faivre, L., CHU Bordeaux [Bordeaux], UMR 1011, Institut National de la Santé et de la Recherche Médicale (INSERM), Ouvrages hydrauliques et hydrologie (UR OHAX), Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA), 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 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), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Laboratoire de cytogénétique (CHU de Dijon), 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 [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Génétique Clinique, Hôpital Femme Mère Enfant, Centre Hospitalier Universitaire de Lyon, Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy], Service de Génétique clinique, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Clinique de Génétique médicale Guy Fontaine [CHRU LIlle], Laboratoire Histologie Embryologie Cytogénétique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF)-Centre National de la Recherche Scientifique (CNRS), Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Aix Marseille Université (AMU)-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), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), and 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)
Subjects: Male, Microarray, Chromosome Disorders, 0302 clinical medicine, MESH: Child, MESH: Syndrome, MESH: In Situ Hybridization, Fluorescence, Child, Genetics (clinical), Growth Disorders, In Situ Hybridization, Fluorescence, Genetics, 0303 health sciences, Comparative Genomic Hybridization, MESH: Chromosome Disorders, Syndrome, Microdeletion syndrome, MESH: Growth Disorders, Phenotype, MESH: Infant, 3. Good health, MESH: Young Adult, Child, Preschool, Female, Chromosome Deletion, Chromosomes, Human, Pair 4, Haploinsufficiency, MESH: Chromosomes, Human, Pair 4, MESH: Abnormalities, Multiple, Adolescent, MESH: Chromosome Deletion, Biology, MESH: Language Development Disorders, MESH: Intellectual Disability, 03 medical and health sciences, Young Adult, Gene mapping, Intellectual Disability, medicine, Humans, Abnormalities, Multiple, Language Development Disorders, Genetically modified animal, 030304 developmental biology, MESH: Adolescent, MESH: Humans, MESH: Child, Preschool, Infant, medicine.disease, MESH: Male, Developmental disorder, MESH: Comparative Genomic Hybridization, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Female, 030217 neurology & neurosurgery, Comparative genomic hybridization
Abstract: International audience; BACKGROUND Genome-wide screening of large patient cohorts with mental retardation using microarray-based comparative genomic hybridisation (array-CGH) has recently led to identification several novel microdeletion and microduplication syndromes. METHODS Owing to the national array-CGH network funded by the French Ministry of Health, shared information about patients with rare disease helped to define critical intervals and evaluate their gene content, and finally determine the phenotypic consequences of genomic array findings. RESULTS In this study, nine unrelated patients with overlapping de novo interstitial microdeletions involving 4q21 are reported. Several major features are common to all patients, including neonatal muscular hypotonia, severe psychomotor retardation, marked progressive growth restriction, distinctive facial features and absent or severely delayed speech. The boundaries and the sizes of the nine deletions are different, but an overlapping region of 1.37 Mb is defined; this region contains five RefSeq genes: PRKG2, RASGEF1B, HNRNPD, HNRPDL and ENOPH1. DISCUSSION Adding new individuals with similar clinical features and 4q21 deletion allowed us to reduce the critical genomic region encompassing two genes, PRKG2 and RASGEF1B. PRKG2 encodes cGMP-dependent protein kinase type II, which is expressed in brain and in cartilage. Information from genetically modified animal models is pertinent to the clinical phenotype. RASGEF1B is a guanine nucleotide exchange factor for Ras family proteins, and several members have been reported as key regulators of actin and microtubule dynamics during both dendrite and spine structural plasticity. CONCLUSION Clinical and molecular delineation of 4q21 deletion supports a novel microdeletion syndrome and suggests a major contribution of PRKG2 and RASGEF1B haploinsufficiency to the core phenotype.
Published: 2010

13. Distinct effects of allelic NFIX mutations on nonsense-mediated mRNA decay engender either a sotos-like or a Marshall-Smith syndrome

Author: MALAN, Valérie, Rajan, Diana, Thomas, Sophie, Shaw, Adam, Louis dit Picard, Hélène, Layet, Valérie, Till, Marianne, Van Haeringen, Arie, Mortier, Geert, Nampoothiri, Sheela, Puseljić, Silvija, Legeai-Mallet, Laurence, Carter, Nigel, Vekemans, Michel, Munnich, Arnold, Hennekam, Raoul, Colleaux, Laurence, Cormier-Daire, Valérie, Pušeljić, Silvija, 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), Unité de Cytogénétique et Génétique Médicale, Groupe Hospitalier du Havre-Hôpital Gustave Flaubert, Service de cytogénétique constitutionnelle, Hospices Civils de Lyon (HCL)-CHU de Lyon-Centre Neuroscience et Recherche, Department of Clinical Genetics, Leiden University Medical Centre, Department of Medical Genetics, Antwerp University Hospital [Edegem] (UZA), Amrita Institute of Medical Sciences and Research Center, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Clinical Genetics, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), Imagine - Institut des maladies génétiques (IMAGINE - U1163), CHU Cochin [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, and Paediatrics
Subjects: Male, Candidate gene, MESH: Chromosomes, Human, Pair 19, RNA Stability, Nonsense-mediated decay, DNA Mutational Analysis, MESH: Base Sequence, MESH: NFI Transcription Factors, Marshall–Smith syndrome, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH: Child, Genetics(clinical), MESH: Syndrome, MESH: Codon, Nonsense, MESH: DNA Mutational Analysis, Child, Genetics (clinical), In Situ Hybridization, Genetics, 0303 health sciences, Comparative Genomic Hybridization, biology, MESH: Genetic Testing, Reverse Transcriptase Polymerase Chain Reaction, 030305 genetics & heredity, MESH: RNA Stability, Syndrome, NFIX, MESH: Gene Expression Regulation, 3. Good health, Codon, Nonsense, Female, medicine.symptom, Adult, MESH: Abnormalities, Multiple, MESH: Mutation, Adolescent, Nonsense mutation, Molecular Sequence Data, Article, Frameshift mutation, 03 medical and health sciences, MESH: In Situ Hybridization, medicine, Humans, Abnormalities, Multiple, Genetic Testing, RNA, Messenger, Alleles, 030304 developmental biology, MESH: RNA, Messenger, MESH: Adolescent, MESH: Humans, MESH: Molecular Sequence Data, Base Sequence, MESH: Alleles, Macrocephaly, MESH: Adult, medicine.disease, MESH: Male, MESH: Comparative Genomic Hybridization, NFI Transcription Factors, Gene Expression Regulation, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Overgrowth syndrome, Mutation, biology.protein, Human medicine, Chromosomes, Human, Pair 19, MESH: Female
Abstract: International audience; By using a combination of array comparative genomic hybridization and a candidate gene approach, we identified nuclear factor I/X (NFIX) deletions or nonsense mutation in three sporadic cases of a Sotos-like overgrowth syndrome with advanced bone age, macrocephaly, developmental delay, scoliosis, and unusual facies. Unlike the aforementioned human syndrome, Nfix-deficient mice are unable to gain weight and die in the first 3 postnatal weeks, while they also present with a spinal deformation and decreased bone mineralization. These features prompted us to consider NFIX as a candidate gene for Marshall-Smith syndrome (MSS), a severe malformation syndrome characterized by failure to thrive, respiratory insufficiency, accelerated osseous maturation, kyphoscoliosis, osteopenia, and unusual facies. Distinct frameshift and splice NFIX mutations that escaped nonsense-mediated mRNA decay (NMD) were identified in nine MSS subjects. NFIX belongs to the Nuclear factor one (NFI) family of transcription factors, but its specific function is presently unknown. We demonstrate that NFIX is normally expressed prenatally during human brain development and skeletogenesis. These findings demonstrate that allelic NFIX mutations trigger distinct phenotypes, depending specifically on their impact on NMD.
Published: 2010

14. Phenotypic spectrum of STRA6 mutations: from Matthew-Wood syndrome to non-lethal anophthalmia

Author: Nicolas, Chassaing, Christelle, Golzio, Sylvie, Odent, Léopoldine, Lequeux, Adeline, Vigouroux, Jelena, Martinovic-Bouriel, Francesco Danilo, Tiziano, Lucia, Masini, Francesca, Piro, Giovanna, Maragliano, Anne-Lise, Delezoide, Tania, Attié-Bitach, Sylvie, Manouvrier-Hanu, Heather C, Etchevers, Patrick, Calvas, Service de génétique médicale, CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), IFR Necker-Enfants Malades (IRNEM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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 clinique, hôpital Sud, Institut de Génétique et Développement de Rennes (IGDR), Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Institute of Medical Genetics, Università cattolica del Sacro Cuore [Milano] (Unicatt), Institute of Obstetrics and Gynecology, Operative Unit of Pathology, San Giovanni Ospedale, Complex Unit of Neonatology, Service de Biologie du Développement, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Laboratoire de Génétique Clinique, Hôpital Jeanne de Flandre [Lille]-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), De Villemeur, Hervé, Service Génétique Médicale [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Physiopathologie Toulouse Purpan (ex IFR 30 et IFR 150), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR30-IFR150-Institut National de la Santé et de la Recherche Médicale ( INSERM ), IFR Necker-Enfants Malades ( IRNEM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), 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 ), Hôpital Sud, Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140-Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Università Cattolica del Sacro Cuore, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré, and Hôpital Jeanne de Flandre [Lille]-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille )
Subjects: Male, MESH: Fatal Outcome, MESH : Molecular Sequence Data, MESH: Anophthalmos, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Amino Acid Sequence, Settore MED/03 - GENETICA MEDICA, MESH : Syndrome, Fatal Outcome, MESH : Female, MESH: Syndrome, [SDV.BDD]Life Sciences [q-bio]/Development Biology, MESH : Sequence Alignment, MESH : Amino Acid Sequence, MESH : Infant, Syndrome, MESH : Adult, MESH: Infant, MESH : Phenotype, Phenotype, Female, MESH: Membrane Proteins, MESH : Mutation, Adult, MESH: Abnormalities, Multiple, MESH: Mutation, stra6, MESH : Male, Molecular Sequence Data, MESH: Sequence Alignment, MESH: Phenotype, [SDV.BDD] Life Sciences [q-bio]/Development Biology, Humans, Abnormalities, Multiple, Amino Acid Sequence, [ SDV.BDD ] Life Sciences [q-bio]/Development Biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Molecular Sequence Data, MESH: Humans, MESH : Abnormalities, Multiple, MESH : Humans, MESH : Anophthalmos, Anophthalmos, Infant, Membrane Proteins, MESH: Adult, MESH: Male, MESH : Fatal Outcome, MESH : Membrane Proteins, Mutation, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Sequence Alignment, MESH: Female
Abstract: International audience; Matthew-Wood, Spear, PDAC or MCOPS9 syndrome are alternative names used to refer to combinations of microphthalmia/anophthalmia, malformative cardiac defects, pulmonary dysgenesis, and diaphragmatic hernia. Recently, mutations in STRA6, encoding a membrane receptor for vitamin A-bearing plasma retinol binding protein, have been identified in such patients. We performed STRA6 molecular analysis in three fetuses and one child diagnosed with Matthew-Wood syndrome and in three siblings where two adult living brothers are affected with combinations of clinical anophthalmia, tetralogy of Fallot, and mental retardation. Among these patients, six novel mutations were identified, bringing the current total of known STRA6 mutations to seventeen. We extensively reviewed clinical data pertaining to all twenty-one reported patients with STRA6 mutations (the seven of this report and fourteen described elsewhere) and discuss additional features that may be part of the syndrome. The clinical spectrum associated with STRA6 deficiency is even more variable than initially described.
Published: 2009

15. Rhombencephalosynapsis and related anomalies: a neuropathological study of 40 fetal cases

Author: Pascale Marcorelles, Annie Laquerrière, Céline de la Rochebrochard, Dominique Carles, Laurent Pasquier, Véronique David, Mathilde Ferry, Marie-Josée Perez, Fanny Pelluard, Claude Bendavid, Sylvie Odent, Philippe Loget, Service de génétique clinique, hôpital Sud, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Service d'Anatomie Pathologique, Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], CHU Pontchaillou [Rennes], Laboratoire d'anatomie pathologique, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Laboratoire de pathologie, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service de biologie moléculaire, Hôpital Pontchaillou, Service de radiologie et imagerie médicale [Rennes] = Radiology [Rennes], Endothélium microcirculatoire cérébral et lésions du système nerveux central au cours du développement (Néovasc), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie et Cytologie Pathologique [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-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), and De Villemeur, Hervé
Subjects: Male, Pathology, [SDV.GEN] Life Sciences [q-bio]/Genetics, Cerebral Ventricles, 030218 nuclear medicine & medical imaging, Craniofacial Abnormalities, 0302 clinical medicine, Holoprosencephaly, Cerebellum, MESH: Craniofacial Abnormalities, MESH: Syndrome, Agenesis of the corpus callosum, [SDV.BDD]Life Sciences [q-bio]/Development Biology, MESH: Hydrocephalus, Brain, Syndrome, Lobar holoprosencephaly, Anatomy, Immunohistochemistry, 3. Good health, medicine.anatomical_structure, Agenesis, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Abnormality, Hydrocephalus, medicine.medical_specialty, MESH: Abnormalities, Multiple, Clinical Neurology, Biology, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, MESH: Brain, Fetus, [SDV.BDD] Life Sciences [q-bio]/Development Biology, medicine, Humans, Abnormalities, Multiple, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.GEN]Life Sciences [q-bio]/Genetics, Third ventricle, MESH: Humans, MESH: Fetus, MESH: Immunohistochemistry, medicine.disease, MESH: Male, MESH: Cerebellum, MESH: Cerebral Ventricles, Neurology (clinical), MESH: Female, 030217 neurology & neurosurgery, Ventriculomegaly
Abstract: International audience; Rhombencephalosynapsis is an uncommon cerebellar malformation defined by vermian agenesis with fusion of the hemispheres and of the dentate nuclei. Embryologic and genetic mechanisms are still unknown, and to date, no animal models are available. Ultrasound diagnosis is generally suspected after 22 weeks of gestation, and usually the abnormality is suggested by ventriculomegaly. Morphological analysis of 40 fetuses after medical termination of pregnancy allowed us to confirm that rhombencephalosynapsis was always associated with other brain abnormalities or malformations: Purkinje cell heterotopias, fusion of colliculi, forking and/or atresia of the aqueduct and of the third ventricle resulting in a fusion of the thalami, agenesis of the corpus callosum, lobar holoprosencephaly and neural tube defects. Pons and medulla were very infrequently abnormal. Furthermore, complete autopsy made it possible to separate either pure neurologic phenotypes, or associated with extraneural anomalies from syndromic forms: Gomez-Lopez-Hernandez syndrome (1 case) and VACTERL-H syndrome (6 cases). The number of our fetal cases strongly suggests that VACTERL-H association related with rhombencephalosynapsis emerges as a non-random association. Furthermore, recurrence and consanguinity were noted in two different families, which argue for a sporadic or inherited cause. From our results, it could be suggested that rhombencephalosynapsis may be due to defective genes regulating formation of the roof plate and the development of midline cerebellar primordium at the junction of the mesencephalon and of the first rhombomere.
Published: 2009

16. Identification of 23 TGFBR2 and 6 TGFBR1 gene mutations and genotype-phenotype investigations in 457 patients with Marfan syndrome type I and II, Loeys-Dietz syndrome and related disorders

Author: Clarisse Baumann, Henri Plauchu, Didier Lacombe, Valérie Cormier-Daire, Marc Sznajder, Guillaume Jondeau, Stanislas Lyonnet, Chantal Stheneur, Bertrand Moura, Catherine Boileau, Mireille Claustres, Gwenaëlle Collod-Béroud, Christine Muti, Bertrand Chevallier, Claudine Junien, Marlène Rio, David Attias, Laurence Faivre, Laurent Gouya, Gilles Sultan, Jean-Marie Le Parc, Service de pédiatrie, urgences enfants, Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, Consultation Marfan, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bichat, Physiologie Cellulaire des Regulations Hormonales, Nutritionnelles et Pharmacologiques, Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques, Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques ( CIC-EC ), Université de Bourgogne ( UB ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), 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 biochimie, d'hormonologie et de génétique moléculaire, UFR Paris-Ile-de-France-Ouest, Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ), Interactions de l'épithelium intestinal avec le système immunitaire, Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service d'ophtalmologie, Service de Rhumatologie, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Département de Génétique Médicale, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré, Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP)-Hopital Necker-Enfants Malades, Service de Génétique, Hôtel Dieu, Service de génétique médicale, Université de Bordeaux ( UB ) -CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service de cardiologie, Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ), Hémostase, bio-ingénierie et remodelage cardiovasculaires ( LBPC ), Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris 13 ( UP13 ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Galilée, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ) - Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Ambroise Paré, Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Bichat, 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 Montpellier 1 (UM1) - IFR3 - Institut National de la Santé et de la Recherche Médicale (INSERM) - Université de Montpellier (UM), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB) - Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon) - Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Ambroise Paré, Laboratoire de Génétique Moléculaire, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier) - Hôpital Arnaud de Villeneuve, Handicaps génétiques de l'enfant, Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Robert Debré, Assistance publique - Hôpitaux de Paris (AP-HP) - Hopital Necker-Enfants Malades, Université de Bordeaux (UB) - CHU Bordeaux [Bordeaux] - Groupe hospitalier Pellegrin, Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Bichat - Claude Bernard [Paris] - Université Paris Diderot - Paris 7 (UPD7), Hémostase, bio-ingénierie et remodelage cardiovasculaires (LBPC), Université Paris 13 (UP13) - Université Paris Diderot - Paris 7 (UPD7) - Université Sorbonne Paris Cité (USPC) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Institut Galilée, Service de pédiatrie, urgences enfants [CHU Ambroise-Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bichat, Pharmacologie, toxicologie et signalisation cellulaire (U747), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de biochimie, d'hormonologie et de génétique moléculaire [CHU Amrboise Paré], Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'ophtalmologie [CHU Ambroise Paré], Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7)-Université Paris 13 (UP13)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Galilée, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), COLLOD-BEROUD, Gwenaëlle, Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut Galilée-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, Proband, Marfan syndrome, Pathology, MESH : Receptors, Transforming Growth Factor beta, MESH : Polymorphism, Genetic, DNA Mutational Analysis, Receptor, Transforming Growth Factor-beta Type I, MESH : Genotype, [SDV.GEN] Life Sciences [q-bio]/Genetics, 030204 cardiovascular system & hematology, Gene mutation, MESH : Child, Preschool, Loeys–Dietz syndrome, MESH : Syndrome, MESH: Genotype, Aortic aneurysm, 0302 clinical medicine, MESH : Child, MESH: Child, Genotype, MESH: Syndrome, MESH : Female, MESH: DNA Mutational Analysis, Child, Genetics (clinical), TGFBR1, TAAD, 0303 health sciences, MESH: Middle Aged, MESH : Aortic Aneurysm, Thoracic, MESH: Infant, Newborn, MESH : Infant, Syndrome, Middle Aged, MESH : Adult, Phenotype, MESH: Infant, MESH: Amino Acid Substitution, 3. Good health, TGFBR2, genotype-phenotype, MESH : Phenotype, Child, Preschool, MESH: Aortic Aneurysm, Thoracic, Female, MESH: Receptors, Transforming Growth Factor beta, MESH : Mutation, Adult, MESH : Protein-Serine-Threonine Kinases, medicine.medical_specialty, MESH: Abnormalities, Multiple, MESH: Mutation, Adolescent, MESH : Male, MESH : DNA Mutational Analysis, Protein Serine-Threonine Kinases, Biology, MESH: Phenotype, MESH : Infant, Newborn, MESH: Protein-Serine-Threonine Kinases, MESH: Marfan Syndrome, 03 medical and health sciences, MESH : Amino Acid Substitution, MESH : Adolescent, MESH: Polymorphism, Genetic, Genetics, medicine, Humans, Abnormalities, Multiple, MESH : Middle Aged, Gene, 030304 developmental biology, MESH: Adolescent, [SDV.GEN]Life Sciences [q-bio]/Genetics, Loeys-Dietz Syndrome, Polymorphism, Genetic, MESH: Humans, MESH : Marfan Syndrome, Aortic Aneurysm, Thoracic, MESH : Abnormalities, Multiple, MESH: Child, Preschool, MESH : Humans, Infant, Newborn, Receptor, Transforming Growth Factor-beta Type II, Infant, MESH: Adult, medicine.disease, MESH: Male, Amino Acid Substitution, Mutation, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Receptors, Transforming Growth Factor beta, MESH: Female
Abstract: International audience; TGFBR1 and TGFBR2 gene mutations have been associated with Marfan syndrome types 1 and 2, Loeys-Dietz syndrome and isolated familial thoracic aortic aneurysms or dissection. In order to investigate the molecular and clinical spectrum of TGFBR2 mutations we screened the gene in 457 probands suspected of being affected with Marfan syndrome or related disorders that had been referred to our laboratory for molecular diagnosis. We identified and report 23 mutations and 20 polymorphisms. Subsequently, we screened the TGFBR1 gene in the first 74 patients for whom no defect had been found, and identified 6 novel mutations and 12 polymorphisms. Mutation-carrying probands displayed at referral a large clinical spectrum ranging from the Loeys-Dietz syndrome and neonatal Marfan syndrome to isolated aortic aneurysm. Furthermore, a TGFBR1 gene mutation was found in a Shprintzen-Goldberg syndrome patient. Finally, we observed that the yield of mutation detection within the two genes was very low : 4.8% for classical MFS, 4.6% for incomplete MFS and 1% for TAAD in the TGFBR2 gene; 6.2%, 6.2% and 7% respectively in the TGFBR1 gene; in contrast to LDS, where the yield was exceptionally high (87.5%).
Published: 2008

17. TCF4 deletions in Pitt-Hopkins Syndrome

Author: Jacqueline Arfi, Julia Rankin, Michel Goossens, Gilles Morin, Laurent Villard, Anne Moncla, Pierre Sarda, Chantal Missirian, Tessa Fredriksen, Jean Claude Lambert, Brigitte Chabrol, Thierry Gaillon, Michèle Mathieu-Dramard, Dominique Martin-Coignard, Irina Giurgea, Nicole Philip, Fabienne Giuliano, Sandra Whalen, Christèle Dubourg, Pierre Cacciagli, Institut Mondor de recherche biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), 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), Department of Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Service de génétique médicale, CHU Amiens-Picardie, Service de génétique, Centre Hospitalier Le Mans (CH Le Mans), Service de biologie moléculaire, Hôpital Pontchaillou, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Service de pédiatrie et neurologie pédiatrique, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Hôpital l'Archet, Unité de Génétique Médicale et Foetopathologie, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, De Villemeur, Hervé, Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Developmental Disabilities, DNA Mutational Analysis, Pitt–Hopkins syndrome, MESH: Codon, Terminator, Gene mutation, MESH: Hyperventilation, MESH: Mental Retardation, MESH: Child, Hyperventilation, MESH: Syndrome, MESH: DNA Mutational Analysis, Child, Genetics (clinical), Sequence Deletion, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], Genetics, Comparative Genomic Hybridization, 0303 health sciences, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 030305 genetics & heredity, Syndrome, MESH: Sequence Deletion, Phenotype, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Stop codon, 3. Good health, Child, Preschool, Codon, Terminator, Female, TCF Transcription Factors, Haploinsufficiency, Transcription Factor 7-Like 2 Protein, MESH: Abnormalities, Multiple, MESH: Mutation, Adolescent, Locus (genetics), Biology, MESH: Phenotype, 03 medical and health sciences, Intellectual Disability, medicine, Humans, Abnormalities, Multiple, Gene, 030304 developmental biology, MESH: Adolescent, MESH: Humans, Point mutation, MESH: Child, Preschool, medicine.disease, Molecular biology, MESH: Male, MESH: Comparative Genomic Hybridization, MESH: Karyotyping, MESH: Developmental Disabilities, Karyotyping, Mutation, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Chromosomes, Human, Pair 18, MESH: Chromosomes, Human, Pair 18, MESH: Female, MESH: TCF Transcription Factors
Abstract: International audience; Pitt-Hopkins syndrome (PHS) is a probably underdiagnosed, syndromic mental retardation disorder, marked by hyperventilation episodes and characteristic dysmorphism (large beaked nose, wide mouth, fleshy lips, and clubbed fingertips). PHS was shown to be caused by de novo heterozygous mutations of the TCF4 gene, located in 18q21. We selected for this study 30 unrelated patients whose phenotype overlapped PHS but which had been initially addressed for Angelman, Mowat-Wilson, or Rett syndromes. In 10 patients we identified nine novel mutations (four large cryptic deletions, including one in mosaic, and five small deletions), and a recurrent one. So far, a total of 20 different TCF4 gene mutations have been reported, most of which either consist in deletion of significant portions of the TCF4 coding sequence, or generate premature stop codons. No obvious departure was observed between the patients harboring point mutations and large deletions at the 18q21 locus, further supporting TCF4 haploinsufficiency as the molecular mechanism underling PHS. In this report, we also further specify the phenotypic spectrum of PHS, enlarged to behavior, with aim to increase the rate and specificity of PHS diagnosis.
Published: 2008

18. Le syndrome de Mayer-Rokitansky-Küster-Hauser (MRKH) : clinique et génétique [The Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: clinical description and genetics]

Author: Morcel, Karine, Guerrier, Daniel, Watrin, Tanguy, Pellerin, Isabelle, Levêque, Jean, Service de Gynécologie et Obstétrique [Rennes] = Gynaecology [Rennes], CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), and De Villemeur, Hervé
Subjects: [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, MESH: Abnormalities, Multiple, MESH: Amenorrhea, MESH: Humans, MESH: DiGeorge Syndrome, MESH: Phenotype, MESH: Magnetic Resonance Imaging, MESH: France, MESH: Genetic Screening, MESH: Vagina, MESH: Diagnosis, Differential, [SDV.BDD] Life Sciences [q-bio]/Development Biology, MESH: Uterus, MESH: Syndrome, MESH: Incidence, MESH: Female, [SDV.BDD]Life Sciences [q-bio]/Development Biology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; The Mayer-Rokitansky-K?r-Hauser (MRKH) syndrome is characterized by congenital aplasia of the uterus and the upper part (two-third) of the vagina. It may be isolated (type I) or associated with other malformations (type II or MURCS association). These latter involve the upper urinary tract, the skeleton and, to a lesser extent, the otologic sphere or the heart. The incidence of MRKH syndrome has been estimated as 1 in 4500 women. The prime feature is a primary amenorrhea in women presenting otherwise with normal development of secondary sexual characteristics and normal external genitalia. However, the vagina is reduced to a vaginal dimple with variable depth. The ovaries are normal and functional as well as the endocrine status. Karyotype is 46,XX, with no visible chromosome modification. The phenotypic manifestations of MRKH syndrome overlap with various other syndromes or malformations and thus require accurate delineation as well as differential diagnosis. For a long time, the syndrome has been considered as a sporadic anomaly, but increasing familial cases now support the hypothesis of a genetic cause currently under investigation. The syndrome appears to be transmitted as an autosomal dominant trait with incomplete penetrance and variable expressivity.
Published: 2008

19. [Changes in prenatal ultrasound practices after the Perruche decision and Law no. 2002-303 dated 4 March 2002]

Author: Léticée , Nadia, Moutard , Marie-Laure, Moutel , Grégoire, Ville , Yves, Centre de diagnostic prénatal et de médecine fœtale, Institut de Puériculture et de Périnatalogie, Service de neuropédiatrie, GHU Ouest, Laboratoire d'éthique médicale et médecine légale (LEM), Université Paris Descartes - Paris 5 (UPD5), Service de gynécologie et obstétrique [CHI Poissy-Saint Germain], CHI Poissy-Saint-Germain, Duchange, Nathalie, Laboratoire d'éthique médicale et médecine légale ( LEM ), Université Paris Descartes - Paris 5 ( UPD5 ), and Service de gynécologie et obstétrique [Poissy - Saint-Germain-en-Laye]]
Subjects: Male, Legislation, Medical, MESH: Abnormalities, Multiple, MESH : Male, Wrongful Life, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Ultrasonography, Prenatal, MESH: Wrongful Life, MESH : Physician's Practice Patterns, MESH: Pregnancy, Pregnancy, Surveys and Questionnaires, Humans, MESH : Female, Abnormalities, Multiple, Practice Patterns, Physicians', MESH : France, MESH: Physician's Practice Patterns, [ SDV.MHEP.GEO ] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Physician-Patient Relations, MESH: Humans, MESH : Abnormalities, Multiple, MESH: Questionnaires, MESH : Wrongful Life, MESH : Humans, MESH : Questionnaires, MESH: Ultrasonography, Prenatal, MESH: Legislation, Medical, MESH : Physician-Patient Relations, [SDV.ETH] Life Sciences [q-bio]/Ethics, MESH: Male, [SDV.ETH]Life Sciences [q-bio]/Ethics, MESH: France, MESH : Pregnancy, [SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, MESH : Legislation, Medical, [ SDV.ETH ] Life Sciences [q-bio]/Ethics, MESH: Physician-Patient Relations, Female, France, MESH : Ultrasonography, Prenatal, MESH: Female
Abstract: OBJECTIVE: The aim of this study was to evaluate the effects of French law (court rulings in the Perruche decision and its progeny as well as the statute enacted on March 4, 2002 to reverse or moderate this jurisprudence) on physicians' prenatal diagnosis and fetal medicine practices. METHODS: We sent questionnaires to 186 physician-ultrasonographers in two French districts, inquiring about changes in their daily practice and their provision of information to and communication with the future parents, as well as their opinions about the future of their specialization. RESULTS: We received 54 responses (29%): 40% of respondents found it more difficult to tell patients about fetal anomalies. Written and oral information, medical reports and explanations about the limitations of ultrasound have improved substantially in content for 64% and are better used for 42%. Some clinicians (24.1%) report that they take the future parents' emotions into account more often. Some try to be more distant (13%) or more neutral (9.3%). More than half (51.9%) request the opinion of a center for prenatal diagnosis and fetal medicine more often and 20.4% request karyotyping more often. In all, 7.4% believe that their counseling now leads more often towards abortions. CONCLUSION: Although practitioners had an extremely negative perception of the case law and some were also unhappy with the new statute, these did lead to the reorganization and formalization of their practices. We can see that judicial decisions taken in a specific, individual situation can change collective practices and influence--or even overturn--public health strategies. The respondents' intention to take parents' emotions into account suggests they will find a common language to communicate with them. It is nonetheless necessary to organize a nationwide debate about the objectives of fetal ultrasound.
Published: 2006

20. TBP as a candidate gene for mental retardation in patients with subtelomeric 6q deletions

Author: Zsuzsanna Callaerts-Vegh, R. Frank Kooy, Irwin Davidson, Edwin Reyniers, Rob van Luijk, Winnie Courtens, Jan Wauters, Stefaan Scheers, Liesbeth Rooms, Rudi D'Hooge, Leen Van Aerschot, Gabrielle Mengus, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, and Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Candidate gene, Microcephaly, Monozygotic twin, MESH: TATA-Box Binding Protein, Anxiety, Mice, MESH: Mental Retardation, MESH: Animals, Genetics (clinical), Genetics, 0303 health sciences, 030305 genetics & heredity, Subtelomere, MESH: Memory Disorders, Null allele, Pedigree, Chemistry, Chromosomes, Human, Pair 6, Female, MESH: Twins, Monozygotic, Chromosome Deletion, MESH: Abnormalities, Multiple, MESH: Chromosomes, Human, Pair 6, Adolescent, MESH: Pedigree, MESH: Chromosome Deletion, Biology, 03 medical and health sciences, Gene mapping, Intellectual Disability, medicine, Diseases in Twins, Animals, Humans, Abnormalities, Multiple, Gene, MESH: Mice, 030304 developmental biology, MESH: Adolescent, Memory Disorders, MESH: Humans, MESH: Anxiety, Breakpoint, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Twins, Monozygotic, medicine.disease, TATA-Box Binding Protein, MESH: Male, Human medicine, MESH: Diseases in Twins, MESH: Female
Abstract: International audience; Monozygotic twin brothers with a subtelomeric 6q deletion presented with mental retardation, microcephaly, seizures, an enlarged cisterna magna, dimpling at elbows, a high arched palate and a thin upper lip. The same subtelomeric deletion was detected in the mother of the patients, presenting with a milder phenotype. We narrowed down the breakpoint to a region of approximately 100 kb and estimated the size of the terminal deletion to be 1.2 Mb. This region contains four known and seven putative genes. Comparison of the deletion with other reported patients showed TBP was the most plausible candidate gene for the mental retardation in this syndrome. We verified that the TBP gene expression was halved in our patients using real-time PCR. Cognitive and behavioural tests performed on previously described heterozygous tbp mice suggested that TBP is potentially involved in cognitive development.
Published: 2006

21. Distinguishing the four genetic causes of Jouberts syndrome-related disorders

Author: Enza Maria Valente, Lihadh Al-Gazali, Enrico Bertini, Hülya Kayserili, Clara Barbot, Sarah E. Marsh, Michel Koenig, László Sztriha, Eugen Boltshauser, Carmelo Salpietro, Marco Castori, Bruno Dallapiccola, Moez Gribaa, Tracy Dixon-Salazar, Asma A. Al-Tawari, Jean Messer, C. Geoffrey Woods, Joseph G. Gleeson, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I
Subjects: Male, Genetic Linkage, Developmental Disabilities, TMEM67, Chromosome Disorders, 0302 clinical medicine, MESH: Child, Polymicrogyria, Juvenile nephronophthisis, Child, Genetics, 0303 health sciences, MESH: Chromosome Disorders, medicine.diagnostic_test, Brain, Pedigree, 3. Good health, MESH: Cerebellar Ataxia, Neurology, Child, Preschool, RPGRIP1L, Female, Adult, MESH: Abnormalities, Multiple, Cerebellar Ataxia, MESH: Pedigree, government.form_of_government, Locus (genetics), Biology, Joubert syndrome, Central nervous system disease, 03 medical and health sciences, MESH: Brain, medicine, Humans, Abnormalities, Multiple, 030304 developmental biology, Genetic testing, MESH: Humans, MESH: Child, Preschool, MESH: Adult, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, MESH: Male, MESH: Developmental Disabilities, government, Neurology (clinical), Neuroscience, MESH: Linkage (Genetics), MESH: Female, 030217 neurology & neurosurgery
Abstract: International audience; Jouberts syndrome-related disorders are a group of recessively inherited conditions showing cerebellar vermis hypoplasia and the molar tooth sign of the midbrain-hindbrain junction. Recent analyses have suggested at least three loci, JBTS1 (9q34.3), -2 (11p11.2-q12.3), and -3 (6q23), but the phenotypic spectrum associated with each locus has not been delineated. In addition, deletions of the NPHP1 gene, usually responsible for isolated juvenile nephronophthisis, are occasionally encountered among Jouberts syndrome-related disorder patients. Here, we describe four novel families showing evidence of linkage to two of these loci, provide a 3.6Mb refinement of the JBTS2 locus, and perform a detailed comparison of all linked families identified so far, to define the clinical and radiographical hallmarks for each genetic condition. We find that JBTS1 and -3 primarily show features restricted to the central nervous system, with JBTS1 showing largely pure cerebellar and midbrain-hindbrain junction involvement, and JBTS3 displaying cerebellar, midbrain-hindbrain junction, and cerebral cortical features, most notably polymicrogyria. Conversely, JBTS2 is associated with multiorgan involvement of kidney, retina, and liver, in addition to the central nervous system features, and results in extreme phenotypic variability. This provides a useful framework for genetic testing strategies and prediction of which patients are most likely to experience development of systemic complications.
Published: 2005

22. New FKRP mutations causing congenital muscular dystrophy associated with mental retardation and central nervous system abnormalities. Identification of a founder mutation in Tunisian families

Author: Pascale Guicheney, Chahnez Triki, S. Makri, Slah Mrad, Brigitte Estournet, Nacim Louhichi, Norma B. Romero, Mériem Méziou, Susana Quijano-Roy, Hammadi Ayadi, Faiza Fakhfakh, Pascale Richard, Laboratoire de Génétique Moléculaire Humaine, Faculté de Médecine de Sfax, Service de neurologie, Hopital Habib Bourguiba - Habib Bourguiba Hospital [Sfax], Service de Pédiatrie, Rééducation et Réanimation Neurorespiratoire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Raymond Poincaré [AP-HP], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Etablissement Hospitalier Spécialisé Ali Ait Idir, Physiopathologie et thérapie du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by funds from the Secrétariat d'Etat à la Recherche Scientifique et à la Technologie (Tunisia), the Institut National de la Santé et de la Recherche Médicale (INSERM), Association Française contre les Myopathies (AFM), and the European Commission (contract N° QLG1-CT1999-00870)., Unité Fonctionnelle de Cardiogénétique et Myogénétique Moléculaire et Cellulaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Guicheney, Pascale, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)
Subjects: Male, Microcephaly, Glycosylation, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Founder Effect, Muscular Dystrophies, MESH: Magnetic Resonance Imaging, 0302 clinical medicine, cerebellar cysts, Cerebellum, MESH: Mental Retardation, MESH: Child, Missense mutation, MESH: Proteins, Muscular dystrophy, Child, Genetics (clinical), founder-haplotype, 0303 health sciences, Fukutin-related protein, medicine.diagnostic_test, biology, Homozygote, MESH: Glycosylation, Magnetic Resonance Imaging, Founder Effect, Pedigree, 3. Good health, Child, Preschool, Congenital muscular dystrophy, Female, medicine.symptom, MESH: Tunisia, FKRP gene, MESH: Homozygote, medicine.medical_specialty, Tunisia, MESH: Abnormalities, Multiple, MESH: Pedigree, mental retardation, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Intellectual Disability, Internal medicine, Fukuyama congenital muscular dystrophy, Genetics, medicine, Humans, Abnormalities, Multiple, Pentosyltransferases, 030304 developmental biology, Family Health, [SDV.GEN]Life Sciences [q-bio]/Genetics, Muscle biopsy, MESH: Humans, business.industry, MESH: Child, Preschool, Proteins, Muscle weakness, MESH: Haplotypes, medicine.disease, MESH: Muscular Dystrophies, MESH: Cerebellum, MESH: Male, Endocrinology, Haplotypes, biology.protein, MESH: Family Health, business, MESH: Female, 030217 neurology & neurosurgery
Abstract: International audience; The congenital muscular dystrophies (CMD) constitute a clinically and genetically heterogeneous group of autosomal recessive myopathies. Patients show congenital hypotonia, muscle weakness, and dystrophic changes on muscle biopsy. Mutations in four genes (FKT1, POMGnT1, POMT1, FKRP) encoding putative glycosyltransferases have been identified in a subset of patients characterized by a deficient glycosylation of alpha-dystroglycan on muscle biopsy. FKRP mutations account for a broad spectrum of patients with muscular dystrophy, from a severe congenital form with or without mental retardation (MDC1C) to a much milder limb-girdle muscular dystrophy (LGMD2I). We identified two novel homozygous missense FKRP mutations, one, A455D, in six unrelated Tunisian patients and the other, V405L, in an Algerian boy. The patients, between the ages of 3 and 12 years, presented with a severe form of MDC1C with calf hypertrophy and high serum creatine kinase levels. None had ever walked. Two had cardiac dysfunction and one strabismus. They all had mental retardation, microcephaly, cerebellar cysts, and hypoplasia of the vermis. White matter abnormalities were found in five, mostly when cranial magnetic resonance imaging was performed at a young age. These abnormalities were shown to regress in one patient, as has been observed in patients with Fukuyama CMD. Identification of a new microsatellite close to the FKRP gene allowed us to confirm the founder origin of the Tunisian mutation. These results strongly suggest that particular FKRP mutations in the homozygous state induce structural and clinical neurological lesions in addition to muscular dystrophy. They also relate MDC1C to other CMD with abnormal protein glycosylation and disordered brain function.
Published: 2004

23. In frame fibrillin-1 gene deletion in autosomal dominant Weill-Marchesani syndrome

Author: John R. Samples, M. Le Merrer, Gwenaëlle Collod-Béroud, N. Dagoneau, Maurice Godfrey, Catherine Boileau, Mary K. Wirtz, Valérie Cormier-Daire, Arnold Munnich, Robert J. Gorlin, Laurence Faivre, Handicaps génétiques de l'enfant ( Inserm U393 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Department of Oral Science, University of Minnesota Health Sciences Center, Department of Ophthalmology, Casey Eye Institute, Oregon Health Sciences University, Department of Pediatrics and Munroe Center for Human Genetics, University of Nebraska Omaha, Génétique, chromosome et cancer, COLLOD-BEROUD, Gwenaëlle, Handicaps génétiques de l'enfant (Inserm U393), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Minnesota Medical School, University of Minnesota System-University of Minnesota System, Oregon Health and Science University [Portland] (OHSU), University of Nebraska System-University of Nebraska System, and University of Nebraska [Omaha]
Subjects: Male, MESH: Extracellular Matrix Proteins, Reading Frames, Fibrillin-1, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH : Gene Deletion, MESH : Child, Preschool, Marfan Syndrome, Exon, 0302 clinical medicine, MESH : Child, MESH: Child, MESH : Microfilament Pro, MESH : Female, Eye Abnormalities, Child, 10. No inequality, Growth Disorders, Genetics (clinical), Genes, Dominant, Genetics, Extracellular Matrix Proteins, 0303 health sciences, Microfilament Proteins, Syndrome, MESH : Genes, Dominant, Middle Aged, MESH: Growth Disorders, MESH : Adult, MESH: Eye Abnormalities, Weill–Marchesani syndrome, Pedigree, Microspherophakia, Child, Preschool, Female, Fibrillin, Adult, MESH : Limb Deformities, Congenital, MESH: Abnormalities, Multiple, MESH: Limb Deformities, Congenital, Adolescent, MESH : Male, Short Report, Limb Deformities, Congenital, MESH: Microfilament Pro, Locus (genetics), Biology, Fibrillins, MESH: Marfan Syndrome, 03 medical and health sciences, MESH : Extracellular Matrix Proteins, MESH : Adolescent, MESH : Eye Abnormalities, medicine, Humans, Abnormalities, Multiple, MESH : Growth Disorders, Allele, 030304 developmental biology, MESH: Adolescent, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH : Marfan Syndrome, MESH : Abnormalities, Multiple, Genetic heterogeneity, Brachydactyly, MESH: Child, Preschool, MESH : Humans, MESH: Adult, medicine.disease, MESH: Male, eye diseases, MESH: Gene Deletion, 030221 ophthalmology & optometry, MESH: Genes, Dominant, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, MESH: Female, Gene Deletion
Abstract: Weill-Marchesani syndrome (WMS) is a connective tissue disorder characterised by short stature, brachydactyly, joint stiffness, and characteristic eye anomalies including microspherophakia, ectopia of the lenses, severe myopia, and glaucoma. Both autosomal recessive (AR) and autosomal dominant (AD) modes of inheritance have been described and a gene for AR WMS has recently been mapped to chromosome 19p13.3-p13.2. Here, we report on the exclusion of chromosome 19p13.3-p13.2 in a large AD WMS family and show that, despite clinical homogeneity, AD and AR WMS are genetically heterogeneous entities. Because two AD WMS families were consistent with linkage to chromosome 15q21.1, the fibrillin-1 gene was sequenced and a 24 nt in frame deletion within a latent transforming growth factor-beta1 binding protein (LTBP) motif of the fibrillin-1 gene was found in a AD WMS family (exon 41, 5074_5097del). This in frame deletion cosegregated with the disease and was not found in 186 controls. This study strongly suggests that AD WMS and Marfan syndrome are allelic conditions at the fibrillin-1 locus and adds to the remarkable clinical heterogeneity of type I fibrillinopathies.
Published: 2003

24. TP63 gene mutation in ADULT syndrome

Author: Stanislas Lyonnet, Christine Francannet, Gaëlle Bougeard, Thierry Frebourg, Arnold Munnich, Jeanne Amiel, Valérie Raclin, Université Paris Descartes - Paris 5 (UPD5), 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), Unité de Génétique Médicale, Hôtel-Dieu-CHU Clermont-Ferrand, 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 Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Ectrodactyly, MESH: Abnormalities, Multiple, MESH: Limb Deformities, Congenital, MESH: Mutation, Genotype, Genetic Linkage, Limb Deformities, Congenital, MESH: Genetic Linkage, Locus (genetics), Disease, Biology, MESH: Genotype, 03 medical and health sciences, Genetic linkage, MESH: Child, TP63, Genetics, medicine, Humans, Missense mutation, Abnormalities, Multiple, MESH: Syndrome, Allele, Child, Alleles, Genetics (clinical), Genes, Dominant, 030304 developmental biology, 0303 health sciences, MESH: Humans, MESH: Alleles, 030305 genetics & heredity, Syndrome, medicine.disease, MESH: Nipples, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Nipples, Mutation, Female, MESH: Genes, Dominant, MESH: Female
Abstract: International audience; TP63 gene mutations have recently been shown to be disease causing in EEC and SHFM. Two other overlapping syndromes with ectrodactyly as a major feature, have been mapped to chromosome 3q27 close by the TP63 locus, namely the LMS and ADULT syndromes. Here, we report on a missense TP63 gene mutation in an isolated ADULT syndrome case. This finding widens the spectrum of abnormalities to be ascribed to TP63 gene in human and emphasise on the variable roles of the different Tp63 isotypes.
Published: 2001

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24 results on '"MESH: Abnormalities, Multiple"'

1. Recurrence of an early postzygotic rescue of an inherited unbalanced translocation resulting in mosaic segmental uniparental isodisomy of chromosome 11q in siblings

2. Severe central apnea secondary to cerebellar dysplasia in a child: look past Joubert syndrome

3. Early-infantile onset epilepsy and developmental delay caused by bi-allelic GAD1 variants

4. Growth charts in Kabuki syndrome 1

5. Mutations in the BAF-complex subunit DPF2 associated with Coffin-Siris syndrome

6. The scalp hair collar and tuft signs: A retrospective multicenter study of 78 patients with a systematic review of the literature

7. TRα receptor mutations extend the spectrum of syndromes of reduced sensitivity to thyroid hormone

8. A Homozygous PDE6D Mutation in Joubert Syndrome Impairs Targeting of Farnesylated INPP5E Protein to the Primary Cilium

9. Involvement of ITIH5, a candidate gene for congenital uterovaginal aplasia (Mayer-Rokitansky-Küster-Hauser syndrome), in female genital tract development

10. Diagnosis of fetal urinary tract malformations: prenatal management and postnatal outcome

11. Utero-vaginal aplasia (Mayer-Rokitansky-Küster-Hauser syndrome) associated with deletions in known DiGeorge or DiGeorge-like loci

12. Microdeletion at chromosome 4q21 defines a new emerging syndrome with marked growth restriction, mental retardation and absent or severely delayed speech

13. Distinct effects of allelic NFIX mutations on nonsense-mediated mRNA decay engender either a sotos-like or a Marshall-Smith syndrome

14. Phenotypic spectrum of STRA6 mutations: from Matthew-Wood syndrome to non-lethal anophthalmia

15. Rhombencephalosynapsis and related anomalies: a neuropathological study of 40 fetal cases

16. Identification of 23 TGFBR2 and 6 TGFBR1 gene mutations and genotype-phenotype investigations in 457 patients with Marfan syndrome type I and II, Loeys-Dietz syndrome and related disorders

17. TCF4 deletions in Pitt-Hopkins Syndrome

18. Le syndrome de Mayer-Rokitansky-Küster-Hauser (MRKH) : clinique et génétique [The Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: clinical description and genetics]

19. [Changes in prenatal ultrasound practices after the Perruche decision and Law no. 2002-303 dated 4 March 2002]

20. TBP as a candidate gene for mental retardation in patients with subtelomeric 6q deletions

21. Distinguishing the four genetic causes of Jouberts syndrome-related disorders

22. New FKRP mutations causing congenital muscular dystrophy associated with mental retardation and central nervous system abnormalities. Identification of a founder mutation in Tunisian families

23. In frame fibrillin-1 gene deletion in autosomal dominant Weill-Marchesani syndrome

24. TP63 gene mutation in ADULT syndrome

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24 results on '"MESH: Abnormalities, Multiple"'

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