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1. Cost of exome analysis in patients with intellectual disability: a micro-costing study in a French setting

Author: Soilly, Al, Robert-Viard, C, Besse, C, Bruel, Al, Gerard, B, Boland, A, Piton, A, Duffourd, Y, Muller, J, Poë, C, Jouan, T, El Doueiri, S, Faivre, L, Bacq-Daian, D, Isidor, B, Genevieve, D, Odent, S, Philip, N, Doco-Fenzy, M, Lacombe, D, Asensio, Ml, Deleuze, Jf, Binquet, C, Thauvin-Robinet, C, Lejeune, C, Arpin, S, Blanchet, P, Blesson, S, Boute-Benejean, O, Busa, T, Colin, E, Coubes, C, Devillard, F, Edery, P, El Chehadeh, S, Fradin, M, Goldenberg, A, Guerrot, A-M, Herenger, Y, Houcinat, N, Jean-Marcais, N, Jouk, P., Lambert, L, Lavillaureix, A, Legendre, M, Leheup, B, Manouvrier, S, Mercier, S, Moutton, S, Nizon, M, Pasquier, L, Petit, F, Pinson, L, Poirsier, C, Pons, L, Putoux, A, Quelin, C, Renaud, M, Rossi, M, Sorlin, A, Spodenkiewicz, M, Thevenon, J, Toutain, A, Van-Gils, J, Vanlerberghe, C, Verloes, A, Vincent, M, Vincent-Delorme, C, Willems, M, Ziegler, A, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), 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 National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre National de Recherche en Génomique Humaine (CNRGH), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre hospitalier universitaire de Nantes (CHU Nantes), Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), FHU TRANSLAD (CHU de Dijon), and This study was funded by the French Ministry of Health as part of the 2015 Medico-Economic Research Program.
Subjects: Exome sequencing, MESH: France, MESH: Exome, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Cost analysis, Intellectual disability, Micro-costing, MESH: Intellectual Disability
Abstract: Background: With the development of next generation sequencing technologies in France, exome sequencing (ES) has recently emerged as an opportunity to improve the diagnosis rate of patients presenting an intellectual disability (ID). To help French policy makers determine an adequate tariff for ES, we aimed to assess the unit cost per ES diagnostic test for ID from the preparation of the pre-analytical step until the report writing step and to identify its main cost drivers.Methods: A micro-costing bottom-up approach was conducted for the year 2018 in a French setting as part of the DISSEQ study, a cost-effectiveness study funded by the Ministry of Health and performed in collaboration with the GAD (Génétique des Anomalies du Développement), a genetic team from the Dijon University Hospital, and a public sequencing platform, the Centre National de Recherche en Génomique Humaine (CNRGH). The analysis was conducted from the point of view of these two ES stakeholders. All of the resources (labor, equipment, disposables and reagents, reusable material) required to analyze blood samples were identified, collected and valued. Several sensitivity analyses were performed.Results: The unit nominal cost per ES diagnostic test for ID was estimated to be €2,019.39. Labor represented 50.7% of the total cost. The analytical step (from the preparation of libraries to the analysis of sequences) represented 88% of the total cost. Sensitivity analyses suggested that a simultaneous price decrease of 20% for the capture kit and 50% for the sequencing support kit led to an estimation of €1,769 per ES diagnostic test for ID.Conclusion: This is the first estimation of ES cost to be done in the French setting of ID diagnosis. The estimation is especially influenced by the price of equipment kits, but more generally by the organization of the centers involved in the different steps of the analysis and the time period in which the study was conducted. This information can now be used to define an adequate tariff and assess the efficiency of ES.Trial registration: ClinicalTrials.gov identifier NCT03287206 on September 19, 2017.
Published: 2023

2. Antenatal ultrasound features of isolated recurrent copy number variation in 7q11.23 (Williams syndrome and 7q11.23 duplication syndrome)

Author: Cécile Courdier, John Boudjarane, Valérie Malan, Christine Muti, Brian Sperelakis‐Beedham, Sylvie Odent, Sylvie Jaillard, Chloé Quelin, Cédric Le Caignec, Olivier Patat, Charlotte Dubucs, Sophie Julia, Caroline Schluth‐Bolard, Carole Goumy, Sylvia Redon, Jean‐Baptiste Gaillard, Minh Tuan Huynh, Céline Dupont, Anne‐Claude Tabet, Guillaume Cogan, François Vialard, Rodolphe Dard, Guillaume Jedraszak, Florence Jobic, Mathilde Lefebvre, Geneviève Quenum, Saori Inai, Mélanie Rama, Fanny Sauvestre, Frédéric Coatleven, Julie Thomas, Caroline Rooryck, Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier de Versailles André Mignot (CHV), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de Cytogénétique et de Biologie Cellulaire, Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], 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), Unité différenciation épidermique et auto-immunité rhumatoïde (UDEAR), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Cytogénétique Constitutionnelle [Hospices civils de Lyon], Hospices Civils de Lyon (HCL), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Service de Cytogénétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Unité de Génétique Chromosomique [Montpellier], Département de Génétique Médicale, Maladies Rares et Médecine Personnalisée [Montpellier], Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre hospitalier universitaire de Nantes (CHU Nantes), AP-HP Hôpital universitaire Robert-Debré [Paris], CHI Poissy-Saint-Germain, Biologie de la Reproduction, Environnement, Epigénétique & Développement (BREED), École nationale vétérinaire - Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CHU Amiens-Picardie, HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de génétique médicale et oncogénétique [CHU Amiens Picardie], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Libourne, Service de Génétique Médicale [Lille], Institut de génétique médicale-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de pathologie [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Centre Hospitalier Universitaire de Bordeaux (CHU de Bordeaux), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), and None
Subjects: [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Obstetrics and Gynecology, Genetics (clinical), [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Objective: We aimed to gather fetal cases carrying a 7q11.23 copy number variation (CNV) and collect precise clinical data to broaden knowledge of antenatal features in these syndromes.Methods: We retrospectively recruited unrelated cases with 7q11.23 deletion, known as Williams-Beuren syndrome (WBS), or 7q11.23 duplication who had prenatal ultrasound findings. We collected laboratory and clinical data, fetal ultrasound, cardiac ultrasound and fetal autopsy reports from 18 prenatal diagnostic centers throughout France.Results: 40 fetuses with WBS were collected and the most common features were intra-uterine growth retardation (IUGR) (70.0%, 28/40), cardiovascular defects (30.0%, 12/40), polyhydramnios (17.5%, 7/40) and protruding tongue (15.0%, 6/40). Fetal autopsy reports were available for 11 cases and were compared with ultrasound prenatal features. Four cases of fetuses with 7q11.23 microduplication were collected and prenatal ultrasound signs were variable and often isolated.Conclusion: This work strengthens the fact that 7q11.23 CNVs are associated with a broad spectrum of antenatal presentations. IUGR and cardiovascular defects were the most frequent ultrasound signs. By reporting the biggest series of antenatal WBS, we aim to better delineate distinctive signs in fetuses with 7q11.23 CNVs.
Published: 2023

3. Anti-CD20 therapies in multiple sclerosis: From pathology to the clinic

Author: Jérôme de Sèze, Elisabeth Maillart, Antoine Gueguen, David A. Laplaud, Laure Michel, Eric Thouvenot, Hélène Zephir, Luc Zimmer, Damien Biotti, Roland Liblau, Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, CIC Strasbourg (Centre d’Investigation Clinique Plurithématique (CIC - P) ), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nouvel Hôpital Civil de Strasbourg-Hôpital de Hautepierre [Strasbourg], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Fondation Ophtalmologique Adolphe de Rothschild [Paris], Centre hospitalier universitaire de Nantes (CHU Nantes), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer (MOBIDIC), Université de Rennes (UR)-Etablissement français du sang [Rennes] (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Toulouse III - Paul Sabatier (UT3), 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), and Novartis
Subjects: ublituximab, rituximab, ocrelizumab, [SDV]Life Sciences [q-bio], Immunology, Immunology and Allergy, [SDV.IMM]Life Sciences [q-bio]/Immunology, multiple sclerosis, anti-CD20, ofatumumab
Abstract: International audience; The immune system plays a significant role in multiple sclerosis. While MS was historically thought to be T cell-mediated, multiple pieces of evidence now support the view that B cells are essential players in multiple sclerosis pathogenic processes. High-efficacy disease-modifying therapies that target the immune system have emerged over the past two decades. Anti-CD20 monoclonal antibodies selectively deplete CD20+ B and CD20+ T cells and efficiently suppress inflammatory disease activity. These monotherapies prevent relapses, reduce new or active magnetic resonance imaging brain lesions, and lessen disability progression in patients with relapsing multiple sclerosis. Rituximab, ocrelizumab, and ofatumumab are currently used in clinical practice, while phase III clinical trials for ublituximab have been recently completed. In this review, we compare the four anti-CD20 antibodies in terms of their mechanisms of action, routes of administration, immunological targets, and pharmacokinetic properties. A deeper understanding of the individual properties of these molecules in relation to their efficacy and safety profiles is critical for their use in clinical practice.
Published: 2023

4. <scp>Skraban‐Deardorff</scp> syndrome: Six new cases of <scp> WDR 26 </scp> ‐related disease and expansion of the clinical phenotype

Author: Laurence Faivre, Varoona Bizaoui, Christèle Dubourg, Frédéric Tran Mau-Them, Wilfrid Carré, Amélie Piton, Sylvie Odent, Lionel Van Maldergem, Ange-Line Bruel, Laurent Pasquier, Marie Faoucher, Bénédicte Gérard, Mélanie Fradin, Alinoë Lavillaureix, Auriane Cospain, Florence Demurger, Jessica Assoumani, Elise Schaefer, Centre de référence Maladies Rares CLAD-Ouest [Rennes], CHU Pontchaillou [Rennes], Les Hôpitaux Universitaires de Strasbourg (HUS), 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), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Groupe Hospitalier Bretagne Sud (GHBS), 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 ), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), FHU TRANSLAD (CHU de Dijon), Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), and Chard-Hutchinson, Xavier
Subjects: Male, 0301 basic medicine, Proband, Pediatrics, medicine.medical_specialty, Adolescent, [SDV]Life Sciences [q-bio], Developmental Disabilities, Skraban-Deardorff syndrome, Disease, 030105 genetics & heredity, Young Adult, 03 medical and health sciences, Intellectual disability, Genetics, medicine, WDR26, Humans, Abnormalities, Multiple, hypotonia, Ataxic Gait, Child, Genetics (clinical), Adaptor Proteins, Signal Transducing, [SDV.GEN]Life Sciences [q-bio]/Genetics, Muscle biopsy, medicine.diagnostic_test, business.industry, Infant, Syndrome, medicine.disease, Gait, Hypotonia, 3. Good health, [SDV] Life Sciences [q-bio], Phenotype, 030104 developmental biology, speech therapy, intellectual disability, Child, Preschool, Mutation, Cohort, language development disorders, Female, medicine.symptom, business
Abstract: International audience; Skraban-Deardorff syndrome (a disease related to variations in the WDR26 gene; OMIM #617616) was first described in a cohort of 15 individuals in 2017. The syndrome comprises intellectual deficiency, severe speech impairment, ataxic gait, seizures, mild hypotonia with feeding difficulties during infancy, and dysmorphic features. Here, we report on six novel heterozygous de novo pathogenic variants in WDR26 in six probands. The patients’ phenotypes were consistent with original publication. One patient displayed marked hypotonia with an abnormal muscle biopsy; this finding warrants further investigation. Gait must be closely monitored, in order to highlight any musculoskeletal or neurological abnormalities and prompt further examinations. Speech therapy and alternative communication methods should be initiated early in the clinical follow-up, in order to improve language and oral eating and drinking.
Published: 2021

5. Glycogenin-1 deficiency mimicking limb-girdle muscular dystrophy

Author: Robert-Yves Carlier, Françoise Chapon, Guillaume Nicolas, Valérie Biancalana, Pascal Laforêt, Maxime Fournier, Edoardo Malfatti, Claire Lefeuvre, Stéphane Schaeffer, Hôpital Raymond Poincaré [AP-HP], Service de Neurologie [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), Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Anatomie Pathologique [CHU Caen], Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)
Subjects: Pathology, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Case Report, Gene mutation, Biceps, Glycogen storage disease type XV, GYG-1, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Deltoid muscle, Genetics, medicine, Muscular dystrophy, Molecular Biology, lcsh:QH301-705.5, lcsh:R5-920, 030219 obstetrics & reproductive medicine, Muscle biopsy, PBM-2, medicine.diagnostic_test, business.industry, Polyglucosan body myopathy-2, Muscle weakness, Neuromuscular disease, medicine.disease, 3. Good health, lcsh:Biology (General), Distal Myopathies, medicine.symptom, business, lcsh:Medicine (General), 030217 neurology & neurosurgery, Limb-girdle muscular dystrophy, Glycogenin-1, GSD XV
Abstract: Glycogen storage disease type XV (GSD XV) is a recently described muscle glycogenosis due to glycogenin-1 (GYG1) deficiency characterized by the presence of polyglucosan bodies on muscle biopsy (Polyglucosan body myopathy-2, PGBM2). Here we describe a 44 year-old man with limb-girdle muscle weakness mimicking a limb-girdle muscular dystrophy (LGMD), and early onset exertional myalgia. Neurologic examination revealed a waddling gait with hyperlordosis, bilateral asymmetric scapular winging, mild asymmetric deltoid and biceps brachii weakness, and pelvic-girdle weakness involving the gluteal muscles and, to a lesser extent, the quadriceps. Serum creatine kinase levels were slightly elevated. Electrophysiological examination showed a myopathic pattern. There was no cardiac or respiratory involvement. Whole-body muscle MRI revealed atrophy and fat replacement of the tongue, biceps brachii, pelvic girdle and erector spinae. A deltoid muscle biopsy showed the presence of PAS-positive inclusions that remained non-digested with alpha-amylase treatment. Electron microscopy studies confirmed the presence of polyglucosan bodies. A diagnostic gene panel designed by the Genetic Diagnosis Laboratory of Strasbourg University Hospital (France) for 210 muscular disorders genes disclosed two heterozygous, pathogenic GYG1 gene mutations (c.304G>C;p.(Asp102His) + c.164_165del). Considering the clinical heterogeneity found in the previously described 38 GYG-1 deficient patients, we suggest that GYG1 should be systematically included in targeted NGS gene panels for LGMDs, distal myopathies, and metabolic myopathies., Highlights • Glycogen storage disease type XV (GSD XV) is a recently described muscle glycogenosis due to glycogenin-1 (GYG1) deficiency characterized by the presence of polyglucosan bodies on muscle biopsy. • Here is the presentation of a 44 year-old man with limb-girdle muscle weakness mimicking a limb-girdle muscular dystrophy. • The large heterogeneity of phenotypic spectrum of GYG-1 deficiency suggests its inclusion in NGS gene panels targeted.
Published: 2020

6. Genotype-first in a cohort of 95 fetuses with multiple congenital abnormalities: when exome sequencing reveals unexpected fetal phenotype-genotype correlations

Author: Tania Attié-Bitach, Philippe Jonveaux, Alice Goldenberg, Antonio Vitobello, Nicole Laurent, Marjolaine Willems, Valérie Kremer, Dominique Gaillard, Chloé Quélin, Sebastien Moutton, Marion Aubert-Lenoir, Yannis Duffourd, Anne-Sophie Lebre, Anne-Claire Brehin, James Lespinasse, Yline Capri, Nolwenn Jean-Marçais, Maria Cristina Antal, Frédéric Tran Mau-Them, Nathalie Marle, Daphné Lehalle, Nicolas Bourgon, Sophie Blesson, Bernard Foliguet, Laetita Lambert, Nicole Bigi, Mélanie Fradin, Emilie Tisserant, Christel Thauvin-Robinet, Ange-Line Bruel, Elisabeth Alanio, Marie-Hélène Saint-Frison, Christine Francannet, Anne-Marie Guerrot, Paul Kuentz, Elise Schaefer, Anne-Marie Beaufrere, Sylvie Odent, Francine Arbez-Gindre, Laurence Faivre, Christophe Philippe, Julien Thevenon, Sophie Patrier-Sallebert, Nada Houcinat, Celine Poirisier, Sophie Nambot, Mathilde Lefebvre, Mirna Assoum, Françoise Girard-Lemaitre, Sophie Collardeau-Frachon, Marie-José Perez, Jean-Louis Mandel, Jean-Pierre Mazutti, Renaud Touraine, Philippe Loget, Salima El Chehadeh, Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Equipe GAD (LNC - U1231), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, CHU Strasbourg, Hôpital de Hautepierre [Strasbourg], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), European Organization for Nuclear Research (CERN), Service de Génétique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Universitaire de Reims (CHU Reims), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service d'Anatomie pathologique [CHRU Besançon], 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), Centre de référence Maladies Rares CLAD-Ouest [Rennes], CHU Pontchaillou [Rennes], Hôpital Lapeyronie [Montpellier] (CHU), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Biomécanique Humaine Georges Charpak (IBHGC), Université Sorbonne Paris Nord-Arts et Métiers Sciences et Technologies, HESAM Université (HESAM)-HESAM Université (HESAM), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, CHU Clermont-Ferrand, CHU Rouen, Normandie Université (NU), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Métropole Savoie [Chambéry], CHU Saint-Etienne, Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Hôpital Robert Debré, Plateau technique de Biologie [CHU de Dijon], Centre Hospitalier Universitaire [Grenoble] (CHU), CarMeN, laboratoire, Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, 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 ), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), 14-013 FOETEX, Interregional French PHRC, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)
Subjects: Candidate gene, medicine.medical_specialty, Genotype, [SDV]Life Sciences [q-bio], Biology, Congenital Abnormalities, Cohort Studies, complex traits, 03 medical and health sciences, Fetus, Molecular genetics, medicine, Humans, Abnormalities, Multiple, Exome, Clinical significance, genetics, Gene, Genetic Association Studies, Genetics (clinical), Exome sequencing, 030304 developmental biology, Genetics, 0303 health sciences, 030305 genetics & heredity, Sequence Analysis, DNA, Phenotype, [SDV] Life Sciences [q-bio], molecular genetics, reproductive medicine
Abstract: PurposeMolecular diagnosis based on singleton exome sequencing (sES) is particularly challenging in fetuses with multiple congenital abnormalities (MCA). Indeed, some studies reveal a diagnostic yield of about 20%, far lower than in live birth individuals showing developmental abnormalities (30%), suggesting that standard analyses, based on the correlation between clinical hallmarks described in postnatal syndromic presentations and genotype, may underestimate the impact of the genetic variants identified in fetal analyses.MethodsWe performed sES in 95 fetuses with MCA. Blind to phenotype, we applied a genotype-first approach consisting of combined analyses based on variants annotation and bioinformatics predictions followed by reverse phenotyping. Initially applied to OMIM-morbid genes, analyses were then extended to all genes. We complemented our approach by using reverse phenotyping, variant segregation analysis, bibliographic search and data sharing in order to establish the clinical significance of the prioritised variants.ResultssES rapidly identified causal variant in 24/95 fetuses (25%), variants of unknown significance in OMIM genes in 8/95 fetuses (8%) and six novel candidate genes in 6/95 fetuses (6%).ConclusionsThis method, based on a genotype-first approach followed by reverse phenotyping, shed light on unexpected fetal phenotype-genotype correlations, emphasising the relevance of prenatal studies to reveal extreme clinical presentations associated with well-known Mendelian disorders.
Published: 2020

7. The enrichment of breakpoints in late-replicating chromatin provides novel insights into chromoanagenesis mechanisms

Author: Chatron, N., Giannuzzi, G., Rollat-Farnier, P., Diguet, F., Porcu, E., Yammine, T., Uguen, K., Bellil, Z., Zillhardt, J. Lauer, Sorlin, A., Ader, F., Afenjar, A., Andrieux, J., Bardel, Claire, Calpena, E., Chantot-Bastaraud, S., Callier, P., Chelloug, N., Chopin, E., Cordier, M., Dubourg, C., Faivre, L., Girard, F., Heide, S., Herenger, Y., Jaillard, S., Keren, B., Knight, S. J. L., Lespinasse, J., Lohmann, L., Marle, N., Maroofian, R., Masurel-Paulet, Alice, Mathieu-Dramard, M., Metay, C., Pagnamenta, A. T., Portnoi, M., Prieur, F., Rio, M., Siffroi, J., Valence, S., Taylor, J. C., Wilkie, A. O. M., Edery, P., Reymond, A., Sanlaville, D., Schluth-Bolard, C., Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon, Departement de Neurologie (HCL), Université de Lausanne = University of Lausanne (UNIL), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Assistance publique-Hôpitaux de Paris - Espace éthique (AP-HP Espace éthique), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Trousseau [APHP], Service de neurophysiologie clinique (CHRU Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), The Weatherall Institute of Molecular Medicine, University of Oxford, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Strasbourg, The Wellcome Trust Centre for Human Genetics [Oxford], Centre Hospitalier Métropole Savoie [Chambéry], Laboratoire CERBA [Saint Ouen l'Aumône], University College of London [London] (UCL), CHU Amiens-Picardie, CHU Henri Mondor [Créteil], Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), CHU Necker - Enfants Malades [AP-HP], Université Paris 1 Panthéon-Sorbonne (UP1), Chard-Hutchinson, Xavier, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], CHU Henri Mondor, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), 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), Université de Lausanne (UNIL), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Oxford [Oxford], 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), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: [SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2020

8. Conditional switching of KIF2A mutation provides new insights into cortical malformation pathogeny

Author: Maria Osipenko, Hamid Meziane, Binnaz Yalcin, Gabrielle Rudolf, John S. Allingham, Ekaterina L. Ivanova, Maria-Victoria Hinckelmann, Loic Broix, Johan G. Gilet, Valerie Skory, Benjamin H. Kwok, Marie-Christine Birling, Jérémie Courraud, Daria Trofimova, Nathalie Drouot, Jamel Chelly, Nadia Bahi-Buisson, Paul Voulleminot, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Queen's University [Kingston, Canada], Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Institut Clinique de la Souris (ICS), French National Infrastructure for Mouse Phenogenomics (PHENOMIN), Service de Neurologie [CHU Strasbourg], Hôpital de Hautepierre [Strasbourg]-Centre Hospitalier Universitaire de Strasbourg (CHU de Strasbourg ), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut de Recherche en Immunologie et en Cancérologie [UdeM-Montréal] (IRIC), Université de Montréal (UdeM), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, EU Seventh Framework Programme FP7 under the projects GENCODYS (COLLABORATION PROJECT-2009-2.1.1-1/241995 to Ja.C.), DESIRE (grant agreement no. 602531 to Ja.C.), the French state funds through the ‘Agence Nationale de la Recherche’ under the projects ANR-15-CE16–0018-01 and the programme Investissements d’Avenir labeled (ANR-10-IDEX-0002-02, ANR-10-LABX-0030-INRT to B.Y. and Ja.C.)., ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010), European Project: 241995,EC:FP7:HEALTH,FP7-HEALTH-2009-two-stage,GENCODYS(2010), European Project: 602531,HEALTH,FP7-HEALTH-2013-INNOVATION-1,DESIRE(2013), YALCIN, Binnaz, Initiative d'excellence - Par-delà les frontières, l'Université de Strasbourg - - UNISTRA2010 - ANR-10-IDEX-0002 - IDEX - VALID, Genetic and Epigenetic Networks in Cognitive Dysfunction - GENCODYS - - EC:FP7:HEALTH2010-05-01 - 2015-04-30 - 241995 - VALID, Development and Epilepsy - Strategies for Innovative Research to improve diagnosis, prevention and treatment in children with difficult to treat Epilepsy - DESIRE - - HEALTH2013-01-01 - 2018-09-30 - 602531 - VALID, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)
Subjects: Male, Microcephaly, hippocampus, mouse model, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Kinesins, Hippocampus, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, medicine.disease_cause, knock-in, Mice, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Gene knockin, Genetics, medicine, Animals, Missense mutation, Molecular Biology, Genetics (clinical), 030304 developmental biology, Mice, Knockout, Neurons, 0303 health sciences, Mutation, videomicroscopy, neuronal migration, [SDV.GEN]Life Sciences [q-bio]/Genetics, Behavior, Animal, Transition (genetics), [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, apoptosis, General Medicine, General Article Two, malformations of cortical development, medicine.disease, in utero electroporation, microtubule dynamics, Phenotype, Mice, Inbred C57BL, Repressor Proteins, cortex, Neuroscience, 030217 neurology & neurosurgery, KIF2A
Abstract: By using the Cre-mediated genetic switch technology, we were able to successfully generate a conditional knock-in mouse, bearing the KIF2A p.His321Asp missense point variant, identified in a subject with malformations of cortical development. These mice present with neuroanatomical anomalies and microcephaly associated with behavioral deficiencies and susceptibility to epilepsy, correlating with the described human phenotype. Using the flexibility of this model, we investigated RosaCre-, NestinCre- and NexCre-driven expression of the mutation to dissect the pathophysiological mechanisms underlying neurodevelopmental cortical abnormalities. We show that the expression of the p.His321Asp pathogenic variant increases apoptosis and causes abnormal multipolar to bipolar transition in newborn neurons, providing therefore insights to better understand cortical organization and brain growth defects that characterize KIF2A-related human disorders. We further demonstrate that the observed cellular phenotypes are likely to be linked to deficiency in the microtubule depolymerizing function of KIF2A.
Published: 2020

9. Syndrome Tricho-rhino-phalangien de type I: description clinique et moléculaire chez 15 cas non apparentés

Author: Bourgois, Alexia, Bizaoui, Varoona, Ranguin, Kara, Armand, Thibaud, Arpin, Stéphanie, Bonneau, Dominique, El Chehadeh, Salima, Gruchy, Nicolas, Lambert, Laëtitia, Lichtenberger, Lydia, Mathieu, Michèle, Morin, Gilles, Richard, Nicolas, Schaefer, Elise, Godin, Manon, Gérard, Marion, Molin, Arnaud, 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), Service de Génétique [CHU Lyon] (Centre de pathologie de l'Est), Hospices civils de Lyon (HCL), Laboratoire de Génétique Moléculaire [CHU Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, CHU Strasbourg, Centre Hospitalier Universitaire de Nancy (CHU Nancy), Centre Hospitalier d'Abbeville, Unité de génétique médicale et oncogénétique [CHU Amiens Picardie], CHU Amiens-Picardie, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), and RANGUIN, Kara
Subjects: [SDV.GEN]Life Sciences [q-bio]/Genetics, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, [SDV.GEN] Life Sciences [q-bio]/Genetics, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: National audience; Résumé : Le syndrome tricho-rhino-phalangien (TRPS) de type I (MIM190350) est un syndrome malformatif autosomique dominant associant une dysmorphie faciale avec anomalies capillaires (cheveux fins et clairsemés qui poussent lentement) et nez bulbeux et un retard de croissance avec atteinte épiphysaire (extrémités, hanches notamment). Il est dû à des mutations perte de fonction du gène TRPS1 (8q23.3).Il existe deux autres sous-types de TRPS :- le type II, caractérisé par l’existence d’exostoses multiples, est causé par des microdélétions 8q23 emportant les gènes TRPS1 et EXT1- Ie type III, également causé par des mutations du gène TRPS1, dont le phénotype est plus sévère.L’objectif est de décrire le phénotype et le génotype des patients atteints de TRPS I à partir de l’étude rétrospective multicentrique d’une cohorte de 15 patients.La cohorte comprend 5 hommes et 10 femmes avec un âge médian de 27 ans. 4 cas sont sporadiques et 11 cas familiaux, avec un âge médian au diagnostic de 19 ans. Nous rapportons 5 mutations faux-sens, localisées dans les exons 6 et 7, 4 frameshift dans les exons 3 à 7, 2 non sens et 1 mutation intronique. Trois réarrangements intragéniques (2 délétions et 1 duplication) ont été détectés par analyse du profil de couverture en séquençage massif en parallèle et confirmés par MLPA (Multiplex Ligation-dependent Probe Amplification).Le phénotype de la cohorte comprend les éléments classiquement observés dans le TRPS I : un retard statural allant jusqu’à -3DS (n=6/15), des brachydactylies et brachymétacarpies (n=9/15), des épiphyses en cône (n=5/15) et une dysmorphie avec cheveux fins et clairsemés, un nez bulbeux et un front haut (respectivement n=8/15, 5/15 et 4/15).Un retard psychomoteur est présent chez les 3 patients ayant un réarrangement intragénique de TRPS1. La déficience intellectuelle dans le TRPS I est rapportée à une fréquence égale à celle de la population générale. Aucune corrélation phénotype-génotype claire n’a été établie jusqu’à présent. Un retard de croissance intra utérin (RCIU) est observé chez 4 patients sur les 7 pour qui des données anténatales étaient disponibles, bien que cet élément n’ait été rapporté qu’une fois dans la littérature.Une étude prospective de plus grande envergure parait nécessaire afin de préciser si le RCIU et la déficience intellectuelle font partie intégrante du TRPS I et de mieux comprendre la relation phénotype-génotype dans ce syndrome.
Published: 2020

10. De novo TBR1 variants cause a neurocognitive phenotype with ID and autistic traits: report of 25 new individuals and review of the literature

Author: Nambot, Sophie, Faivre, Laurence, Mirzaa, Ghayda, Thevenon, Julien, Bruel, Ange-Line, Mosca-Boidron, Anne-Laure, Masurel-Paulet, Alice, Goldenberg, Alice, Le Meur, Nathalie, Charollais, Aude, Mignot, Cyril, Petit, Florence, Rossi, Massimiliano, Metreau, Julia, Layet, Valérie, Amram, Daniel, Boute-Bénéjean, Odile, Bhoj, Elizabeth, Cousin, Margot, Kruisselbrink, Teresa, Lanpher, Brendan, Klee, Eric, Fiala, Elise, Grange, Dorothy, Meschino, Wendy, Hiatt, Susan, Cooper, Gregory, Olivié, Hilde, Smith, Wendy, Dumas, Meghan, Lehman, Anna, Inglese, Cara, Nizon, Mathilde, Guerrini, Renzo, Vetro, Annalisa, Kaplan, Eitan, Miramar, Dolores, van Gils, Julien, Fergelot, Patricia, Bodamer, Olaf, Herkert, Johanna, Pajusalu, Sander, Õunap, Katrin, Filiano, James, Smol, Thomas, Piton, Amélie, Gérard, Bénédicte, Chantot-Bastaraud, Sandra, Bienvenu, Thierry, Li, Dong, Juusola, Jane, Devriendt, Koen, Bilan, Frederic, Poé, Charlotte, Chevarin, Martin, Jouan, Thibaud, Tisserant, Emilie, Rivière, Jean-Baptiste, Tran Mau-Them, Frédéric, Philippe, Christophe, Duffourd, Yannis, Dobyns, William, Hevner, Robert, Thauvin-Robinet, Christel, Couvet, Sandrine, 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), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, FHU TRANSLAD (CHU de Dijon), Center for Integrative Brain Research [Seattle, WA, USA], University of Washington [Seattle]-Seattle Children's Research Institute, Department of Pediatrics [Seattle], University of Washington [Seattle], Unité fonctionnelle d' Innovation en Diagnostic Génomique des Maladies Rares (CHU Dijon) (UF6254), Département de génétique [CHU Rouen] (Centre Normandie de Génomique et de Médecine Personnalisée), CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Service de pédiatrie médicale et médecine de l'adolescent [Rouen], Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), 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), Clinique de Génétique médicale Guy Fontaine [CHRU LIlle], Service de Génétique [CHU Lyon] (Centre de pathologie de l'Est), Hospices civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Genetics of Neurodevelopment (GENDEV), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Service de Neurologie Pédiatrique [CHU Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Département de génétique (groupe hospitalier le Havre), Groupe Hospitalier du Havre, Centre Hospitalier Intercommunal de Créteil (CHIC), Department of Pediatrics [Philadelphia, PA, USA] (Division of Genetics), Children’s Hospital of Philadelphia (CHOP ), The Center for Applied Genomics [Philadelphia, PA, USA], Mayo Clinic [Rochester], Department of Pediatrics [Saint Louis, MO, USA] (Division of Genetics and Genomic Medicine), Washington University in Saint Louis (WUSTL), Department of Genetics [Saint-Louis], HudsonAlpha Institute for Biotechnology [Huntsville, AL], University Hospitals Leuven [Leuven], Maine Medical Center, University of British Columbia [Vancouver], Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Meyer Children's Hospital [Florence, Italie], Università degli Studi di Firenze = University of Florence (UniFI), CHU Bordeaux [Bordeaux], Department of Genetics [Boston], Harvard Medical School [Boston] (HMS), University Medical Center Groningen [Groningen] (UMCG), University of Tartu, Dartmouth Hitchcock Medical Center [Lebanon, NH, USA] (DHMC), Service de Génétique Médicale [Lille], Institut de génétique médicale-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], UF de Génétique chromosomique [CHU Trousseau], Service de Génétique et Biologie Moléculaires [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), GeneDx [Gaithersburg, MD, USA], Service Génétique Médicale [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, and Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)
Subjects: Proband, Candidate gene, INTELLECTUAL DISABILITY, MESH: Hippocampus, [SDV]Life Sciences [q-bio], MESH: Cognition, MESH: Neocortex, MESH: Child, Intellectual disability, MESH: Craniofacial Abnormalities, MESH: Animals, MESH: Syndrome, Genetics (clinical), Genetics, PROGENITORS, biology, Phenotype, NEOCORTEX, [SDV] Life Sciences [q-bio], EXPRESSION, GENES, MESH: Mutation, MESH: T-Box Domain Proteins, MESH: Autistic Disorder, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, MESH: Phenotype, Article, REGION, MESH: Intellectual Disability, NEUROGENESIS, Dysgenesis, FEZF2, medicine, MESH: Mice, MESH: Adolescent, MESH: Humans, MUTATIONS, business.industry, MESH: Child, Preschool, MESH: Adult, medicine.disease, MESH: Male, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, biology.protein, Autism, TBR1, business, Neurocognitive, MESH: Female
Abstract: International audience; TBR1, a T-box transcription factor expressed in the cerebral cortex, regulates the expression of several candidate genes for autism spectrum disorders (ASD). Although TBR1 has been reported as a high-confidence risk gene for ASD and intellectual disability (ID) in functional and clinical reports since 2011, TBR1 has only recently been recorded as a human disease gene in the OMIM database. Currently, the neurodevelopmental disorders and structural brain anomalies associated with TBR1 variants are not well characterized. Through international data sharing, we collected data from 25 unreported individuals and compared them with data from the literature. We evaluated structural brain anomalies in seven individuals by analysis of MRI images, and compared these with anomalies observed in TBR1 mutant mice. The phenotype included ID in all individuals, associated to autistic traits in 76% of them. No recognizable facial phenotype could be identified. MRI analysis revealed a reduction of the anterior commissure and suggested new features including dysplastic hippocampus and subtle neocortical dysgenesis. This report supports the role of TBR1 in ID associated with autistic traits and suggests new structural brain malformations in humans. We hope this work will help geneticists to interpret TBR1 variants and diagnose ASD probands.
Published: 2020

11. X-linked muscular dystrophy in a Labrador Retriever strain: phenotypic and molecular characterisation

Author: Jean-Laurent Thibaud, Christophe Béroud, Adeline Vulin, Kevin M. Flanigan, Nicolas Wein, Nathalie Deburgrave, Stéphane Blot, Jean-Claude Kaplan, Isabel Punzón, Laurent Tiret, Cécile Peccate, Robert B. Weiss, Catherine Escriou, Inès Barthélémy, Nadège Calmels, Luis Garcia, Carole Drougard, Gestionnaire, Hal Sorbonne Université, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), École nationale vétérinaire - Alfort (ENVA), Service de biochimie et de génétique moléculaire [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, University of Utah School of Medicine [Salt Lake City], Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Ohio State University [Columbus] (OSU), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Génétique Moléculaire [Hôpital de la Timone - APHM], 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)-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), Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), École nationale vétérinaire d'Alfort (ENVA), Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), and Centre de Recherche en Myologie
Subjects: 0301 basic medicine, Male, lcsh:Diseases of the musculoskeletal system, Duchenne muscular dystrophy, [SDV]Life Sciences [q-bio], Canine, Dystrophin, 03 medical and health sciences, 0302 clinical medicine, Dogs, LRMD, DMD, medicine, Dog, X-linked muscular dystrophy, Animals, Orthopedics and Sports Medicine, Animal model, Disease-causing Mutation, Muscular dystrophy, Muscle, Skeletal, Molecular Biology, Gene, Genetics, Genes, Modifier, biology, Research, Inversion, Cell Biology, medicine.disease, Phenotype, 3. Good health, Muscular Dystrophy, Duchenne, [SDV] Life Sciences [q-bio], Disease Models, Animal, 030104 developmental biology, Mutation, biology.protein, Labrador Retriever, lcsh:RC925-935, Dp71, 030217 neurology & neurosurgery, Neuromuscular disorders
Abstract: Background Canine models of Duchenne muscular dystrophy (DMD) are a valuable tool to evaluate potential therapies because they faithfully reproduce the human disease. Several cases of dystrophinopathies have been described in canines, but the Golden Retriever muscular dystrophy (GRMD) model remains the most used in preclinical studies. Here, we report a new spontaneous dystrophinopathy in a Labrador Retriever strain, named Labrador Retriever muscular dystrophy (LRMD). Methods A colony of LRMD dogs was established from spontaneous cases. Fourteen LRMD dogs were followed-up and compared to the GRMD standard using several functional tests. The disease causing mutation was studied by several molecular techniques and identified using RNA-sequencing. Results The main clinical features of the GRMD disease were found in LRMD dogs; the functional tests provided data roughly overlapping with those measured in GRMD dogs, with similar inter-individual heterogeneity. The LRMD causal mutation was shown to be a 2.2-Mb inversion disrupting the DMD gene within intron 20 and involving the TMEM47 gene. In skeletal muscle, the Dp71 isoform was ectopically expressed, probably as a consequence of the mutation. We found no evidence of polymorphism in either of the two described modifier genes LTBP4 and Jagged1. No differences were found in Pitpna mRNA expression levels that would explain the inter-individual variability. Conclusions This study provides a full comparative description of a new spontaneous canine model of dystrophinopathy, found to be phenotypically equivalent to the GRMD model. We report a novel large DNA mutation within the DMD gene and provide evidence that LRMD is a relevant model to pinpoint additional DMD modifier genes.
Published: 2020

12. 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

13. Morphological features in juvenile Huntington disease associated with cerebellar atrophy — magnetic resonance imaging morphometric analysis

Author: Guillaume Deverrière, Clémentine Dumant-Forrest, Jean-Nicolas Dacher, Alice Goldenberg, Catherine Vanhulle, Emmanuel Gerardin, Pierre-Hugues Vivier, Lucie Guyant-Maréchal, Pauline Treguier, Abderrahmane Hedjoudje, Isabelle Michelet, Didier Devys, Gaël Nicolas, Service d'imagerie médicale [CHU Rouen], Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Hôpital Charles Nicolle [Rouen]-CHU Rouen, Normandie Université (NU), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Service de pédiatrie néonatale et réanimation - neuropédiatrie [CHU Rouen], Hôpital Charles Nicolle [Rouen]-CHU Rouen, Service de neurophysiologie [Rouen], Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, DACHER, Jean Nicolas, Hôpital Charles Nicolle [Rouen], and Normandie Université (NU)-Normandie Université (NU)-CHU Rouen
Subjects: Male, 0301 basic medicine, Cerebellum, Pathology, medicine.medical_specialty, Caudate nucleus, Grey matter, 03 medical and health sciences, 0302 clinical medicine, Cerebellar Diseases, Cortex (anatomy), mental disorders, medicine, Humans, Radiology, Nuclear Medicine and imaging, MESH: Brain, Cerebellar atrophy, Children, Juvenile Huntington disease, Magnetic resonance imaging, Voxel-based morphometry, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Child, medicine.diagnostic_test, Cerebrum, business.industry, Siblings, Putamen, Infant, Magnetic Resonance Imaging, nervous system diseases, Huntington Disease, 030104 developmental biology, medicine.anatomical_structure, nervous system, [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Child, Preschool, Pediatrics, Perinatology and Child Health, Female, Atrophy, business, 030217 neurology & neurosurgery
Abstract: International audience; BACKGROUND:The imaging features of Huntington disease are well known in adults, unlike in juvenile-onset Huntington disease.OBJECTIVE:To conduct a morphometric magnetic resonance imaging (MRI) analysis in three juvenile Huntington disease patients (ages 2, 4 and 6 years old) to determine whether quantitative cerebral and cerebellar morphological metrics may provide diagnostically interesting patterns of cerebellar and cerebellar atrophy.MATERIALS AND METHODS:We report the cases of three siblings with extremely early presentations of juvenile Huntington disease associated with dramatic expansions of the morbid paternal allele from 43 to more than 100 CAG trinucleotide repeats. Automatic segmentation of MRI images of the cerebrum and cerebellum was performed and volumes of cerebral substructures and cerebellar lobules of juvenile Huntington disease patients were compared to those of 30 normal gender- and age-matched controls. Juvenile Huntington disease segmented volumes were compared to those of age-matched controls by using a z-score.RESULTS:Three cerebral substructures (caudate nucleus, putamen and globus pallidus) demonstrated a reduction in size of more than three standard deviations from the normal mean although it was not salient in one of them at clinical reading and was not diagnosed. The size of cerebellum lobules, cerebellum grey matter and cerebellum cortex was reduced by more than two standard deviations in the three patients. The cerebellar atrophy was predominant in the posterior lobe.CONCLUSION:Our study sheds light on atrophic cerebral and cerebellar structures in juvenile Huntington disease. Automatic segmentations of the cerebellum provide patterns that may be of diagnostic interest in this disease.
Published: 2018

14. SCA13 causes dominantly inherited non-progressive myoclonus ataxia

Author: Claire Ewenczyk, Mathilde Renaud, Claire Guissart, Solveig Montaut, Emmanuelle Apartis, Jean-Baptiste Chanson, André Pierre Legrand, Alexandra Durr, Mathieu Anheim, Jean Muller, Christine Tranchant, Michel Koenig, Vincent Laugel, CHU Strasbourg, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de physiologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL), CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Male, Myoclonus, 0301 basic medicine, Pediatrics, Movement disorders, Audiology, 0302 clinical medicine, Autosomal dominant cerebellar ataxia, Neurogenetics, Cerebellar ataxia, Movement disorder, Neurologic Examination, medicine.diagnostic_test, Brain, Electroencephalography, Middle Aged, 3. Good health, Ataxins, Neurology, Spinocerebellar ataxia, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, Adult, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Ataxia, Adolescent, Neurological examination, Young Adult, 03 medical and health sciences, mental disorders, medicine, Humans, Spinocerebellar Ataxias, Family Health, Electromyography, business.industry, medicine.disease, nervous system diseases, 030104 developmental biology, Mutation, Neurology (clinical), Geriatrics and Gerontology, Age of onset, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery
Abstract: Introduction Spinocerebellar ataxia 13 (SCA13) is a rare autosomal dominant cerebellar ataxia. To our knowledge, its association to movement disorders has never been described. We aimed at reporting 8 new SCA13 cases with a focus on movement disorders especially myoclonus. Methods We performed a detailed neurological examination and neurophysiological recording in 8 patients consecutively diagnosed with SCA13 between December 2013 and October 2015 and followed up in two French tertiary centers. Results We identified mild subcortical myoclonus in all patients, with a homogenous clinical and electrophysiological pattern. Myoclonus ataxia was very slowly progressive, like the other symptoms of the disease, whatever the age of onset. Patients with R423H mutation had an earlier age of onset than patients with R420H mutation. Conclusions Myoclonus appears to be frequent in SCA13. SCA13 should be considered facing non-progressive autosomal dominant myoclonus ataxia, and polymyographic recording should be included in the diagnosis work.
Published: 2017

15. A no-stop mutation in MAGEB4 is a possible cause of rare X-linked azoospermia and oligozoospermia in a consanguineous Turkish family

Author: Moncef Benkhalifa, Stéphane Viville, Sabine Kliesch, Nicolas Charlet-Berguerand, Munevver Serdarogullari, Angeline Gaucherot, Isabelle Aknin, Ozlem Okutman, Frank Tüttelmann, Viviana Herbepin, Mustafa Bahceci, Meral Gultomruk, Ellen Goossens, Jean Marie Garnier, Valérie Lamour, Yoni Baert, Jean Muller, Emre Bakircioglu, Valerie Skory, Marius Teletin, Albrecht Röpke, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Dynamique des interactions Hôte pathogène, Université de Strasbourg (UNISTRA), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Les Hôpitaux Universitaires de Strasbourg (HUS), Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Vrije Universiteit Brussel (VUB), Sisli Florence Nightingale Hospital [Istanbul, Turkey], University of Münster, CHU de Saint-Étienne Hôpital Nord (Saint Etienne), Université de Picardie Jules Verne (UPJV), Nouvel Hôpital Civil de Strasbourg, Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Périnatalité et Risques Toxiques - UMR INERIS_I 1 (PERITOX), Institut National de l'Environnement Industriel et des Risques (INERIS)-Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, CHARLET BERGUERAND, NICOLAS, Biology of the Testis, Basic (bio-) Medical Sciences, Faculty of Medicine and Pharmacy, and Surgical clinical sciences
Subjects: Male, RNA, Messenger/genetics, 0301 basic medicine, [SDV]Life Sciences [q-bio], Aucun, Whole Exome Sequencing, Sciences du Vivant [q-bio]/Génétique, Male infertility, Consanguinity, 0302 clinical medicine, Gene Frequency, Neoplasm Proteins/genetics, Genes, X-Linked, genetics, Exome, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), Exome sequencing, Azoospermia, Genetics, Sanger sequencing, 030219 obstetrics & reproductive medicine, Homozygote, Obstetrics and Gynecology, General Medicine, Neoplasm Proteins, Pedigree, [SDV] Life Sciences [q-bio], Antigens, Neoplasm/genetics, Sciences du Vivant [q-bio]/Biologie de la reproduction, Mutation (genetic algorithm), symbols, Azoospermia/genetics, Adult, Child, preschool, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, Biology, Polymorphism, Single Nucleotide, Infertility, Male/genetics, 03 medical and health sciences, symbols.namesake, Antigens, Neoplasm, Exome Sequencing, medicine, Humans, RNA, Messenger, Gene, Infertility, Male, Oligospermia/genetics, pathology, Oligospermia, medicine.disease, Genes, X-Linked/genetics, 030104 developmental biology, Reproductive Medicine, mutation, Developmental Biology
Abstract: PURPOSE: The purpose of this study was to identify mutations that cause non-syndromic male infertility using whole exome sequencing of family cases. METHODS: We recruited a consanguineous Turkish family comprising nine siblings with male triplets; two of the triplets were infertile as well as one younger infertile brother. Whole exome sequencing (WES) performed on two azoospermic brothers identified a mutation in the melanoma antigen family B4 (MAGEB4) gene which was confirmed via Sanger sequencing and then screened for on control groups and unrelated infertile subjects. The effect of the mutation on messenger RNA (mRNA) and protein levels was tested after in vitro cell transfection. Structural features of MAGEB4 were predicted throughout the conserved MAGE domain. RESULTS: The novel single-base substitution (c.1041A>T) in the X-linked MAGEB4 gene was identified as a no-stop mutation. The mutation is predicted to add 24 amino acids to the C-terminus of MAGEB4. Our functional studies were unable to detect any effect either on mRNA stability, intracellular localization of the protein, or the ability to homodimerize/heterodimerize with other MAGE proteins. We thus hypothesize that these additional amino acids may affect the proper protein interactions with MAGEB4 partners. CONCLUSION: The whole exome analysis of a consanguineous Turkish family revealed MAGEB4 as a possible new X-linked cause of inherited male infertility. This study provides the first clue to the physiological function of a MAGE protein. journal article 2017 May 2017 04 11 imported
Published: 2017

16. De novo variants in CNOT3 cause a variable neurodevelopmental disorder

Author: A. van Haeringen, Laurence Faivre, S Tomkins, Amélie Piton, Shelagh Joss, Emmelien Aten, C I de Bie, Ruth Newbury-Ecob, Emma Kivuva, R Ibitoye, Els A. J. Peeters, Miranda Splitt, Bronwyn Kerr, F Tranmauthem, Nicola Foulds, Andrew Collins, J Kennedy, David Geneviève, Marije Koopmans, Richard Martin, Sarah F. Smithson, Nolwenn Jean-Marçais, Jacques C. Giltay, Institute of Genetic Medicine [Newcastle], Newcastle University [Newcastle], Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Leiden University Medical Center (LUMC), University of Southampton, University Medical Center [Utrecht], 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), University of Glasgow, University Hospitals Bristol, Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester], University of Exeter Medical School, University of Exeter, Unité de Biotechnologie, Biocatalyse et Biorégulation (U3B), Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS), St. Michael's Hospital, Haga Teaching Hospital [Hague], University of Bristol [Bristol], Laboratoire de Diagnostic Génétique [CHU Strasbourg], and Université de Strasbourg (UNISTRA)-CHU Strasbourg
Subjects: Male, Proband, Developmental Disabilities, Developmental disorder, Mutation, Missense, Novo variants in CNOT3, Hypotonia, Haploinsufficiency, Biology, Article, 03 medical and health sciences, Neurodevelopmental disorder, Intellectual Disability, Exome Sequencing, Genetics, medicine, Humans, Learning, Missense mutation, Exome, Genetic Predisposition to Disease, Amino Acid Sequence, Genetic Association Studies, Genetics (clinical), Exome sequencing, Behavior, 0303 health sciences, 030305 genetics & heredity, Genetic Variation, medicine.disease, United Kingdom, Musculoskeletal Abnormalities, Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Neurodevelopmental Disorders, Muscle Hypotonia, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, Ireland, Sequence Alignment, Transcription Factors
Abstract: International audience; As a result of exome-based sequencing work performed by the DDD study, de novo variants in CNOT3 have emerged as a newly recognised cause of a developmental disorder. This paper describes molecular and clinical details of 16 probands with developmental disorders and de novo CNOT3 variants. It is the first such description of the developmental phenotype associated with CNOT3 variants. Eight of these cases were discovered as part of the DDD study, while the other eight were found as a result of large-scale sequencing work performed by other groups. A highly specific phenotype was not recognised in these 16 cases. The most consistent phenotypic features seen in subjects with de novo variants in CNOT3 were hypotonia, relatively small stature, developmental delay, behavioural problems and intellectual disability. There is no easily recognisable facial phenotype, but some common dysmorphic features such as anteverted nares, thin upper lip and low set eyebrows were shared among some of the probands. Haploinsufficiency appears to be the most likely mechanism of action, with eight cases found to have protein-truncating variants. Of the other eight cases (all missense variants), three share an amino acid substitution at the same position which may therefore represent an important functional domain.
Published: 2019

17. Particular forms of xeroderma pigmentosum and Cockayne syndrome in the Tunisian population

Author: Chikhaoui, A., Krawa, I., Calmels, N., Obringer, C., Elouej, S., Sandre-Giovannoli, A., Levy, N., Zghal, M., Ricchetti, M., Laugel, V., Turki, I., Abdelhak, S., Houda Yacoub-Youssef, Laboratoire de Génomique Biomédicale et Oncogénétique - Biomedical Genomics and Oncogenetics Laboratory (LR11IPT05), Université de Tunis El Manar (UTM)-Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Institut national de neurologie Mongi-Ben Hamida [Tunis], Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Charles Nicolle [Tunis], Département de Biologie du Développement et Cellules souches - Department of Developmental and Stem Cell Biology, Institut Pasteur [Paris], Cellules Souches et Développement / Stem Cells and Development, and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV.GEN]Life Sciences [q-bio]/Genetics
Abstract: Annual Meeting of the British-Society-for-Investigative-Dermatology, Univ Bradford, Bradford, ENGLAND, APR 01-03, 2019; International audience; International Symposium on Xeroderma Pigmentosum and other Nucleotide Excision Repair Disorders Downing College, University of Cambridge, Cambridge, UK. 20–22 March 2019
Published: 2019

18. Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing

Author: Girard, Elodie, Eon-Marchais, Séverine, Olaso, François, Renault, Anne, Damiola, Francesca, Dondon, Marie-Gabrielle, Barjhoux, Laure, Goidin, Didier, Meyer, François, Le Gal, Dorothée, Beauvallet, Juana, Mebirouk, Noura, Lonjou, Christine, Coignard, Julie, Marcou, Morgane, Cavaciuti, Eve, Baulard, François, Bihoreau, François, Cohen-Haguenauer, Odile, Leroux, Dominique, Penet, Jean, Fert-Ferrer, Sandra, Colas, Chrystelle, Frebourg, Thierry, Eisinger, François, Adenis, Claude, Fajac, Anne, Gladieff, Laurence, Tinat, Julie, Floquet, Anne, Chiesa, Jean, Giraud, Sophie, Mortemousque, Isabelle, Soubrier, Florent, Audebert-Bellanger, Séverine, Limacher, Jean-Marc, Lasset, Christine, Lejeune-Dumoulin, Sophie, Dreyfus, Catherine, Bignon, Yves-Jean, Longy, Michel, Pujol, Pascal, Venat-Bouvet, Laurence, Bonadona, Valérie, Berthet, Pascaline, Luporsi, Elisabeth, Maugard, Christine, Noguès, Catherine, Delnatte, Capucine, Fricker, Paul, Gesta, Paul, Faivre, Laurence, Lortholary, Alain, Buecher, Bruno, Caron, Olivier, Gauthier-Villars, Marion, Coupier, Isabelle, Servant, Nicolas, Boland, Anne, Mazoyer, Sylvie, Deleuze, Jean-François, Stoppa-Lyonnet, Dominique, Andrieu, Nadine, Lesueur, Fabienne, Université Paris sciences et lettres (PSL), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), Life Sciences and Diagnostics Group [Les Ulis, France], Agilent Technologies France, Laboratoire Information, Milieux, Médias, Médiations - EA 3820 (I3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université de Toulon (UTLN), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Traitement Algorithmique et Matériel de la Communication, de l'Information et de la Connaissance (TAMCIC), Ecole Nationale Supérieure des Télécommunications de Bretagne-Centre National de la Recherche Scientifique (CNRS), CRLCC Jean Godinot, Centre Hospitalier de Chambéry (C.H.de Chambéry), 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), Département de Génétique [Institut Curie, Paris] (Unité de Pharmacogénomique), Institut Curie [Paris], Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Claudius Regaud, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Département d'oncologie médicale, Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Laboratoire de Cytogénétique, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Génétique épidémiologique et moléculaire des pathologies cardiovasculaires, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Génétique Moléculaire et d'Histocompatibilité [Brest], Hôpital Morvan [Brest]-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Hôpital pasteur [Colmar], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Sainte Catherine [Avignon], Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Département de pathologie, Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Hôpital Dupuytren [CHU Limoges], Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Consultation d'Oncogénétique, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Alexis Vautrin (CAV), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Laboratoire d'Oncogénétique, CRLCC René Huguenin, CRLCC René Gauducheau, Service d'Oncologie Médicale [Strasbourg] (UNICANCER Centre Paul Strauss), Centre Paul Strauss : Centre Régional de Lutte contre le Cancer (CRLCC), Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Centre Catherine-de-Sienne [Nantes] (CCS), Service de Génétique Oncologique, Onco-génétique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Unité d'Oncogénétique, CRLCC Val d'Aurelle - Paul Lamarque, 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), Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Grant sponsor: comprehensive cancer center SiRIC, Grant numbers: INCa-DGOS-4654, Grant sponsor: Fondation ARC pour la recherche sur le cancer, Grant numbers: PJA 20151203365, Grant sponsor: France Génomique National infrastructure, Grant numbers: ANR-10-INBS-09, Grant sponsor: Institut National du Cancer (INCa), Grant numbers: b2008-029/LL-LC, Grant sponsor: Ligue Comité de Paris, Grant numbers: RS15/75-78, Grant sponsor: Ligue Nationale Contre le Cancer, Grant numbers: PRE05/DSL PRE07/DSL PRE11/NA., Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), Cancer et génôme: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Epidémiologie des cancers : Radiocarcinogénèse et effets iatrogènes des traitements, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), E06, Centre de Recherche en Cancérologie de Lyon (CRCL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), CRESS, Université de Franche-Comté (UFC), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service de génétique médicale CHU Grenoble Hôpital Couple Enfant, CHU Grenoble, CHU Saint-Antoine [APHP], Génétique du cancer et des maladies neuropsychiatriques (GMFC), Centre oscar lambert, service d'hématologie chu, CHU Tenon [APHP], CRLCC Institut Claudius Regaud, Centre Beninois pour l'Environnement et le développement économique et Social (CEBEDES), Service de Génétique Clinique [CHRU Nïmes], Centre Hospitalier Régional Universitaire de Nîmes (CHRU Nîmes), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP], Service de Pédiatrie et de Génétique Médicale, Hôpital Jeanne de Flandre [Lille], Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne (IMoST), Université Clermont Auvergne (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Jean Perrin, CRLCC Jean Perrin, Institut Bergonié - CRLCC Bordeaux, Service d'Oncologie médicale [CHU Limoges], CHU Limoges, Génétique épidémiologique et structures des populations humaines (Inserm U535), Epidémiologie, sciences sociales, santé publique (IFR 69), Université Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-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 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Régional de Lutte contre le Cancer François Baclesse (CRLC François Baclesse ), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Laboratoire de diagnostic génétique, Hôpital Universitaire de Strasbourg, Strasbourg, Centre René Gauducheau, Genetic and Immunology Medical Institute (GIMI), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), Fédération Francophone de la Cancérologie Digestive, FFCD, Institut Gustave Roussy (IGR), Service d'oncogénétique, Institut Curie, Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Equipe 6, Université Paris Descartes - Paris 5 (UPD5), Méthodologie statistique et épidémiologie génétique des maladies multifactorielles, Institut National de la Santé et de la Recherche Médicale (INSERM), Section Génétique - Groupe Prédispositions génétiques au cancer, Centre International de Recherche contre le Cancer (CIRC), MINES ParisTech - École nationale supérieure des mines de Paris, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (... - 2019) (UNS), Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure des Télécommunications de Bretagne, 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], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Lille Nord de France (COMUE)-UNICANCER, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), 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), Andrieu, Nadine, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)
Subjects: Adult, DNA Repair, case-control study, [SDV]Life Sciences [q-bio], Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.GEN] Life Sciences [q-bio]/Genetics, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Risk Assessment, Cancer Genetics and Epigenetics, breast cancer, multigene panel testing, [SDV.CAN] Life Sciences [q-bio]/Cancer, Humans, Genetic Predisposition to Disease, Genetic Testing, Aged, Aged, 80 and over, [SDV.GEN]Life Sciences [q-bio]/Genetics, Siblings, case–control study, Middle Aged, [SDV] Life Sciences [q-bio], variant, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Case-Control Studies, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, exome sequencing
Abstract: Pathogenic variants in BRCA1 and BRCA2 only explain the underlying genetic cause of about 10% of hereditary breast and ovarian cancer families. Because of cost‐effectiveness, multigene panel testing is often performed even if the clinical utility of testing most of the genes remains questionable. The purpose of our study was to assess the contribution of rare, deleterious‐predicted variants in DNA repair genes in familial breast cancer (BC) in a well‐characterized and homogeneous population. We analyzed 113 DNA repair genes selected from either an exome sequencing or a candidate gene approach in the GENESIS study, which includes familial BC cases with no BRCA1 or BRCA2 mutation and having a sister with BC (N = 1,207), and general population controls (N = 1,199). Sequencing data were filtered for rare loss‐of‐function variants (LoF) and likely deleterious missense variants (MV). We confirmed associations between LoF and MV in PALB2, ATM and CHEK2 and BC occurrence. We also identified for the first time associations between FANCI, MAST1, POLH and RTEL1 and BC susceptibility. Unlike other associated genes, carriers of an ATM LoF had a significantly higher risk of developing BC than carriers of an ATM MV (ORLoF = 17.4 vs. ORMV = 1.6; p Het = 0.002). Hence, our approach allowed us to specify BC relative risks associated with deleterious‐predicted variants in PALB2, ATM and CHEK2 and to add MAST1, POLH, RTEL1 and FANCI to the list of DNA repair genes possibly involved in BC susceptibility. We also highlight that different types of variants within the same gene can lead to different risk estimates., What's new? Pathogenic variants in BRCA1 and BRCA2 only explain the genetic cause of about 10% of hereditary breast and ovarian cancer families, and the clinical usefulness of testing other genes following the recent introduction of cost‐effective multigene panel sequencing in diagnostics laboratories remains questionable. This large case‐control study describes genetic variation in 113 DNA repair genes and specifies breast cancer relative risks associated with rare deleterious‐predicted variants in PALB2, ATM, and CHEK2. Importantly, different types of variants within the same gene can lead to different risk estimates. The results may help improve risk prediction models and define gene‐specific consensus management guidelines.
Published: 2019

19. Genetic evaluation of patients with non-syndromic male infertility

Author: Moncef Benkhalifa, Ozlem Okutman, Maroua Ben Rhouma, Jean Muller, Stéphane Viville, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Les Hôpitaux Universitaires de Strasbourg (HUS), Périnatalité et Risques Toxiques - UMR INERIS_I 1 (PERITOX), Institut National de l'Environnement Industriel et des Risques (INERIS)-Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, and Nouvel Hôpital Civil de Strasbourg
Subjects: 0301 basic medicine, Infertility, Male, [SDV]Life Sciences [q-bio], media_common.quotation_subject, Fertility, Review, Bioinformatics, Male infertility, 03 medical and health sciences, 0302 clinical medicine, Gene panel, Genetics, medicine, Humans, Spermatogenesis, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), Selection (genetic algorithm), Infertility, Male, media_common, Chromosome Aberrations, 030219 obstetrics & reproductive medicine, business.industry, Obstetrics and Gynecology, General Medicine, medicine.disease, Testicular sperm extraction, 030104 developmental biology, Reproductive Medicine, Evaluation Studies as Topic, Identification (biology), business, Non syndromic, Developmental Biology
Abstract: PURPOSE: This review provides an update on the genetics of male infertility with emphasis on the current state of research, the genetic disorders that can lead to non-syndromic male infertility, and the genetic tests available for patients. METHODS: A comprehensive review of the scientific literature referenced in PubMed was conducted using keywords related to male infertility and genetics. The search included articles with English abstracts appearing online after 2000. RESULTS: Mutations in 31 distinct genes have been identified as a cause of non-syndromic human male infertility, and the number is increasing constantly. Screening gene panels by high-throughput sequencing can be offered to patients in order to identify genes involved in various forms of human non-syndromic infertility. We propose a workflow for genetic tests which takes into account semen alterations. CONCLUSIONS: The identification and characterization of the genetic basis of male infertility have broad implications not only for understanding the cause of infertility but also in determining the prognosis, selection of treatment options, and management of couples. Genetic diagnosis is essential for the success of ART techniques and for preserving future fertility as well as the prognosis for testicular sperm extraction (TESE) and adopted therapeutics.
Published: 2018

20. Disease-causing variants in TCF4 are a frequent cause of intellectual disability: lessons from large-scale sequencing approaches in diagnosis

Author: Anne Boland, Alain Verloes, Jean-François Deleuze, Amélie Piton, Robert Olaso, Jean-Louis Mandel, Laura Mary, Laurence Faivre, Christine Coubes, Bénédicte Gérard, Elise Schaefer, David Geneviève, Claire Feger, Irina Giurgea, Estelle Colin, Francesca Mattioli, Salima El Chehadeh, Dana Timbolschi, Yline Capri, Jennifer Fabre-Teste, Elsa Nourisson, Elisabeth Flori, Magalie Barth, Laurence Perrin, Claire Redin, Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, 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), Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Collège de France (CdF (institution)), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), 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), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Unité fonctionnelle de génétique clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Maladies génétiques d'expression pédiatrique (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), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique, Hôpital de Hautepierre [Strasbourg], Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Service de cytogénétique, Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Physiopathologie, conséquences fonctionnelles et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-IFR2-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de Génotypage, Institut de Génomique, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service d'hématologie et immunologie, 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), Physiopathologie des maladies génétiques d'expression pédiatrique (UMRS_933), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Inst MitoVasc, Equipe MitoLab, Université d'Angers (UA), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU de Montpellier], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7), Physiopathologie des maladies génétiques d'expression pédiatrique, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, Male, [SDV]Life Sciences [q-bio], Intellectual disability, Disease, 030105 genetics & heredity, Bioinformatics, medicine.disease_cause, Transcription Factor 4, MESH: Young adult, MESH: Child, Hyperventilation, 10. No inequality, Child, MESH: Transcription factor 4 / genetics, Genetics (clinical), MESH: Hyperventilation / genetics, Sanger sequencing, Mutation, High-Throughput Nucleotide Sequencing, TCF4, 3. Good health, Phenotype, MESH: Facies, Child, Preschool, Cohort, symbols, Female, MESH: Hight-throughput Nucleotide sequencing, Adult, MESH: Mutation, Adolescent, MESH: Phenotype, Article, MESH: Child, preschool, 03 medical and health sciences, symbols.namesake, Young Adult, Genetics, medicine, Humans, MESH: Adolescent, MESH: Humans, MESH: Hyperventilation / diagnosis, business.industry, Facies, MESH: Adult, medicine.disease, MESH: Male, MESH: Intellectual Disability / pathology, Human genome, business, Large-Scale Sequencing, MESH: Female
Abstract: IF 3.636 (2017); International audience; High-throughput sequencing (HTS) of human genome coding regions allows the simultaneous screen of a large number of genes, significantly improving the diagnosis of non-syndromic intellectual disabilities (ID). HTS studies permit the redefinition of the phenotypical spectrum of known disease-causing genes, escaping the clinical inclusion bias of gene-by-gene Sanger sequencing. We studied a cohort of 903 patients with ID not reminiscent of a well-known syndrome, using an ID-targeted HTS of several hundred genes and found de novo heterozygous variants in TCF4 (transcription factor 4) in eight novel patients. Piecing together the patients from this study and those from previous large-scale unbiased HTS studies, we estimated the rate of individuals with ID carrying a disease-causing TCF4 mutation to 0.7%. So far, TCF4 molecular abnormalities were known to cause a syndromic form of ID, Pitt–Hopkins syndrome (PTHS), which combines severe ID, developmental delay, absence of speech, behavioral and ventilation disorders, and a distinctive facial gestalt. Therefore, we reevaluated ten patients carrying a pathogenic or likely pathogenic variant in TCF4 (eight patients included in this study and two from our previous ID-HTS study) for PTHS criteria defined by Whalen and Marangi. A posteriori, five patients had a score highly evocative of PTHS, three were possibly consistent with this diagnosis, and two had a score below the defined PTHS threshold. In conclusion, these results highlight TCF4 as a frequent cause of moderate to profound ID and broaden the clinical spectrum associated to TCF4 mutations to nonspecific ID.
Published: 2018

21. CoDE-seq, an augmented whole-exome sequencing, enables the accurate detection of CNVs and mutations in Mendelian obesity and intellectual disability

Author: Montagne, Louise, Derhourhi, Mehdi, Piton, Amélie, Toussaint, Bénédicte, Durand, Emmanuelle, Vaillant, Emmanuel, Thuillier, Dorothée, Gaget, Stefan, De Graeve, Franck, Rabearivelo, Iandry, Lansiaux, Amélie, Lenne, Bruno, Sukno, Sylvie, Desailloud, Rachel, Cnop, Miriam, Nicolescu, Ramona, Cohen, Lior, Zagury, Jean-François, Amouyal, Mélanie, Weill, Jacques, Muller, Jean, Sand, Olivier, Delobel, Bruno, Froguel, Philippe, Bonnefond, Amélie, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, 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), Institut Français du Proche-Orient (IFPO), MIN AFF ETRANG-Centre National de la Recherche Scientifique (CNRS), Recherche translationnelle sur le diabète - U 1190 (RTD), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), European Genomic Institute for Diabetes - FR 3508 (EGID), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL), Hôpital Saint Vincent de Paul de Lille, Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Périnatalité et Risques Toxiques - UMR INERIS_I 1 (PERITOX), Institut National de l'Environnement Industriel et des Risques (INERIS)-Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Université libre de Bruxelles (ULB), Laboratoire génomique, bioinformatique et applications (GBA), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université (HESAM)-HESAM Université (HESAM), Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'endocrinologie pédiatrique [CHU Lille], Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imperial College London, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Ministère de l'Europe et des Affaires étrangères (MEAE)-Centre National de la Recherche Scientifique (CNRS), Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), and HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)
Subjects: Adult, Male, lcsh:Internal medicine, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, DNA Copy Number Variations, endocrine system diseases, [SDV]Life Sciences [q-bio], Intellectual disability, Exome Sequencing, mental disorders, Humans, Point Mutation, Genetic Testing, Obesity, Child, lcsh:RC31-1245, ComputingMilieux_MISCELLANEOUS, Oligonucleotide Array Sequence Analysis, Copy number variation, Augmented whole-exome sequencing, High-Throughput Nucleotide Sequencing, Sciences bio-médicales et agricoles, Child, Preschool, Next-generation sequencing, Female, Original Article, Molecular diagnosis, Algorithms
Abstract: The molecular diagnosis of extreme forms of obesity, in which accurate detection of both copy number variations (CNVs) and point mutations, is crucial for an optimal care of the patients and genetic counseling for their families. Whole-exome sequencing (WES) has benefited considerably this molecular diagnosis, but its poor ability to detect CNVs remains a major limitation. We aimed to develop a method (CoDE-seq) enabling the accurate detection of both CNVs and point mutations in one step., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2018

22. Assessment of a Targeted Gene Panel for Identification of Genes Associated With Movement Disorders

Author: Montaut, Solveig, Tranchant, Christine, Drouot, Nathalie, Rudolf, Gabrielle, Guissart, Claire, Tarabeux, Julien, Stemmelen, Tristan, Velt, Amandine, Fourrage, Cécile, Nitschké, Patrick, Gerard, Bénédicte, Mandel, Jean-Louis, Koenig, Michel, Chelly, Jamel, Anheim, Mathieu, Parkinson\textquoterights, French, Consortium, Movement Disorders, CHU Strasbourg, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [Strasbourg], CHU Strasbourg-Hopital Civil, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), The Clinical Bioinformatics laboratory (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme Bioinformatique [SFR Necker] (BIP-D), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), Collège de France (CdF (institution)), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)
Subjects: 0301 basic medicine, Male, Myoclonus, Movement disorders, [SDV]Life Sciences [q-bio], Whole Exome Sequencing, 0302 clinical medicine, 80 and over, Prospective Studies, Age of Onset, Child, Exome sequencing, Original Investigation, Dystonia, Aged, 80 and over, Movement Disorders, High-Throughput Nucleotide Sequencing, Middle Aged, 3. Good health, Phenotype, Dystonic Disorders, Child, Preschool, Female, medicine.symptom, Sequence Analysis, Adult, medicine.medical_specialty, Adolescent, Cerebellar Ataxia, Genotype, 03 medical and health sciences, Young Adult, Parkinsonian Disorders, Chorea, Internal medicine, Exome Sequencing, medicine, Humans, Preschool, Aged, Cerebellar ataxia, Genetic heterogeneity, business.industry, Infant, DNA, Sequence Analysis, DNA, medicine.disease, 030104 developmental biology, Neurology (clinical), Age of onset, business, 030217 neurology & neurosurgery, Dystonic disorder
Abstract: International audience; Importance: Movement disorders are characterized by a marked genotypic and phenotypic heterogeneity, complicating diagnostic work in clinical practice and molecular diagnosis. Objective: To develop and evaluate a targeted sequencing approach using a customized panel of genes involved in movement disorders. Design, Setting and Participants: We selected 127 genes associated with movement disorders to create a customized enrichment in solution capture array. Targeted high-coverage sequencing was applied to DNA samples taken from 378 eligible patients at 1 Luxembourgian, 1 Algerian, and 25 French tertiary movement disorder centers between September 2014 and July 2016. Patients were suspected of having inherited movement disorders because of early onset, family history, and/or complex phenotypes. They were divided in 5 main movement disorder groups: parkinsonism, dystonia, chorea, paroxysmal movement disorder, and myoclonus. To compare approaches, 23 additional patients suspected of having inherited cerebellar ataxia were included, on whom whole-exome sequencing (WES) was done. Data analysis occurred from November 2015 to October 2016. Main Outcomes and Measures: Percentages of individuals with positive diagnosis, variants of unknown significance, and negative cases; mutational frequencies and clinical phenotyping of genes associated with movement disorders. Results: Of the 378 patients (of whom 208 were male [55.0%]), and with a median (range) age at disease onset of 31 (0-84) years, probable pathogenic variants were identified in 83 cases (22.0%): 46 patients with parkinsonism (55% of 83 patients), 21 patients (25.3%) with dystonia, 7 patients (8.4%) with chorea, 7 patients (8.4%) with paroxysmal movement disorders, and 2 patients (2.4%) with myoclonus as the predominant phenotype. Some genes were mutated in several cases in the cohort. Patients with pathogenic variants were significantly younger (median age, 27 years; interquartile range [IQR], 5-36 years]) than the patients without diagnosis (median age, 35 years; IQR, 15-46 years; P = .04). Diagnostic yield was significantly lower in patients with dystonia (21 of 135; 15.6%; P = .03) than in the overall cohort. Unexpected genotype-phenotype correlations in patients with pathogenic variants deviating from the classic phenotype were highlighted, and 49 novel probable pathogenic variants were identified. The WES analysis of the cohort of 23 patients with cerebellar ataxia led to an overall diagnostic yield of 26%, similar to panel analysis but at a cost 6 to 7 times greater. Conclusions and Relevance: High-coverage sequencing panel for the delineation of genes associated with movement disorders was efficient and provided a cost-effective diagnostic alternative to whole-exome and whole-genome sequencing.
Published: 2018

23. MED13L-related intellectual disability: involvement of missense variants and delineation of the phenotype

Author: Bertrand Isidor, Christine Francannet, D. Li, Samuel W. Baker, Gaëlle Vieville, Martine Doco-Fenzy, David Geneviève, I. Giurgea, Anna Gréen, Emily Fassi, Caroline Nava, Roseline Caumes, C. Fournier, Alexandra Afenjar, Françoise Devillard, Yuri A. Zarate, Damien Sanlaville, Michael Field, Elisabetta Lapi, Sandra Whalen, Emma Bedoukian, Alice Goldenberg, S. Steinwall Larsen, Jamal Ghoumid, Marjolaine Willems, M. Wenzel, Isabelle Marey, Sylvie Picker-Minh, Thomas Smol, Anne-Marie Guerrot, Dominique Bonneau, Gaetan Lesca, Delphine Héron, Elizabeth J. Bhoj, Véronique Satre, Sylvie Manouvrier-Hanu, Christine Coubes, Alain Verloes, Margarita Stefanova, Gaël Nicolas, Amélie Piton, Odile Boute-Benejean, Laurence Faivre, Caroline Thuillier, Bénédicte Gérard, Nicolas Chatron, Florence Petit, Beth Keena, Elise Boudry-Labis, C. Colson, Sonia Bouquillon, Avni Santani, Boris Keren, Lisa Ewans, Tony Roscioli, N. Le Meur, Paul Kuentz, Bryan L. Krock, Catherine Roche-Lestienne, Anne Dieux-Coeslier, Alban Ziegler, Pascale Saugier-Veber, Cyril Mignot, Vera M. Kalscheuer, Addie I. Nesbitt, Charles Coutton, Service de Génétique Médicale [Lille], Institut de génétique médicale-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364 (RADEME), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Pôle de Biologie Pathologie Génétique [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de Cytogénétique Constitutionnelle [Hospices civils de Lyon], Hospices Civils de Lyon (HCL), CHU Trousseau [APHP], Children’s Hospital of Philadelphia (CHOP ), Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Laboratoire de Génétique Chromosomique [CHU de Grenoble], CHU Grenoble, University of New South Wales [Canberra Campus] (UNSW), 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), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Maladies génétiques d'expression pédiatrique (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), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Linköping university hospital, Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Azienda Ospedaliero Universitaria A. Meyer [Firenze, Italy], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Unité fonctionnelle de génétique clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, University of Arkansas for Medical Sciences (UAMS), Max Planck Institute for Molecular Genetics (MPIMG), Max-Planck-Gesellschaft, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Service de génétique et embryologie médicales [CHU Trousseau], Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Montpellier, Equipe GAD (LNC - U1231), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Institut de génétique médicale-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction ( RADEME ), Hôpital Jeanne de Flandre [Lille]-Université de Lille-Centre Hospitalier Régional Universitaire de Lille ( CHRU de Lille ) -Clinique de Génétique médicale Guy Fontaine [CHRU LIlle]-Centre de référence maladies rares Anomalies du développement [CHRU Lille], Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Laboratoire de Probabilités et Modèles Aléatoires (LPMA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de recherche en Hydrodynamique, Énergétique et Environnement Atmosphérique (LHEEA), École Centrale de Nantes (ECN)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Service de Génétique Clinique, Hôpital Femme Mère Enfant, Centre Hospitalier Universitaire de Lyon, Laboratoire Hippolyte Fizeau (FIZEAU), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire de la Côte d'Azur, Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Systèmes de Référence Temps Espace (SYRTE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire de Paris, PSL Research University (PSL)-PSL Research University (PSL)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique [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), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU de Montpellier], Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), APERAM, Inconnu, CHU Clermont-Ferrand, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), FHU TRANSLAD, Département de génétique [CHU Rouen] (Centre Normandie de Génomique et de Médecine Personnalisée), CHU Pitié-Salpêtrière [APHP], Fossil Fuel Chemistry, University of Sofia, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), 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 Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), and International Livestock Research Institute
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, Pediatrics, Ataxia, Mutation, Missense, Intellectual disability, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Phenotype, MESH: Intellectual Disability, 03 medical and health sciences, Cellular and Molecular Neuroscience, Epilepsy, MESH: Mediator Complex, MESH: Child, Genetics, medicine, Missense mutation, Humans, Mediator complex, Child, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, Genetics (clinical), MESH: Mutation, Missense, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, business.industry, MESH: Child, Preschool, medicine.disease, Human genetics, Hypotonia, MESH: Male, 3. Good health, MED13L, Cardiopathy, 030104 developmental biology, Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Child, Preschool, Medical genetics, Female, medicine.symptom, Haploinsufficiency, business, MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: IF 3.269; International audience; Molecular anomalies in MED13L, leading to haploinsufficiency, have been reported in patients with moderate to severe intellectual disability (ID) and distinct facial features, with or without congenital heart defects. Phenotype of the patients was referred to "MED13L haploinsufficiency syndrome." Missense variants in MED13L were already previously described to cause the MED13L-related syndrome, but only in a limited number of patients. Here we report 36 patients with MED13L molecular anomaly, recruited through an international collaboration between centers of expertise for developmental anomalies. All patients presented with intellectual disability and severe language impairment. Hypotonia, ataxia, and recognizable facial gestalt were frequent findings, but not congenital heart defects. We identified seven de novo missense variations, in addition to protein-truncating variants and intragenic deletions. Missense variants clustered in two mutation hot-spots, i.e., exons 15-17 and 25-31. We found that patients carrying missense mutations had more frequently epilepsy and showed a more severe phenotype. This study ascertains missense variations in MED13L as a cause for MED13L-related intellectual disability and improves the clinical delineation of the condition.
Published: 2018

24. Defining the phenotypic spectrum of SLC6A1 mutations

Author: Elena Gardella, Diane Doummar, Orrin Devinsky, Nicola Specchio, Holly Dubbs, Lance H. Rodan, Caroline Nava, Elise Schaefer, Jessica E. Shaw, Desiree Czapansky-Beilman, Tarja Linnankivi, Rikke S. Møller, Helenius J. Schelhaas, Kathrine L. Helbig, Jakob Christensen, Jamel Chelly, Gemma L. Carvill, Sarah E. Hopkins, Sara Chadwick Reichert, Marina Trivisano, Amélie Piton, Candace T. Myers, Pasquale Striano, Katrine M Johannesen, Alexandra Afenjar, Judith S. Verhoeven, John Millichap, Yongjin Yoo, Oriano Mecarelli, Murim Choi, Jong Hee Chae, Joseph G. Gleeson, Heather C Mefford, Gaetan Lesca, Laura Pisani, Boris Keren, Sha Tang, Marie Thérèse Abi-Warde, Carolina Courage, Ingo Helbig, Deb K. Pal, Guido Rubboli, Lynne M. Bird, Manuela Pendziwiat, Cyril Mignot, Shan Tang, J. Lawrence Merritt, Yvonne G. Weber, Anna-Elina Lehesjoki, Wen-Hann Tan, Anne de Saint Martin, Mark Nespeca, University of Southern Denmark (SDU), CHU Strasbourg, Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, 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), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Boston Children's Hospital, Seoul National University [Seoul] (SNU), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Neuropédiatrie [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), University of Genoa (UNIGE), and Children’s Hospital of Philadelphia (CHOP )
Subjects: Male, 0301 basic medicine, Pediatrics, Epilepsies, Myoclonic, Epilepsies, Neurodegenerative, Epilepsies, Myoclonic/complications, Intellectual Disability/complications, Cohort Studies, Epilepsy, 0302 clinical medicine, 2.1 Biological and endogenous factors, Neurodevelopmental Disorders/complications, Aetiology, Valproic Acid/therapeutic use, Child, Atonic seizure, Ataxia/complications, Seizure types, Anticonvulsants/therapeutic use, Electroencephalography, MAE, Language Development Disorders/complications, Phenotype, Treatment Outcome, Neurology, Child, Preschool, Neurological, Speech delay, Anticonvulsants, Epilepsy, Generalized, Female, medicine.symptom, Partial, Adult, GABA Plasma Membrane Transport Proteins, medicine.medical_specialty, SLC6A1, epilepsy, epilepsy genetics, Adolescent, Epilepsies, Partial/complications, Epilepsy, Generalized/complications, Clinical Sciences, Mutation, Missense, GABA Plasma Membrane Transport Proteins/genetics, Status epilepticus, Article, Young Adult, 03 medical and health sciences, Childhood absence epilepsy, Clinical Research, Intellectual Disability, Behavioral and Social Science, Genetics, medicine, Humans, Language Development Disorders, Generalized epilepsy, Preschool, Genetic Association Studies, Neurology & Neurosurgery, Generalized, business.industry, Valproic Acid, Neurosciences, medicine.disease, Brain Disorders, 030104 developmental biology, Myoclonic astatic epilepsy, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Neurodevelopmental Disorders, Mutation, Ataxia, Epilepsies, Partial, Neurology (clinical), Missense, Myoclonic, business, 030217 neurology & neurosurgery
Abstract: OBJECTIVE: Pathogenic SLC6A1 variants were recently described in patients with myoclonic atonic epilepsy (MAE) and intellectual disability (ID). We set out to define the phenotypic spectrum in a larger cohort of SCL6A1-mutated patients.METHODS: We collected 24 SLC6A1 probands and 6 affected family members. Four previously published cases were included for further electroclinical description. In total, we reviewed the electroclinical data of 34 subjects.RESULTS: Cognitive development was impaired in 33/34 (97%) subjects; 28/34 had mild to moderate ID, with language impairment being the most common feature. Epilepsy was diagnosed in 31/34 cases with mean onset at 3.7 years. Cognitive assessment before epilepsy onset was available in 24/31 subjects and was normal in 25% (6/24), and consistent with mild ID in 46% (11/24) or moderate ID in 17% (4/24). Two patients had speech delay only, and 1 had severe ID. After epilepsy onset, cognition deteriorated in 46% (11/24) of cases. The most common seizure types were absence, myoclonic, and atonic seizures. Sixteen cases fulfilled the diagnostic criteria for MAE. Seven further patients had different forms of generalized epilepsy and 2 had focal epilepsy. Twenty of 31 patients became seizure-free, with valproic acid being the most effective drug. There was no clear-cut correlation between seizure control and cognitive outcome. Electroencephalography (EEG) findings were available in 27/31 patients showing irregular bursts of diffuse 2.5-3.5 Hz spikes/polyspikes-and-slow waves in 25/31. Two patients developed an EEG pattern resembling electrical status epilepticus during sleep. Ataxia was observed in 7/34 cases. We describe 7 truncating and 18 missense variants, including 4 recurrent variants (Gly232Val, Ala288Val, Val342Met, and Gly362Arg).SIGNIFICANCE: Most patients carrying pathogenic SLC6A1 variants have an MAE phenotype with language delay and mild/moderate ID before epilepsy onset. However, ID alone or associated with focal epilepsy can also be observed.
Published: 2018

25. Wiedemann-Steiner syndrome as a major cause of syndromic intellectual disability: A study of 33 French cases

Author: Thierry Bienvenu, Sarah Baer, Yves Alembik, Laurent Pasquier, A.S. Lebre, Elise Schaefer, Sylvie Sukno, Caroline Nava, Cindy Colson, Didier Lacombe, Michèle Mathieu-Dramard, Valérie Cormier-Daire, Thomas Smol, Delphine Héron, Alice Goldenberg, Odile Boute, Martine Doco-Fenzy, Julien Thevenon, David Geneviève, Boris Keren, Nicole Philip, Catherine Vincent-Delorme, Sophie Rondeau, Alexandra Afenjar, Bruno Delobel, Damien Haye, G. Boursier, Marjolaine Willems, Amélie Piton, Mélanie Fradin, Alice Masurel, A. Petit, Bénédicte Gérard, Bertrand Isidor, Marie-Pierre Cordier, Pascale Saugier-Veber, Gilles Morin, Gaetan Lesca, Julien Van-Gils, Bénédicte Duban-Bedu, Maude Grelet, Juliette Piard, Laboratoire de recherche en Hydrodynamique, Énergétique et Environnement Atmosphérique (LHEEA), École Centrale de Nantes (ECN)-Centre National de la Recherche Scientifique (CNRS), Université Catholique de Louvain (UCL), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique clinique, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Clinique de Génétique médicale Guy Fontaine [CHRU LIlle], 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), 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), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Production du lait (PL), Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), 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 clinique, Hôpital Sud, Département de génétique médicale [Hôpital de la Timone - APHM], Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), FHU TRANSLAD, Institut de minéralogie et de physique des milieux condensés (IMPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-IPG PARIS-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Les Hôpitaux Universitaires de Strasbourg (HUS), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, 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), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Service de Génétique [CHU Caen], 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), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Hospices Civils de Lyon (HCL), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe Hospitalier de l'Institut Catholique de Lille (GHICL), Centre Hospitalier Universitaire de Reims (CHU Reims), CHU Pontchaillou [Rennes], Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Marseille, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Bordeaux [Bordeaux], Institut des Sciences de la mécanique et Applications industrielles (IMSIA - UMR 9219), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-École Nationale Supérieure de Techniques Avancées (ENSTA Paris)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-EDF R&D (EDF R&D), EDF (EDF)-EDF (EDF), Unité de génétique médicale et oncogénétique [CHU Amiens Picardie], CHU Amiens-Picardie, 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, 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), Génétique des Anomalies du Développement (GAD), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne (UB), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Saint Vincent de Paul de Lille, Pôle de Biologie Pathologie Génétique [CHU Lille], International Livestock Research Institute, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Biologie Fonctionnelle, Insectes et Interactions (BF2I), Institut National de la Recherche Agronomique (INRA)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU de Montpellier], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Department of Hematology, Le CHCB, Centre Hospitalier de la Côte Basque, CHU Pitié-Salpêtrière [APHP], EDF (EDF), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Department of Neonatal Pediatrics, Rouen University Hospital, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université catholique de Lille (UCL), 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), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-École Nationale Supérieure de Techniques Avancées (ENSTA Paris)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-EDF R&D (EDF R&D), Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Institut de Physique du Globe de Paris (IPG Paris)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Hypertrichosis, Male, Pediatrics, [SDV]Life Sciences [q-bio], MESH: Magnetic Resonance Imaging, Pathognomonic, MESH: Child, Intellectual disability, MESH: Syndrome, Child, MESH: High-Throughput Nucleotide Sequencing, Genetics (clinical), Exome sequencing, ComputingMilieux_MISCELLANEOUS, biology, Wiedemann-Steiner syndrome, High-Throughput Nucleotide Sequencing, Syndrome, KMT2A, MESH: Amino Acid Substitution, Magnetic Resonance Imaging, hypertrichosis, 3. Good health, hairiness, Phenotype, Child, Preschool, cardiovascular system, Female, Disease Susceptibility, France, medicine.symptom, MESH: Tomography, X-Ray Computed, Myeloid-Lymphoid Leukemia Protein, medicine.medical_specialty, MESH: Mutation, Adolescent, MESH: Disease Susceptibility, MESH: Phenotype, Short stature, MESH: Intellectual Disability, 03 medical and health sciences, Hypertrichosis cubiti, Intellectual Disability, Genetics, medicine, Humans, histone methylation, MESH: Adolescent, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, business.industry, MESH: Child, Preschool, MESH: Histone-Lysine N-Methyltransferase, Histone-Lysine N-Methyltransferase, medicine.disease, MESH: Male, MESH: France, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Amino Acid Substitution, MESH: Myeloid-Lymphoid Leukemia Protein, Mutation, biology.protein, business, Tomography, X-Ray Computed, MESH: Female
Abstract: International audience; Wiedemann-Steiner syndrome (WSS) is a rare syndromic condition in which intellectual disability (ID) is associated with hypertrichosis cubiti, short stature, and characteristic facies. Following the identification of the causative gene (KMT2A) in 2012, only 31 cases of WSS have been described precisely in the literature. We report on 33 French individuals with a KMT2A mutation confirmed by targeted gene sequencing, high-throughput sequencing or exome sequencing. Patients' molecular and clinical features were recorded and compared with the literature data. On the molecular level, we found 29 novel mutations. We observed autosomal dominant transmission of WSS in 3 families and mosaicism in one family. Clinically, we observed a broad phenotypic spectrum with regard to ID (mild to severe), the facies (typical or not of WSS) and associated malformations (bone, cerebral, renal, cardiac and ophthalmological anomalies). Hypertrichosis cubiti that was supposed to be pathognomonic in the literature was found only in 61% of our cases. This is the largest series of WSS cases yet described to date. A majority of patients exhibited suggestive features, but others were less characteristic, only identified by molecular diagnosis. The prevalence of WSS was higher than expected in patients with ID, suggesting than KMT2A is a major gene in ID.
Published: 2017

26. De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability

Author: Kury, S., Woerden, G.M. van, Besnard, T., Onori, M.P., Latypova, X., Towne, M.C., Cho, M.T., Prescott, T.E., Ploeg, M.A., Sanders, S., Stessman, H.A.F., Pujol, A., Distel, ben, Robak, L.A., Bernstein, J.A., Denomme-Pichon, A.S., Lesca, G., Sellars, E.A., Berg, J., Carre, W., Busk, O.L., Bon, B.W.M. van, Waugh, J.L., Deardorff, M., Hoganson, G.E., Bosanko, K.B., Johnson, D.S., Dabir, T., Holla, O.L., Sarkar, A., Tveten, K., Bellescize, J. de, Braathen, G.J., Terhal, P.A., Grange, D.K., Haeringen, A. van, Lam, C., Mirzaa, G., Burton, J., Bhoj, E.J., Douglas, J., Santani, A.B., Nesbitt, A.I., Helbig, K.L., Andrews, M.V., Begtrup, A., Tang, S., Gassen, K.L.I. van, Juusola, J., Foss, K., Enns, G.M., Moog, U., Hinderhofer, K., Paramasivam, N., Lincoln, S., Kusako, B.H., Lindenbaum, P., Charpentier, E., Nowak, C.B., Cherot, E., Simonet, T., Ruivenkamp, C.A.L., Hahn, S., Brownstein, C.A., Xia, F., Schmitt, S., Deb, W., Bonneau, D., Nizon, M., Quinquis, D., Chelly, J., Rudolf, G., Sanlaville, D., Parent, P., Gilbert-Dussardier, B., Toutain, A., Sutton, V.R., Thies, J., Peart-Vissers, L.E.L.M., Boisseau, P., Vincent, M., Grabrucker, A.M., Dubourg, C., Tan, W.H., Verbeek, N.E., Granzow, M., Santen, G.W.E., Shendure, J., Isidor, B., Pasquier, L., Redon, R., Yang, Y.P., State, M.W., Kleefstra, T., Cogne, B., Petrovski, S., Retterer, K., Eichler, E.E., Rosenfeld, J.A., Agrawal, P.B., Bezieau, S., Odent, S., Elgersma, Y., Mercier, S., Undiagnosed Dis Network, GEM HUGO, Deciphering Dev Dis Study, Service de génétique médicale [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Neuroscience [Rotterdam, the Netherlands], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Expertise Center for Neurodevelopmental Disorders [Rotterdam, the Netherlands] (ENCORE), Genomics Program and Division of Genetics [Boston, USA], Harvard Medical School [Boston] (HMS)-Boston Children's Hospital-The Manton Center for Orphan Disease Research, Gene Discovery Core [Boston, MA, USA] ( The Manton Center for Orphan Disease Research), Harvard Medical School [Boston] (HMS)-Boston Children's Hospital, GeneDx [Gaithersburg, MD, USA], Department of Medical Genetics [Skien, Norway], Telemark Hospital Trust [Skien, Norway], Department of Psychiatry [San Francisco, CA, USA], University of California [San Francisco] (UCSF), University of California-University of California, Department of Genome Sciences [Seattle] (GS), University of Washington [Seattle], Department of Pharmacology [Omaha, NE, USA], Creighton University Medical School [Omaha, NE, USA], Neurometabolic Diseases Laboratory [Barcelona, Spain], Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), Centre for Biomedical Research on Rare Diseases [Barcelona, Spain] (CIBERER), Hospital Sant Joan de Déu [Barcelona], Institució Catalana de Recerca i Estudis Avançats (ICREA), Department of Medical Biochemistry [Amsterdam, the Netherlands] (Academic Medical Center), University of Amsterdam [Amsterdam] (UvA), Department of Molecular and Human Genetics [Houston, USA], Baylor College of Medecine, Department of Pediatrics [Stanford], Stanford Medicine, Stanford University-Stanford University, Département de Biochimie et Génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Service de Génétique [HCL, Lyon] (Centre de Référence des Anomalies du Développement), Hospices civils de Lyon (HCL), 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), Section of Genetics and Metabolism [Little Rock, AR, USA], University of Arkansas for Medical Sciences (UAMS), Molecular and Clinical Medicine [Dundee, UK] (School of Medicine), University of Dundee [UK]-Ninewells Hospital & Medical School [Dundee, UK], Laboratoire de Génétique Moléculaire & Génomique [CHU Rennes], CHU Pontchaillou [Rennes], Department of Human Genetics [Nijmegen], Radboud University Medical Center [Nijmegen], Department of Neurology [Boston], Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Department of Pediatrics [Philadelphia, PA, USA] (Division of Genetics), Children’s Hospital of Philadelphia (CHOP ), Department of Pediatrics [Chicago, IL, USA] (College of Medicine), University of Illinois [Chicago] (UIC), University of Illinois System-University of Illinois System, Sheffield Children's NHS Foundation Trust, Northern Ireland Regional Genetics Centre [Belfast, UK], Belfast City Hospital-Belfast Health and Social Care Trust, Nottingham Regional Genetics Service [Nottingham, UK], City Hospital Campus [Nottingham, UK]-Nottingham University Hospitals NHS Trust [UK], Département d'Epilepsie, Sommeil et Neurophysiologie Pédiatrique [HCL, Lyon], Hospices Civils de Lyon (HCL), Department of Genetics [Utrecht, the Netherlands], University Medical Center [Utrecht], Department of Pediatrics [Saint Louis, MO, USA] (Division of Genetics and Genomic Medicine), Washington University in Saint Louis (WUSTL), Department of Clinical Genetics [Leiden, the Netherlands], Leiden University Medical Center (LUMC), Department of Pediatrics [Seattle, WA, USA] (Division of Genetic Medicine), University of Washington [Seattle]-Seattle Children’s Hospital, Center for Integrative Brain Research [Seattle, WA, USA], University of Washington [Seattle]-Seattle Children's Research Institute, The Center for Applied Genomics [Philadelphia, PA, USA], Division of Human Genetics [Philadelphia, PA, USA], Department of Pathology and Laboratory Medicine [Philadelphia, PA, USA], University of Pennsylvania [Philadelphia]-Perelman School of Medicine, University of Pennsylvania [Philadelphia], Department of Pathology and Laboratory Medicine [Philadelphia, PA, USA] (Perelman School of Medicine), Division of Clinical Genomics [Aliso Viejo, CA, USA], Ambry Genetics [Aliso Viejo, CA, USA], Division of Neurology [Philadelphia, PA, USA], Institute of Human Genetics [Heidelberg, Germany], Universität Heidelberg [Heidelberg], University of Heidelberg, Medical Faculty, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Service de Neurologie [CHU Strasbourg], Hôpital de Hautepierre [Strasbourg]-Centre Hospitalier Universitaire de Strasbourg (CHU de Strasbourg ), Département de génétique médicale en pédiatrie [CHRU Brest], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service de Génétique [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service de Génétique [CHRU Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Department of Biological Sciences [Limerick, Ireland], University of Limerick (UL), Bernal Institute [Limerick, Ireland], Howard Hughes Medical Institute [Seattle], Howard Hughes Medical Institute (HHMI), 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), Service de Génétique Clinique [CHU Rennes] (Réseau de Génétique et Génomique Médicale), Hôpitaux Universitaires du Grand Ouest, The Wellcome Trust Sanger Institute [Cambridge], Department of Medicine [Melbourne, Australia], University of Melbourne-Austin Health, Division of Newborn Medicine [Boston, MA, USA], Immunobiology of Human αβ and γδ T Cells and Immunotherapeutic Applications (CRCINA-ÉQUIPE 1), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Neurosciences, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Univ Angers, Okina, University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC), 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), Laboratoire de génétique moléculaire et génomique médicale [CHU Rennes], Nottingham University Hospitals NHS Trust (NUH)-City Hospital Campus [Nottingham, UK], Universiteit Leiden-Universiteit Leiden, Department of Pediatrics [Seattle, WA, USA], University of Pennsylvania-Perelman School of Medicine, University of Pennsylvania, Universität Heidelberg [Heidelberg] = Heidelberg University, Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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 ), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Amsterdam Gastroenterology Endocrinology Metabolism, Medical Biochemistry, and Bernardo, Elizabeth
Subjects: 0301 basic medicine, Male, de novo mutations, AMPAR, medicine.disease_cause, Inbred C57BL, Mice, 0302 clinical medicine, Intellectual disability, CAMK2A, Exome, Phosphorylation, Genetics (clinical), Genetics, Neurons, Mutation, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Brain, Phenotype, NMDAR, intellectual disability, Female, Signal transduction, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Signal Transduction, Glutamic Acid, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Article, Cell Line, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Journal Article, Animals, Humans, Protein kinase A, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], synaptic plasticity, medicine.disease, Mice, Inbred C57BL, CAMK2, CAMK2B, 030104 developmental biology, HEK293 Cells, Synaptic plasticity, Calcium-Calmodulin-Dependent Protein Kinase Type 2, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Contains fulltext : 182539.pdf (Publisher’s version ) (Closed access) Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration. For both CAMK2A and CAMK2B, we identified mutations that decreased or increased CAMK2 auto-phosphorylation at Thr286/Thr287. We further found that all mutations affecting auto-phosphorylation also affected neuronal migration, highlighting the importance of tightly regulated CAMK2 auto-phosphorylation in neuronal function and neurodevelopment. Our data establish the importance of CAMK2A and CAMK2B and their auto-phosphorylation in human brain function and expand the phenotypic spectrum of the disorders caused by variants in key players of the glutamatergic signaling pathway.
Published: 2017

27. Autosomal recessive primary microcephaly due to ASPM mutations: An update

Author: Martine Doco-Fenzy, Monique Elmaleh-Bergès, Berten Ceulemans, Sandrine Passemard, David Geneviève, Anita Rauch, Daniel Amram, Anais Ernault, Bernd Wollnick, Christine Francannet, Alain Verloes, Abdelaziz Sefiani, Pascaline Letard, Julie Désir, Marc Abramowicz, Brigitte Benzacken, Clothilde Rivier-Ringenbach, Toni Kasole Lubala, Yusuf Tunca, Vincent El Ghouzzi, Mathilde Nizon, Laurence Faivre, Marion Gérard, Koenraad Devriendt, Nathalie Pouvreau, Sophie Guilmin Crepon, Massimiliano Rossi, Hélène Maurey, C. Geoffrey Woods, Julia Metreau, Séverine Drunat, Michèle Mathieu-Dramard, Yves Sznajer, Cyril Gitiaux, Tiffany Busa, Geneviève Pierquin, Corinne Alberti, Sabine Sigaudy, Elise Schaefer, Stéphanie Arpin, Sébastien Lebon, Marta Bertoli, Pierre Gressens, Sophie Julia, Siham Chafai Elalaoui, Sarah Duerinckx, Sanaa Nasserereddine, Yoann Vial, Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université libre de Bruxelles (ULB), Unité fonctionnelle de génétique clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Antwerp (UA), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Centre Hospitalier Universitaire de Reims (CHU Reims), Hôpital Mohamed V, Rabat, Maroc, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), 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 Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Physiopathologie et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lubumbashi (UNILU), Unité de génétique médicale et oncogénétique [CHU Amiens Picardie], CHU Amiens-Picardie, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), CHU Ibn Rochd [Casablanca], Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire de Liège (CHU-Liège), L'Hôpital Nord-Ouest [Villefranche sur Saône], Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Université Catholique de Louvain = Catholic University of Louvain (UCL), Gülhane School of Medicine, Centre d'Investigation Clinique 1426 (CIC 1426), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Georg-August-University = Georg-August-Universität Göttingen, University of Cambridge [UK] (CAM), University hospital of Zurich [Zurich], Physiopathologie, conséquences fonctionnelles et neuroprotection des atteintes du cerveau en développement, Université Paris Diderot - Paris 7 (UPD7)-IFR2-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Jean Verdier [Bondy], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), UFR Santé, Médecine et Biologie Humaine (UFR SMBH), Université Paris 13 (UP13), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), 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), SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV), CHU Clermont-Ferrand, Département de génétique médicale, maladies rares et médecine personnalisée [CHRU de Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de neurologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], CHU Toulouse [Toulouse], Hospices Civils de Lyon (HCL), 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), Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Service de neuropédiatrie et maladies métaboliques [CHU Robert-Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), 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), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), UCL - (SLuc) Centre de génétique médicale UCL, UCL - SSS/IREC/SLUC - Pôle St.-Luc, Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Lubumbashi, Georg-August-University [Göttingen], Richard, Nicolas, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Neuroprotection du Cerveau en Développement ( PROTECT ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpital Jean Verdier, UFR Santé, Médecine et Biologie Humaine ( UFR SMBH ), Université Paris 13 ( UP13 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), Hôpital Bretonneau-CHRU Tours, Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Universitaire de Reims ( CHU Reims ), Université de Reims Champagne-Ardenne ( URCA ) -Université de Picardie Jules Verne ( UPJV ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Service de Génétique Clinique [Caen], Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -CHU Caen, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Hospices Civils de Lyon ( HCL ), Centre de recherche en neurosciences de Lyon ( CRNL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre d'Investigation Clinique 1426 ( CIC 1426 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré, Passemard, Sandrine [0000-0002-0242-4566], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Male, Microcephaly, MESH: Geography, Intellectual disability, ASPM, brain development, brain imaging, MESH: Cognition, [SDV.GEN] Life Sciences [q-bio]/Genetics, Spindle pole body, MESH: Magnetic Resonance Imaging, Cohort Studies, Neurodevelopmental disorder, Cognition, MESH: Nerve Tissue Proteins, MESH: Cohort Studies, Genetics (clinical), MESH: Genetic Association Studies, Genetics, 0303 health sciences, Geography, primary microcephaly, 030305 genetics & heredity, Brain development, MESH: Infant, Magnetic Resonance Imaging, 3. Good health, intellectual disability, Child, Preschool, Autosomal Recessive Primary Microcephaly, Brain size, Female, MESH: Mutation, Brain imaging, Nerve Tissue Proteins, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, MESH: Microcephaly, Primary microcephaly, 03 medical and health sciences, medicine, Humans, Family, Gene, MESH: Family, Genetic Association Studies, 030304 developmental biology, Centrosome, MCPH, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Genetic heterogeneity, MESH: Child, Preschool, Infant, medicine.disease, MESH: Male, 030104 developmental biology, centrosome, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, Human medicine, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, MESH: Female
Abstract: Autosomal recessive microcephaly or MicroCephaly Primary Hereditary (MCPH) is a genetically heterogeneous neurodevelopmental disorder characterized by a reduction in brain volume, indirectly measured by an occipitofrontal circumference (OFC) 2 standard deviations or more below the age- and sex-matched mean (-2SD) at birth and -3SD after 6 months, and leading to intellectual disability of variable severity. The Abnormal SPindle-like Microcephaly gene (ASPM), the human ortholog of the Drosophila melanogaster 'abnormal spindle' gene (asp), encodes ASPM, a protein localized at the centrosome of apical neuroprogenitor cells and involved in spindle pole positioning during neurogenesis. Loss-of-function mutations in ASPM cause MCPH5, which affects the majority of all MCPH patients worldwide. Here, we report 47 unpublished patients from 39 families carrying 28 new ASPM mutations, and conduct an exhaustive review of the molecular, clinical, neuroradiological and neuropsychological features of the 282 families previously reported (with 161 distinct ASPM mutations). Furthermore, we show that ASPM-related microcephaly is not systematically associated with intellectual deficiency and discuss the association between the structural brain defects (strong reduction in cortical volume and surface area) that modify the cortical map of these patients and their cognitive abilities. This article is protected by copyright. All rights reserved. ispartof: Human Mutation vol:39 issue:3 pages:319-332 ispartof: location:United States status: published
Published: 2017

28. Translation of Expanded CGG Repeats into FMRpolyG Is Pathogenic and May Contribute to Fragile X Tremor Ataxia Syndrome

Author: Marie-Christine Birling, Chantal Sellier, Frank Ruffenach, Cécile Martinat, Marie Wattenhofer-Donzé, Stéphane Viville, Ronald A.M. Buijsen, Mustapha Oulad-Abdelghani, Hamid Meziane, Peter K. Todd, Alexandre Vincent, Guillaume Pavlovic, Pascal Eberling, Hugues Jacobs, Verónica Martínez-Cerdeño, Flora Tassone, Marie-France Champy, Laura Jung, Fang He, Nicolas Charlet-Berguerand, Philippe Tropel, Mathieu Anheim, Angeline Gaucherot, Tania Sorg, Renate K. Hukema, Mathilde Joint, Rob Willemsen, Sam Natla, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Michigan [Ann Arbor], University of Michigan System, Institut Clinique de la Souris (ICS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA), Hôpital de Hautepierre [Strasbourg], University of California [Davis] (UC Davis), University of California, Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Nouvel Hôpital Civil de Strasbourg, Institut de Parasitologie et de Pathologie Tropicale (IPPTS), Université de Strasbourg (UNISTRA), Université d'Évry-Val-d'Essonne (UEVE), Institut des cellules souches pour le traitement et l'étude des maladies monogéniques (I-STEM), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon, Association française contre les myopathies (AFM-Téléthon), Centre for Integrative Biology - CBI (Inserm U964 - CNRS UMR7104 - IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), French National Infrastructure for Mouse Phenogenomics (PHENOMIN), CHU Strasbourg, University of California (UC), Dieterle, Stéphane, and Clinical Genetics
Subjects: Male, 0301 basic medicine, Untranslated region, MESH: Ataxia, [SDV]Life Sciences [q-bio], MESH: Tremor, MESH: Nuclear Lamina, Pathogenesis, Fragile X Mental Retardation Protein, Mice, [SCCO]Cognitive science, Tremor, MESH: Trinucleotide Repeat Expansion, MESH: Animals, Induced pluripotent stem cell, ComputingMilieux_MISCELLANEOUS, Genetics, Fragile X Tremor/Ataxia Syndrome, MESH: Peptides, MESH: Real-Time Polymerase Chain Reaction, General Neuroscience, neurodegeneration, Brain, Translation (biology), 3. Good health, DNA-Binding Proteins, [SDV] Life Sciences [q-bio], MESH: Protein Biosynthesis, Nuclear lamina, MESH: Membrane Proteins, MESH: Fragile X Syndrome, medicine.symptom, congenital, hereditary, and neonatal diseases and abnormalities, near-cognate codon, Ataxia, MESH: Mice, Transgenic, Neuroscience(all), Mice, Transgenic, Biology, Real-Time Polymerase Chain Reaction, MESH: Fragile X Mental Retardation Protein, Article, MESH: Brain, 03 medical and health sciences, RAN translation, medicine, Animals, Humans, RNA, Messenger, MESH: Mice, MESH: RNA, Messenger, Nuclear Lamina, MESH: Humans, Membrane Proteins, RNA, [SCCO] Cognitive science, microsatellite expansion, MESH: Male, nervous system diseases, 030104 developmental biology, Fragile X Syndrome, Protein Biosynthesis, Peptides, Trinucleotide Repeat Expansion, MESH: DNA-Binding Proteins
Abstract: Summary Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by a limited expansion of CGG repeats in the 5′ UTR of FMR1. Two mechanisms are proposed to cause FXTAS: RNA gain-of-function, where CGG RNA sequesters specific proteins, and translation of CGG repeats into a polyglycine-containing protein, FMRpolyG. Here we developed transgenic mice expressing CGG repeat RNA with or without FMRpolyG. Expression of FMRpolyG is pathogenic, while the sole expression of CGG RNA is not. FMRpolyG interacts with the nuclear lamina protein LAP2β and disorganizes the nuclear lamina architecture in neurons differentiated from FXTAS iPS cells. Finally, expression of LAP2β rescues neuronal death induced by FMRpolyG. Overall, these results suggest that translation of expanded CGG repeats into FMRpolyG alters nuclear lamina architecture and drives pathogenesis in FXTAS., Highlights • CGG repeats in the 5′ UTR of FMR1 are translated through initiation to an ACG codon • Translation of CGG repeats in the polyglycine protein, FMRpolyG, is toxic in mice • FMRpolyG binds and disrupts protein of the nuclear lamina, Sellier et al. show that translation of expanded CGG repeats located in the 5′ UTR of the FMR1 gene require an upstream ACG near-cognate initiation codon. Translation of CGG repeats into a short polyglycine-containing protein, FMRpolyG, is pathogenic in mouse models.
Published: 2017

29. GENESIS: a French national resource to study the missing heritability of breast cancer

Author: Sylvie Mazoyer, Valérie Layet, Carole Verny-Pierre, Claude Adenis, Marie-Gabrielle Dondon, Isabelle Mortemousque, Morgane Marcou, Olga M. Sinilnikova, Philippe Jonveaux, Anne Floquet, François Eisinger, Yves-Jean Bignon, Catherine Noguès, Laurence Gladieff, Capucine Delnatte, Olivier Caron, Bruno Buecher, Pascaline Berthet, Anne Fajac, Clotilde Penet, Séverine Eon-Marchais, Sandra Fert-Ferrer, Florent Soubrier, Dominique Stoppa-Lyonnet, Chrystelle Colas, Isabelle Coupier, Christine Lasset, Emmanuelle Barouk-Simonet, Michel Longy, Jean-Pierre Fricker, Jean Chiesa, Sophie Giraud, Dominique Leroux, Catherine Dugast, Sophie Lejeune-Dumoulin, Hélène Dreyfus, Annie Chevrier, Odile Cohen-Haguenauer, Thierry Frebourg, Liliane Demange, Julie Tinat, Fabienne Lesueur, Pascal Pujol, Emmanuelle Mouret-Fourme, Elisabeth Luporsi, Christine Maugard, Dorothée Le Gal, Noura Mebirouk, Séverine Audebert-Bellanger, Laure Barjhoux, Muriel Belotti, Eve Cavaciuti, Marion Gauthier-Villars, Marie-Agnès Collonge-Rame, Paul Gesta, Jean-Marc Limacher, Odile Bera, Lucie Toulemonde, Anne Tardivon, Fabienne Prieur, Laurence Faivre, Juana Beauvallet, Alain Lortholary, Nadine Andrieu, François Cornelis, Marc Frenay, Valérie Sornin, Laurence Venat-Bouvet, Francesca Damiola, Valérie Bonadona, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Université Paris sciences et lettres (PSL), Service de génétique, Institut Curie Paris, Onco-génétique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Catherine-de-Sienne [Nantes] (CCS), CRLCC Eugène Marquis (CRLCC), Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), CRLCC Paul Strauss, CRLCC René Huguenin, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service d'oncogénétique [Centre georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), UNICANCER, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), CRLCC René Gauducheau, Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Centre Léon Bérard [Lyon], Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Département d'Oncologie et Hématologie [Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS), Institut Bergonié [Bordeaux], Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Service d'Oncologie médicale [CHU Limoges], CHU Limoges, Polyclinique de Courlancy, Institut Sainte Catherine [Avignon], Centre Hospitalier Universitaire [Grenoble] (CHU), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Institut Claudius Regaud, Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Département de génétique médicale en pédiatrie [CHRU Brest], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Hôpital Jeanne de Flandre [Lille], Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Hôpital pasteur [Colmar], Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U912 INSERM - Aix Marseille Univ - IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Métropole Savoie [Chambéry], CRLCC Jean Godinot, Institut du cancer Courlancy-Reims, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Hôpital Gustave Flaubert, Service de génétique médicale CHU Grenoble Hôpital Couple Enfant, CHU Grenoble, Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Centre Viggo-Petersen, Service de Génétique Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), CHU de la Martinique [Fort de France], Institut Curie, Département d'Imagerie Médicale (Curie Institute, Department of Medical Imaging), F-75005 Paris, France., Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), UL, NGERE, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), MINES ParisTech - École nationale supérieure des mines de Paris, UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Université Lille Nord de France (COMUE)-UNICANCER, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: 0301 basic medicine, Oncology, Cancer Research, [SDV]Life Sciences [q-bio], Genome-wide association study, Identifies 2, Genome-Wide Association, 0302 clinical medicine, Missing heritability problem, Confer Susceptibility, Susceptibility Loci, 10. No inequality, skin and connective tissue diseases, education.field_of_study, medicine.diagnostic_test, BRCA1 Protein, Middle Aged, 16. Peace & justice, 3. Good health, Neoplasm Proteins, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, Female, France, Research Article, Adult, Risk, medicine.medical_specialty, Population, Breast Neoplasms, 03 medical and health sciences, Germline mutation, Breast cancer, Internal medicine, medicine, Genetics, Humans, Genetic Predisposition to Disease, Genetic Testing, education, Germ-Line Mutation, Alleles, Genetic testing, Aged, Gynecology, BRCA2 Protein, Common Variants, business.industry, Genetic heterogeneity, Cancer, medicine.disease, 030104 developmental biology, business
Abstract: Background Less than 20 % of familial breast cancer patients who undergo genetic testing for BRCA1 and BRCA2 carry a pathogenic mutation in one of these two genes. The GENESIS (GENE SISter) study was designed to identify new breast cancer susceptibility genes in women attending cancer genetics clinics and with no BRCA1/2 mutation. Methods The study involved the French national network of family cancer clinics. It was based on enrichment in genetic factors of the recruited population through case selection relying on familial criteria, but also on the consideration of environmental factors and endophenotypes like mammary density or tumor characteristics to assess potential genetic heterogeneity. One of the initial aims of GENESIS was to recruit affected sibpairs. Siblings were eligible when index cases and at least one affected sister were diagnosed with infiltrating mammary or ductal adenocarcinoma, with no BRCA1/2 mutation. In addition, unrelated controls and unaffected sisters were recruited. The enrolment of patients, their relatives and their controls, the collection of the clinical, epidemiological, familial and biological data were centralized by a coordinating center. Results Inclusion of participants started in February 2007 and ended in December 2013. A total of 1721 index cases, 826 affected sisters, 599 unaffected sisters and 1419 controls were included. 98 % of participants completed the epidemiological questionnaire, 97 % provided a blood sample, and 76 % were able to provide mammograms. Index cases were on average 59 years old at inclusion, were born in 1950, and were 49.7 years of age at breast cancer diagnosis. The mean age at diagnosis of affected sisters was slightly higher (51.4 years). The representativeness of the control group was verified. Conclusions The size of the study, the availability of biological specimens and the clinical data collection together with the detailed and complete epidemiological questionnaire make this a unique national resource for investigation of the missing heritability of breast cancer, by taking into account environmental and life style factors and stratifying data on endophenotypes to decrease genetic heterogeneity.
Published: 2016

30. MSI detection and its pitfalls in CMMRD syndrome in a family with a bi-allelic MLH1 mutation

Author: Meriam Koob, Natacha Entz-Werle, Marie Pierre Chenard, Aurelia Nguyen, Anne Schneider, Gaëlle Bougeard, Christine Maugard, Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de Pathologie, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Développement et physiopathologie de l'intestin et du pancréas, Institut National de la Santé et de la Recherche Médicale (INSERM), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, and Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Oncology, Male, congenital, hereditary, and neonatal diseases and abnormalities, Cancer Research, medicine.medical_specialty, Pathology, Gliomatosis cerebri, MLH1, 03 medical and health sciences, Germline mutation, Neoplastic Syndromes, Hereditary, Internal medicine, Genetics, medicine, PMS2, Humans, Family history, Child, Genetics (clinical), Germ-Line Mutation, ComputingMilieux_MISCELLANEOUS, business.industry, Brain Neoplasms, Microsatellite instability, medicine.disease, digestive system diseases, 3. Good health, Pedigree, MSH6, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MSH2, Female, Microsatellite Instability, business, Colorectal Neoplasms, MutL Protein Homolog 1
Abstract: The constitutional MisMatch Repair deficiency (CMMRD) syndrome is one of the inherited cancer predisposition syndromes. More than two-third patients belonging to a CMMRD family are diagnosed mainly in the first decade with brain cancers and/or hematological malignancies. This syndrome is due to bi-allelic germline mutations in genes of the MMR pathway (MLH1, MSH2, MSH6 or PMS2). Our family report begins with the index case presenting initially with a medulloblastoma, which was even the two relapses in complete remission, when she was diagnosed for an AML. She died after bone marrow transplantation from toxicity. The family history was progressively established when her uncle was diagnosed for a colonic cancer and a cousin for a brain tumor. Surprisingly, her father had an atypical sarcoma but her brother also presented a lymphoma followed by a gliomatosis cerebri. A new MLH1 bi-allelic mutation was identified in this family. More than the diagnostic difficulties, this family report illustrates the complexity of the microsatellite instability detection in CMMRD patients, which has to be discussed further to a more accurate diagnosis in the pediatric setting, and address the question of the proper diagnostic tool to use in such genetic background with hypermutated tumors.
Published: 2016

31. Identity by descent fine mapping of familial adult myoclonus epilepsy (FAME) to 2p11.2–2q11.2

Author: Lyndal Henden, Zaid Afawi, Renzo Guerrini, Christel Depienne, Laura Canafoglia, Boris Keren, Jozef Gecz, Melanie Bahlo, Federico Zara, Laura Licchetta, Pasquale Striano, Douglas E. Crompton, Sara Baldassari, Samuel F. Berkovic, Francesca Bisulli, Edouard Hirsch, Davide Mei, Ingrid E. Scheffer, Caroline Nava, Karl Martin Klein, Mark A. Corbett, Saskia Freytag, Eric LeGuern, Giorgio Casari, Gabrielle Rudolf, Pierre Labauge, Tommaso Pippucci, Paolo Tinuper, Ingo Helbig, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, CHU Strasbourg, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Service de Neurologie [Strasbourg], CHU Strasbourg-Hopital Civil, Henden, Lyndal, Freytag, Saskia, Afawi, Zaid, Baldassari, Sara, Berkovic, Samuel F., Bisulli, Francesca, Canafoglia, Laura, Casari, GIORGIO NEVIO, Crompton, Douglas Ewan, Depienne, Christel, Gecz, Jozef, Guerrini, Renzo, Helbig, Ingo, Hirsch, Edouard, Keren, Bori, Klein, Karl Martin, Labauge, Pierre, Leguern, Eric, Licchetta, Laura, Mei, Davide, Nava, Caroline, Pippucci, Tommaso, Rudolf, Gabrielle, Scheffer, Ingrid Eileen, Striano, Pasquale, Tinuper, Paolo, Zara, Federico, Corbett, Mark, Bahlo, Melanie, Casari, Giorgio, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM)
Subjects: 0301 basic medicine, Male, Candidate gene, Genetics, Genetics (clinical), Genotype, Genetic Linkage, Locus (genetics), Single-nucleotide polymorphism, Epilepsies, Myoclonic, Biology, Identity by descent, Polymorphism, Single Nucleotide, 03 medical and health sciences, Genetic Heterogeneity, 0302 clinical medicine, Genetic, Locus heterogeneity, Seizures, medicine, Humans, Alleles, Genetic heterogeneity, Medicine (all), Chromosome Mapping, Muscle, Smooth, medicine.disease, Founder Effect, 3. Good health, Pedigree, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Chromosomes, Human, Pair 2, Allelic heterogeneity, Female, Candidate Disease Gene, 030217 neurology & neurosurgery
Abstract: International audience; Familial adult myoclonus epilepsy (FAME) is a rare autosomal dominant disorder characterized by adult onset, involuntary muscle jerks, cortical myoclonus and occasional seizures. FAME is genetically heterogeneous with more than 70 families reported worldwide and five potential disease loci. The efforts to identify potential causal variants have been unsuccessful in all but three families. To date, linkage analysis has been the main approach to find and narrow FAME critical regions. We propose an alternative method, pedigree free identity-by-descent (IBD) mapping, that infers regions of the genome between individuals that have been inherited from a common ancestor. IBD mapping provides an alternative to linkage analysis in the presence of allelic and locus heterogeneity by detecting clusters of individuals who share a common allele. Succeeding IBD mapping, gene prioritization based on gene co-expression analysis can be used to identify the most promising candidate genes. We performed an IBD analysis using high-density single nucleotide polymorphism (SNP) array data followed by gene prioritization on a FAME cohort of ten European families and one Australian/New Zealander family; eight of which had known disease loci. By identifying IBD regions common to multiple families, we were able to narrow the FAME2 locus to a 9.78 megabase interval within 2p11.2-q11.2. We provide additional evidence of a founder effect in four Italian families and allelic heterogeneity with at least four distinct founders responsible for FAME at the FAME2 locus. In addition, we suggest candidate disease genes using gene prioritization based on gene co-expression analysis.
Published: 2016

32. The molecular and phenotypic spectrum of IQSEC2-related epilepsy

Author: Michael Field, Andreas Tzschach, Eric H. Kossoff, Kazuhiro Haginoya, Lubov Blumkin, Orna Epstein, David Geneviève, Sara Kivity, Marjolaine Willems, Ayelet Zerem, Cheryl Shoubridge, Elizabeth E. Palmer, Tjitske Kleefstra, Hirotomo Saitsu, Naomichi Matsumoto, David Chitayat, Amélie Piton, Jackie Boyle, Sarah Dugan, Dorit Lev, Tally Lerman-Sagie, Alice Masurel-Paulet, Ilan Linder, Eli Heyman, Esther Leshinsky-Silver, Frederic Tran-Mau-Them, Ryo Sato, Rolph Pfundt, William D. Gaillard, Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), 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), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Diagnostic Génétique [CHU Strasbourg], and Université de Strasbourg (UNISTRA)-CHU Strasbourg
Subjects: Adult, Male, Exome sequencing, 0301 basic medicine, Pediatrics, medicine.medical_specialty, Adolescent, Intellectual disability, Cohort Studies, Young Adult, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, medicine, Guanine Nucleotide Exchange Factors, Humans, Child, Strabismus, Psychiatry, Genetic Association Studies, X-linked, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Epileptic encephalopathy, business.industry, Seizure types, Brain, Electroencephalography, medicine.disease, Magnetic Resonance Imaging, Hypotonia, 3. Good health, Epileptic spasms, Phenotype, 030104 developmental biology, Neurology, Child, Preschool, Mutation, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), medicine.symptom, business, Developmental regression, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery
Abstract: Item does not contain fulltext OBJECTIVE: IQSEC2 is an X-linked gene associated with intellectual disability (ID) and epilepsy. Herein we characterize the epilepsy/epileptic encephalopathy of patients with IQSEC2 pathogenic variants. METHODS: Forty-eight patients with IQSEC2 variants were identified worldwide through Medline search. Two patients were recruited from our early onset epileptic encephalopathy cohort and one patient from personal communication. The 18 patients who have epilepsy in addition to ID are the subject of this study. Information regarding the 18 patients was ascertained by questionnaire provided to the treating clinicians. RESULTS: Six affected individuals had an inherited IQSEC2 variant and 12 had a de novo one (male-to-female ratio, 12:6). The pathogenic variant types were as follows: missense (8), nonsense (5), frameshift (1), intragenic duplications (2), translocation (1), and insertion (1). An epileptic encephalopathy was diagnosed in 9 (50%) of 18 patients. Seizure onset ranged from 8 months to 4 years; seizure types included spasms, atonic, myoclonic, tonic, absence, focal seizures, and generalized tonic-clonic (GTC) seizures. The electroclinical syndromes could be defined in five patients: late-onset epileptic spasms (three) and Lennox-Gastaut or Lennox-Gastaut-like syndrome (two). Seizures were pharmacoresistant in all affected individuals with epileptic encephalopathy. The epilepsy in the other nine patients had a variable age at onset from infancy to 18 years; seizure types included GTC and absence seizures in the hereditary cases and GTC and focal seizures in de novo cases. Seizures were responsive to medical treatment in most cases. All 18 patients had moderate to profound intellectual disability. Developmental regression, autistic features, hypotonia, strabismus, and white matter changes on brain magnetic resonance imaging (MRI) were prominent features. SIGNIFICANCE: The phenotypic spectrum of IQSEC2 disorders includes epilepsy and epileptic encephalopathy. Epileptic encephalopathy is a main clinical feature in sporadic cases. IQSEC2 should be evaluated in both male and female patients with an epileptic encephalopathy.
Published: 2016

33. Genes for spinocerebellar ataxia with blindness and deafness (SCABD/SCAR3, MIM# 271250 and SCABD2)

Author: Haluk Topaloglu, Mireille Claustres, Sacha Ferdinandusse, Bruno Leheup, Elif Acar Arslan, Christine Tranchant, Michel Koenig, Claire Guissart, Ruth Gershoni-Barush, Lise Larrieu, Jean Muller, Ibrahim Oncel, Nathalie Drouot, Mathieu Anheim, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Laboratory Genetic Metabolic Diseases, 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), Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Pediatrics [Hacettepe], Hacettepe University = Hacettepe Üniversitesi, Service de Médecine Infantile III et Génétique Clinique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Rambam Medical Centre, 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), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratory Genetic Metabolic Diseases [Academic Medical Centre], Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), Hôpital de Hautepierre [Strasbourg], and Çocuk Sağlığı ve Hastalıkları
Subjects: 0301 basic medicine, Adult, Male, Biochemistry & Molecular Biology, medicine.medical_specialty, Ataxia, Adolescent, [SDV]Life Sciences [q-bio], Mutation, Missense, Biology, Deafness, Blindness, Article, Receptors, G-Protein-Coupled, 03 medical and health sciences, 0302 clinical medicine, Genetic linkage, Molecular genetics, Genetics, medicine, Missense mutation, Humans, Spinocerebellar Ataxias, Exome, Child, Genetics (clinical), Cells, Cultured, Genetics & Heredity, Adenosine Triphosphatases, Syndrome, medicine.disease, 3. Good health, Pedigree, Wiskott-Aldrich Syndrome Protein Family, 030104 developmental biology, Spinocerebellar ataxia, Medical genetics, ATPases Associated with Diverse Cellular Activities, Female, medicine.symptom, 030217 neurology & neurosurgery, PEX6
Abstract: International audience; Ataxia is a symptom that is often associated with syndromic inherited diseases. We previously reported the linkage of a novel syndrome, ataxia with blindness and deafness (SCAR3/SCABD, OMIM# 271250), to chromosome 6p21-p23 by linkage mapping of an Arab Israeli consanguineous family. We have now identified by whole-exome sequencing a homozygous missense mutation in the Arab Israeli family in the SLC52A2 gene located in 8qter, therefore excluding linkage of this family to 6p. We confirmed the involvement of SLC52A2 by the identification of a second mutation in an independent family with an identical syndromic presentation, which we suggest to name SCABD2. SCABD2 is therefore allelic to Brown-Vialleto-Van Laere syndrome type 2 defined by prominent motoneuronopathy and deafness, and also caused by SLC52A2 mutations. In the course of this project, we identified a clinically similar family with a homozygous missense mutation in PEX6, which is located in 6p21. Therefore, despite false linkage in the initial family, SCABD1/SCAR3 is located in 6p21 and is caused by PEX6 mutations. Both SLC52A2 and PEX6 should be included in screening panels for the diagnosis of syndromic inherited ataxias, particularly as patients with mutations in SLC52A2 can be ameliorated by riboflavin supplementation.
Published: 2015

34. Extensive morphological and immunohistochemical characterization in myotubular myopathy

Author: Michel Fardeau, Norma B. Romero, Jean-Yves Hogrel, Makiko Osawa, Jocelyn Laporte, Valérie Biancalana, M. Shichiji, HAL UPMC, Gestionnaire, Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Tokyo Women's Medical University (TWMU), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Centre de référence des maladies rares neuromusculaires [CHU Pitié-Salpétriêre], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de référence des maladies rares neuromusculaires, 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), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Pathology, medicine.medical_specialty, MTM1, Myotubularin, Morphological pattern, satellite, Biology, 03 medical and health sciences, Behavioral Neuroscience, 0302 clinical medicine, Biopsy, medicine, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Centronuclear myopathy, Centronuclear myopathies, myotubular myopathy, Original Research, 030304 developmental biology, satellite cells, 0303 health sciences, Muscle biopsy, medicine.diagnostic_test, Muscle weakness, Skeletal muscle, medicine.disease, Congenital myopathy, myotubularin, medicine.anatomical_structure, T-tubules, cells, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, 030217 neurology & neurosurgery
Abstract: International audience; The X-linked myotubular myopathy (XLMTM) also called X-linked centronu-clear myopathy is a rare congenital myopathy due to mutations in the MTM1 gene encoding myotubularin. The disease gives rise to a severe muscle weakness in males at birth. The main muscle morphological characteristics (significant number of small muscle fibers with centralized nuclei and type 1 fiber predominance) are usually documented, but the sequence of formation and maintenance of this particular morphological pattern has not been extensively characterized in humans. In this study, we perform a reevaluation of morphological changes in skeletal muscle biopsies in severe XLMTM. We correlate the pathologic features observed in the muscle biopsies of 15 newborns with MTM1-mutations according to the " adjusted-age " at the time of muscle biopsy, focusing on sequential analysis in the early period of the life (from 34 weeks of gestation to 3 months of age). We found a similar morphological pattern throughout the period analyzed; the proportion of myofibers with central nuclei was high in all muscle biopsies, independently of the muscle type, the age of the newborns at time of biopsy and the specific MTM1 mutation. We did not observe a period free of morphological abnormalities in human skeletal muscle as observed in myotubularin-deficient mouse models. In addition, this study demonstrated some features of delayed maturation of the muscle fibers without any increase in the number of satellite cells, associated with a marked disorgani-zation of the muscle T-tubules and cytoskeletal network in the skeletal muscle fibers.
Published: 2013

35. An integrated diagnosis strategy for congenital myopathies

Author: Julie Brocard, Isabelle Marty, Nicole Monnier, Marion Gérard, Edoardo Malfatti, Christine Kretz, Maggie C. Walter, Norma B. Romero, Bernard Jost, H. Karasoy, Valérie Biancalana, Nadia Messaddeq, Joël Lunardi, Stéphanie Le Gras, Jocelyn Laporte, Claire Feger, Nasim Vasli, Peter Reilich, Johann Böhm, Ege Üniversitesi, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Chaire Génétique Humaine, Collège de France (CdF (institution)), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Neurological, Neurosurgical, and Behavioral Sciences, Thérapie des maladies du muscle strié, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), DNA Microarrays and Sequencing Platform, ANTE-INSERM U836, équipe 4, Muscles et pathologies, Biochimie Génétique et Moléculaire, CHU Grenoble-CHU Grenoble, INSERM U836, équipe 4, Muscles et pathologies, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Neurology, Ege University School of Medicine, 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), Ludwig-Maximilians-Universität München (LMU)-Friedrich-Baur-Institute, Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Imaging Center, CHU Grenoble, This work was supported by Institut National de la Sante' et de la Recherche Me'dicale (INSERM), Centre national de la recherche scientifique (CNRS), University of Strasbourg, Colle'ge de France and grants from ANR, GIS Institute for rare diseases and IBiSA, Association Francaise contre les myopathies, Muscular Dystrophy Association (United States of America) and the Myotubular Trust. This work was supported by the INSERM, the CNRS, University of Strasbourg, Colle'ge de France and grants from the Agence Nationale de la Recherche (ANR, grant CM-WES), Muscular Dystrophy Association (MDA, grant 2010-52655) and Myotubular Trust. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., Collège de France - Chaire Génétique Humaine, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Roux-Buisson, Nathalie
Subjects: Male, Pathology, Genetic Screens, Heredity, Biopsy, DNA Mutational Analysis, Gene Identification and Analysis, lcsh:Medicine, [SDV.GEN] Life Sciences [q-bio]/Genetics, Bioinformatics, 0302 clinical medicine, Missense mutation, Exome, lcsh:Science, Exome sequencing, 0303 health sciences, Multidisciplinary, Muscles, Linkage (Genetics), 3. Good health, Pedigree, Phenotype, Medicine, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, medicine.symptom, Research Article, Adult, medicine.medical_specialty, Histology, Nonsense mutation, Molecular Sequence Data, Genetic Counseling, Biology, Muscle disorder, Molecular Genetics, 03 medical and health sciences, Nebulin, Muscular Diseases, Genetic Mutation, medicine, Genetics, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Genetic Testing, Myopathy, 030304 developmental biology, Congenital Hereditary Myopathies, RYR1, Clinical Genetics, [SDV.GEN]Life Sciences [q-bio]/Genetics, Base Sequence, Genetic heterogeneity, lcsh:R, Human Genetics, Sequence Analysis, DNA, Mutation, Genetics of Disease, biology.protein, lcsh:Q, 030217 neurology & neurosurgery
Abstract: WOS: 000321738400157, PubMed ID: 23826317, Congenital myopathies are severe muscle disorders affecting adults as well as children in all populations. The diagnosis of congenital myopathies is constrained by strong clinical and genetic heterogeneity. Moreover, the majority of patients present with unspecific histological features, precluding purposive molecular diagnosis and demonstrating the need for an alternative and more efficient diagnostic approach. We used exome sequencing complemented by histological and ultrastructural analysis of muscle biopsies to identify the causative mutations in eight patients with clinically different skeletal muscle pathologies, ranging from a fatal neonatal myopathy to a mild and slowly progressive myopathy with adult onset. We identified RYR1 (ryanodine receptor) mutations in six patients and NEB (nebulin) mutations in two patients. We found novel missense and nonsense mutations, unraveled small insertions/deletions and confirmed their impact on splicing and mRNA/protein stability. Histological and ultrastructural findings of the muscle biopsies of the patients validated the exome sequencing results. We provide the evidence that an integrated strategy combining exome sequencing with clinical and histopathological investigations overcomes the limitations of the individual approaches to allow a fast and efficient diagnosis, accelerating the patient's access to a better healthcare and disease management. This is of particular interest for the diagnosis of congenital myopathies, which involve very large genes like RYR1 and NEB as well as genetic and phenotypic heterogeneity., Institut National de la Sante et de la Recherche Medicale (INSERM)Institut National de la Sante et de la Recherche Medicale (Inserm); Centre national de la recherche scientifique (CNRS)Centre National de la Recherche Scientifique (CNRS); University of Strasbourg; College de France; GIS Institute; Association Francaise contre les myopathiesAssociation Francaise contre les Myopathies; Muscular Dystrophy Association (United States of America)Muscular Dystrophy Association; Myotubular Trust; Agence Nationale de la Recherche (ANR)French National Research Agency (ANR); Muscular Dystrophy Association (MDA)Muscular Dystrophy Association [2010-52655], This work was supported by Institut National de la Sante et de la Recherche Medicale (INSERM), Centre national de la recherche scientifique (CNRS), University of Strasbourg, College de France and grants from ANR, GIS Institute for rare diseases and IBiSA, Association Francaise contre les myopathies, Muscular Dystrophy Association (United States of America) and the Myotubular Trust. This work was supported by the INSERM, the CNRS, University of Strasbourg, College de France and grants from the Agence Nationale de la Recherche (ANR, grant CM-WES), Muscular Dystrophy Association (MDA, grant 2010-52655) and Myotubular Trust. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Published: 2012

36. A new family with an SLC9A6 mutation expanding the phenotypic spectrum of Christianson syndrome.

Author: Masurel-Paulet A, Piton A, Chancenotte S, Redin C, Thauvin-Robinet C, Henrenger Y, Minot D, Creppy A, Ruffier-Bourdet M, Thevenon J, Kuentz P, Lehalle D, Curie A, Blanchard G, Ghosn E, Bonnet M, Archimbaud-Devilliers M, Huet F, Perret O, Philip N, Mandel JL, and Faivre L
Subjects: Adolescent, Adult, Brain abnormalities, Child, DNA Mutational Analysis, Facies, Family, Female, Genetic Association Studies, Heterozygote, Humans, Magnetic Resonance Imaging, Male, Pedigree, RNA Splice Sites, Sequence Deletion, X Chromosome Inactivation, Ataxia diagnosis, Ataxia genetics, Epilepsy diagnosis, Epilepsy genetics, Genetic Diseases, X-Linked diagnosis, Genetic Diseases, X-Linked genetics, Intellectual Disability diagnosis, Intellectual Disability genetics, Microcephaly diagnosis, Microcephaly genetics, Mutation, Ocular Motility Disorders diagnosis, Ocular Motility Disorders genetics, Phenotype, Sodium-Hydrogen Exchangers genetics
Abstract: Using targeted next generation sequencing, we have identified a splicing mutation (c.526-9_526-5del) in the SLC9A6 gene in a 9-year-old boy with mild intellectual disability (ID), microcephaly, and social interaction disabilities. This intronic microdeletion leads to the skipping of exon 3 and to an in-frame deletion of 26 amino acids in the TM4 domain. It segregates with cognitive impairment or learning difficulties in other members of the family. Mutations in SLC9A6 have been reported in X-linked Christianson syndrome associating severe to profound intellectual deficiency and an Angelman-like phenotype with microcephaly, absent speech, ataxia with progressive cerebellar atrophy, ophthalmoplegia, epilepsy, and neurological regression. The proband and his maternal uncle both have an attenuated phenotype with mild ID, attention deficit disorder, speech difficulties, and mild asymptomatic cerebellar atrophy. The proband also have microcephaly. The mutation cosegregated with learning disabilities and speech difficulties in the female carriers (mother and three sisters of the proband). Detailed neuropsychological, speech, and occupational therapy investigations in the female carriers revealed impaired oral and written language acquisition, with dissociation between verbal and performance IQ. An abnormal phenotype, ranging from learning disability with predominant speech difficulties to mild intellectual deficiency, has been described previously in a large proportion of female carriers. Besides broadening the clinical spectrum of SLC9A6 gene mutations, we present an example of a monogenic origin of mild learning disability. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)
Published: 2016
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37. Identification of 28 novel mutations in the Bardet-Biedl syndrome genes: the burden of private mutations in an extensively heterogeneous disease.

Author: Muller J, Stoetzel C, Vincent MC, Leitch CC, Laurier V, Danse JM, Hellé S, Marion V, Bennouna-Greene V, Vicaire S, Megarbane A, Kaplan J, Drouin-Garraud V, Hamdani M, Sigaudy S, Francannet C, Roume J, Bitoun P, Goldenberg A, Philip N, Odent S, Green J, Cossée M, Davis EE, Katsanis N, Bonneau D, Verloes A, Poch O, Mandel JL, and Dollfus H
Subjects: Adult, Aged, Chromatography, High Pressure Liquid, Chromosome Mapping, Decision Trees, Female, Gene Deletion, Gene Duplication, Gene Frequency, Genetic Testing, Homozygote, Humans, Male, Microsatellite Repeats, Middle Aged, Molecular Sequence Data, Pedigree, Polymorphism, Single Nucleotide, Polymorphism, Single-Stranded Conformational, Sequence Analysis, DNA, Bardet-Biedl Syndrome diagnosis, Bardet-Biedl Syndrome genetics, Mutation
Abstract: Bardet-Biedl syndrome (BBS), an emblematic disease in the rapidly evolving field of ciliopathies, is characterized by pleiotropic clinical features and extensive genetic heterogeneity. To date, 14 BBS genes have been identified, 3 of which have been found mutated only in a single BBS family each (BBS11/TRIM32, BBS13/MKS1 and BBS14/MKS4/NPHP6). Previous reports of systematic mutation detection in large cohorts of BBS families (n > 90) have dealt only with a single gene, or at most small subsets of the known BBS genes. Here we report extensive analysis of a cohort of 174 BBS families for 12/14 genes, leading to the identification of 28 novel mutations. Two pathogenic mutations in a single gene have been found in 117 families, and a single heterozygous mutation in 17 families (of which 8 involve the BBS1 recurrent mutation, M390R). We confirm that BBS1 and BBS10 are the most frequently mutated genes, followed by BBS12. No mutations have been found in BBS11/TRIM32, the identification of which as a BBS gene only relies on a single missense mutation in a single consanguineous family. While a third variant allele has been observed in a few families, they are in most cases missenses of uncertain pathogenicity, contrasting with the type of mutations observed as two alleles in a single gene. We discuss the various strategies for diagnostic mutation detection, including homozygosity mapping and targeted arrays for the detection of previously reported mutations.
Published: 2010
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