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8 results on '"Institut für Medizinische Genetik"'

1. Bainbridge-Ropers syndrome caused by loss-of-function variants in ASXL3: a recognizable condition

Author

Thomas Wieland, Ute Grasshoff, Jean-Baptiste Rivière, André Reis, Ingrid Bader, Holger Prokisch, Tim M. Strom, Ute Hehr, Olaf Rittinger, Elisabeth Graf, Johannes Koch, Ulrike Hüffmeier, Hermann-Josef Lüdecke, Hartmut Engels, Laurence Faivre, Alma Kuechler, Dagmar Wieczorek, Stefanie Beck-Woedl, Tiffany Busa, Wolfgang Sperl, Tobias B. Haack, Johanna Christina Czeschik, Institut für Humangenetik [Essen], Universität Duisburg-Essen = University of Duisburg-Essen [Essen]-Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Institute of Human Genetics, Helmholtz Zentrum München = German Research Center for Environmental Health, Institut für Medizinische Genetik und Angewandte Genomik, Universitäts Klinikum Tübingen, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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, Laboratoire de cytogénétique (CHU de Dijon), Paracelsus Medizinische Privatuniversität = Paracelsus Medical University (PMU), Zentrum für Humangenetik, University Hospital Regensburg, Rheinische Friedrich-Wilhelms-Universität Bonn, Interdisciplinary Center for Clinical Research (laboratory rotation) of the Clinical Center Erlangen of the Friedrich-Alexander-Universitat Erlangen-Nurnberg German Ministry of Research and Education as part of the National Genome Research Network 01GS08164 01GS08167 01GS08163 German Network for Mitochondrial Disorders (mitoNET) 01GM1113 E-Rare project GENOMIT 01GM1207 uniorverbund in der Systemmedizin 'mitOmics' FKZ 01ZX1405C PARI Marfanoid habitus and intellectual deficiency (Regional Council of Burgundy, France) PARI Marfanoid habitus and intellectual deficiency (Dijon University Hospital, France), Universität Duisburg-Essen [Essen]-Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Helmholtz-Zentrum München (HZM), Universität Duisburg-Essen [Essen]-Universitätsklinikum Essen [Universität Duisburg-Essen] ( Uniklinik Essen ), Helmholtz-Zentrum München ( HZM ), Friedrich Alexander University [Erlangen-Nürnberg], Génétique Médicale et Génomique Fonctionnelle ( GMGF ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), 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 ), Paracelsus Medical University, Friedrich-Alexander Universität Erlangen-Nürnberg ( FAU ), Bonn Universität [Bonn], and 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)

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Microcephaly, family, Adolescent, phenotype, Developmental Disabilities, Severe muscular hypotonia, Medizin, Trigonocephaly, 030105 genetics & heredity, Biology, Article, 03 medical and health sciences, Intellectual disability, Genetics, medicine, Humans, Craniofacial, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, novo frameshift mutation, gene, disorders, Genetics (clinical), Infant, Syndrome, medicine.disease, Dermatology, Failure to Thrive, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, intellectual disability, Child, Preschool, bohring-opitz syndrome, Mutation, Failure to thrive, Medical genetics, Female, medicine.symptom, Bohring–Opitz syndrome, Transcription Factors
Abstract

International audience; Truncating ASXL3 mutations were first identified in 2013 by Bainbridge et al. as a cause of syndromic intellectual disability in four children with similar phenotypes using whole-exome sequencing. The clinical features - postulated by Bainbridge et al. to be overlapping with Bohring-Opitz syndrome - were developmental delay, severe feeding difficulties, failure to thrive and neurological abnormalities. This condition was included in OMIM as 'Bainbridge-Ropers syndrome' (BRPS, #615485). To date, a total of nine individuals with BRPS have been published in the literature in four reports (Bainbridge et al., Dinwiddie et al, Srivastava et al. and Hori et al.). In this report, we describe six unrelated patients with newly diagnosed heterozygous de novo loss-of-function variants in ASXL3 and concordant clinical features: severe muscular hypotonia with feeding difficulties in infancy, significant motor delay, profound speech impairment, intellectual disability and a characteristic craniofacial phenotype (long face, arched eyebrows with mild synophrys, downslanting palpebral fissures, prominent columella, small alae nasi, high, narrow palate and relatively little facial expression). The majority of key features characteristic for Bohring-Opitz syndrome were absent in our patients (eg, the typical posture of arms, intrauterine growth retardation, microcephaly, trigonocephaly, typical facial gestalt with nevus flammeus of the forehead and exophthalmos). Therefore we emphasize that BRPS syndrome, caused by ASXL3 loss-of-function variants, is a clinically distinct intellectual disability syndrome with a recognizable phenotype distinguishable from that of Bohring-Opitz syndrome.

Published
2017

2. Deletions of the RUNX2 gene are present in about 10% of individuals with cleidocranial dysplasia

Author

Gundula Leschik, Susanne Morlot, Claus-Eric Ott, Juergen Kohlhase, Louise Brueton, Fabienne Trotier, Claudia M. Haase, Min Ae Lee-Kirsch, Eva Klopocki, Elisabeth Steichen-Gersdorf, Stefan Mundlos, Andrew H. Lane, Dieter Kotzot, Hartmut Peters, David Tegay, Wim Brussel, Encarna Guillén-Navarro, Han G. Brunner, Marleen Simon, Institut für Medizinische Genetik, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Clinical Genetics Unit, Birmingham Women's Hospital, Dept. of Human Genetics, Radboud University Medical Center [Nijmegen], Department of Pediatrics, Hospital Rijnstate Arnhem, Pediatrics, Hospital Virgen de la Arrixaca, Friedrich-Schiller-Universität = Friedrich Schiller University Jena [Jena, Germany], Praxis für Humangenetik, Division of Clinical Genetics, Innsbruck Medical University [Austria] (IMU), Stony Brook University [SUNY] (SBU), State University of New York (SUNY)-State University of New York (SUNY), Klinik für Kinder- und Jugendmedizin, Technische Universität Dresden = Dresden University of Technology (TU Dresden), MVZ wagnerstibbe, Department of Clinical Genetics, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Department of Medicine, New York Institure of Technology (NYIT), Max-Planck-Institut für Molekulare Genetik (MPIMG), Max-Planck-Gesellschaft, Clinical Genetics, and Medical Oncology

Subjects
musculoskeletal diseases, Heterozygote, DNA Mutational Analysis, Biology, medicine.disease_cause, Polymerase Chain Reaction, Short stature, Genomic disorders and inherited multi-system disorders [IGMD 3], 03 medical and health sciences, Exon, 0302 clinical medicine, Skeletal disorder, stomatognathic system, Gene duplication, Genetics, medicine, Humans, Copy-number variation, Multiplex ligation-dependent probe amplification, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Mutation, Cleidocranial Dysplasia, urogenital system, Life Sciences, equipment and supplies, Molecular biology, 3. Good health, medicine.symptom, Gene Deletion, 030217 neurology & neurosurgery
Abstract

Contains fulltext : 88233.pdf (Publisher’s version ) (Closed access) Cleidocranial Dysplasia (CCD) is an autosomal dominant skeletal disorder characterized by hypoplastic or absent clavicles, increased head circumference, large fontanels, dental anomalies, and short stature. Hand malformations are also common. Mutations in RUNX2 cause CCD, but are not identified in all CCD patients. In this study we screened 135 unrelated patients with the clinical diagnosis of CCD for RUNX2 mutations by sequencing analysis and demonstrated 82 mutations 48 of which were novel. By quantitative PCR we screened the remaining 53 unrelated patients for copy number variations in the RUNX2 gene. Heterozygous deletions of different size were identified in 13 patients, and a duplication of the exons 1 to 4 of the RUNX2 gene in one patient. Thus, heterozygous deletions or duplications affecting the RUNX2 gene may be present in about 10% of all patients with a clinical diagnosis of CCD which corresponds to 26% of individuals with normal results on sequencing analysis. We therefore suggest that screening for intragenic deletions and duplications by qPCR or MLPA should be considered for patients with CCD phenotype in whom DNA sequencing does not reveal a causative RUNX2 mutation. 01 augustus 2010

Published
2010

3. Pathogenic FBN1 mutations in 146 adults not meeting clinical diagnostic criteria for Marfan syndrome: further delineation of type 1 fibrillinopathies and focus on patients with an isolated major criterion

Author

Bert Callewaert, A. De Paepe, Mireille Claustres, Laurence Faivre, Lesley C. Adès, Anne H. Child, Eloisa Arbustini, O Bouchot, Uta Francke, P. Comeglio, A. Kiotsekoglou, Maurizia Grasso, Christophe Béroud, Peter N. Robinson, Guillaume Jondeau, Mine Arslan-Kirchner, Claire Bonithon-Kopp, J. De Backer, Gwenaëlle Collod-Béroud, Elodie Gautier, Bart Loeys, Christine Binquet, Catherine Boileau, Paul Coucke, Chantal Stheneur, Kenneth H. Mayer, Jean-Eric Wolf, 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), 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), 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), Center for Medical Genetics [Ghent], Ghent University Hospital, Department of Cardiological Sciences, St George's Hospital, Institute of Genetic Medicine and the Howard Hugues Medical Institute, Johns Hopkins University School of Medicine, Centre for Inherited Cardiovacular Diseases, Foundation IRCCS Policlinico San Matteo, Center for Human Genetics and Laboratory Medicine, Center of Human Genetics and Laboratory Medicine, Institut für Humagenetik, Hannover Medical School [Hannover] (MHH)-Institut für Humagenetik, Service de pédiatrie, urgences enfants [CHU Ambroise-Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Ambroise Paré [AP-HP], Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de chirurgie cardio-vasculaire, Institut für Medizinische Genetik, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Discipline of Paediatrics and Child Health, The University of Sydney, Marfan Research Group, Westmead Hospital [Sydney], Department of Clinical Genetics, Department of Genetics and Pediatrics, Stanford University [Stanford], Consultation Marfan, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bichat, Service de biochimie, d'hormonologie et de génétique moléculaire [CHU Amrboise Paré], Service de cardiologie, Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Montpellier (UM), Service d'Ophtalmologie (CHU de Dijon), Laboratoire de géographie physique : Environnements Quaternaires et Actuels (LGP), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Institut für Physik, Humboldt-Universität zu Berlin, Newtonstr. 15, D-12489 Berlin, Germany, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Hôpital du Bocage, Karlsruhe Institute of Technology (KIT), Apoptose, cancer et immunité (U848), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bichat, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques, Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Université de Montpellier ( UM ), Laboratoire de géographie physique ( LGP ), Université Panthéon-Sorbonne ( UP1 ) -Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ) -Centre National de la Recherche Scientifique ( CNRS ), Groupe Appl. Phys. ( GAP ), GAP, Institut de Physique Nucléaire d'Orsay ( IPNO ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de Physique Nucléaire et de Physique des Particules du CNRS ( IN2P3 ) -Centre National de la Recherche Scientifique ( CNRS ), 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 ), Institut de génétique humaine ( IGH ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ), Karlsruhe Institute of Technology ( KIT ), Apoptose, cancer et immunité ( U848 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), 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 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bichat, Humboldt University Of Berlin, Hannover Medical School [Hannover] ( MHH ) -Institut für Humagenetik, Service de pédiatrie, urgences enfants, Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, UFR Paris-Ile-de-France-Ouest (PIFO), Universitätsmedizin Charité, The University of Sydney [Sydney], The Children's Hospital at Westmead, Service de biochimie, d'hormonologie et de génétique moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), and COLLOD-BEROUD, Gwenaëlle

Subjects
Marfan syndrome, Nosology, Adult, Male, Pediatrics, medicine.medical_specialty, Systemic disease, Fibrillin-1, [ SDV.BBM.BM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease_cause, Fibrillins, Ectopia Lentis, Marfan Syndrome, Cohort Studies, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Genetics, medicine, Missense mutation, Humans, Ectopia lentis, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, 030305 genetics & heredity, Microfilament Proteins, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [ SDV.MHEP.CSC ] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, medicine.disease, Connective tissue disease, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Cohort, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, business
Abstract

International audience; Mutations in the FBN1 gene cause Marfan syndrome (MFS) and have been associated with a wide range of milder overlapping phenotypes. A proportion of patients carrying a FBN1 mutation does not meet diagnostic criteria for MFS, and are diagnosed with "other type I fibrillinopathy." In order to better describe this entity, we analyzed a subgroup of 146 out of 689 adult propositi with incomplete "clinical" international criteria (Ghent nosology) from a large collaborative international study including 1,009 propositi with a pathogenic FBN1 mutation. We focused on patients with only one major clinical criterion, [including isolated ectopia lentis (EL; 12 patients), isolated ascending aortic dilatation (17 patients), and isolated major skeletal manifestations (1 patient)] or with no major criterion but only minor criteria in 1 or more organ systems (16 patients). At least one component of the Ghent nosology, insufficient alone to make a minor criterion, was found in the majority of patients with isolated ascending aortic dilatation and isolated EL. In patients with isolated EL, missense mutations involving a cysteine were predominant, mutations in exons 24-32 were underrepresented, and no mutations leading to a premature truncation were found. Studies of recurrent mutations and affected family members of propositi with only one major clinical criterion argue for a clinical continuum between such phenotypes and classical MFS. Using strict definitions, we conclude that patients with FBN1 mutation and only one major clinical criterion or with only minor clinical criteria of one or more organ system do exist but represent only 5% of the adult cohort.

Published
2009

4. Clinical and mutation-type analysis from an international series of 198 probands with a pathogenic FBN1 exons 24-32 mutation

Author

Mine Arslan-Kirchner, Eloisa Arbustini, A. De Paepe, Paul Coucke, Jean-Eric Wolf, O Bouchot, Bart Loeys, P Khau-Van-Kien, Chantal Stheneur, Peter N. Robinson, Elodie Gautier, Nicola Marziliano, Bert Callewaert, Karin Mayer, Christophe Béroud, P Comeglio, Mireille Claustres, A Kiotsekoglou, Claire Bonithon-Kopp, Laurence Faivre, Lesley C. Adès, Guillaume Jondeau, Anne H. Child, Gwenaëlle Collod-Béroud, Catherine Boileau, Uta Francke, J. De Backer, Christine Binquet, Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), 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), Center for Medical Genetics [Ghent], Ghent University Hospital, Department of Cardiological Sciences, St George's Hospital, Institute of Genetic Medicine and the Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Centre for Inherited Cardiovacular Diseases, Foundation IRCCS Policlinico San Matteo, Center for Human Genetics and Laboratory Medicine, Center of Human Genetics and Laboratory Medicine, Institut für Humagenetik, Hannover Medical School [Hannover] (MHH)-Institut für Humagenetik, Service de pédiatrie, urgences enfants [CHU Ambroise-Paré], Hôpital Ambroise Paré [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire Electronique, Informatique et Image [UMR6306] (Le2i), Université de Bourgogne (UB)-École Nationale Supérieure d'Arts et Métiers (ENSAM), Arts et Métiers Sciences et Technologies, HESAM Université (HESAM)-HESAM Université (HESAM)-Arts et Métiers Sciences et Technologies, HESAM Université (HESAM)-HESAM Université (HESAM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Service de Cardiologie [CHU de Dijon], Service de chirurgie cardio-vasculaire, Institut für Medizinische Genetik, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Discipline of Paediatrics and Child Health, The University of Sydney, Marfan Research Group, Westmead Hospital [Sydney], Department of Clinical Genetics, Department of Genetics [Stanford], Stanford Medicine, Stanford University-Stanford University, Centre de reference national pour le syndrome de Marfan et apparentés, 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), Service de biochimie, d'hormonologie et de génétique moléculaire [CHU Amrboise Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), This study was supported by a grant from the French ministry of health (PHRC 2004), GIS maladies rares 2004, Bourse de la Société Francaise de Cardiologie, Fédération Franc¸aise de Cardiologie 2005 and ANR-05-PCOD-014. BC and BL are respectively a research fellow and a senior clinical investigator of the Fund for Scientific Research – Flanders. AC and PC thank the Marfan Trust and the Bluff Field Charitable Fund for support., 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)-Arts et Métiers Sciences et Technologies, 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)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Service de chirurgie cardio-vasculaire et thoracique (CHU Dijon), COLLOD-BEROUD, Gwenaëlle, 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), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques, Université Montpellier 1 (UM1) - IFR3 - Institut National de la Santé et de la Recherche Médicale (INSERM) - Université de Montpellier (UM), Centre for Medical Genetics, Hannover Medical School [Hannover] (MHH) - Institut für Humagenetik, Service de pédiatrie, urgences enfants, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ) - Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Ambroise Paré, Laboratoire Electronique, Informatique et Image (Le2i), Centre National de la Recherche Scientifique (CNRS) - Université de Bourgogne (UB) - AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Service de Cardiologie II, Centre Hospitalier Universitaire, Laboratoire de Génétique Moléculaire, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier) - Hôpital Arnaud de Villeneuve, Universitätsmedizin Charité, The University of Sydney [Sydney], The Children's Hospital at Westmead, Department of Genetics and Pediatrics, Stanford University [Stanford], Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Bichat - Claude Bernard [Paris], Service de biochimie, d'hormonologie et de génétique moléculaire, Handicaps génétiques de l'enfant, Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM), UFR P.I.F.O, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques ( CIC-EC ), Université de Bourgogne ( UB ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Hannover Medical School [Hannover] ( MHH ) -Institut für Humagenetik, Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, Laboratoire Electronique, Informatique et Image ( Le2i ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], 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 ), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Arts et Métiers (ENSAM), and HESAM Université (HESAM)-HESAM Université (HESAM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement

Subjects
Proband, Marfan syndrome, clinical and mutation-type analysis, congenital, hereditary, and neonatal diseases and abnormalities, Fibrillin-1, DNA Mutational Analysis, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, Fibrillins, Article, Ectopia Lentis, [SHS.INFO] Humanities and Social Sciences/Library and information sciences, Neonatal Marfan syndrome, 03 medical and health sciences, Exon, Genetics, medicine, Humans, Ectopia lentis, Gene, Genetics (clinical), 030304 developmental biology, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Genetic heterogeneity, 030305 genetics & heredity, Microfilament Proteins, Exons, exons 24–32, medicine.disease, Phenotype, 3. Good health, Codon, Nonsense, Mutation (genetic algorithm), Mutation, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, FBN1 mutations
Abstract

International audience; Mutations in the FBN1 gene cause Marfan syndrome (MFS) and a wide range of overlapping phenotypes. The severe end of the spectrum is represented by neonatal MFS, the vast majority of probands carrying a mutation within exons 24-32. We previously showed that a mutation in exons 24-32 is predictive of a severe cardiovascular phenotype even in non-neonatal cases, and that mutations leading to premature truncation codons are under-represented in this region. To describe patients carrying a mutation in this so-called 'neonatal' region, we studied the clinical and molecular characteristics of 198 probands with a mutation in exons 24-32 from a series of 1013 probands with a FBN1 mutation (20%). When comparing patients with mutations leading to a premature termination codon (PTC) within exons 24-32 to patients with an in-frame mutation within the same region, a significantly higher probability of developing ectopia lentis and mitral insufficiency were found in the second group. Patients with a PTC within exons 24-32 rarely displayed a neonatal or severe MFS presentation. We also found a higher probability of neonatal presentations associated with exon 25 mutations, as well as a higher probability of cardiovascular manifestations. A high phenotypic heterogeneity could be described for recurrent mutations, ranging from neonatal to classical MFS phenotype. In conclusion, even if the exons 24-32 location appears as a major cause of the severity of the phenotype in patients with a mutation in this region, other factors such as the type of mutation or modifier genes might also be relevant.

Published
2009

5. Clinical and molecular study of 320 children with Marfan syndrome and related type I fibrillinopathies in a series of 1009 probands with pathogenic FBN1 mutations

Author

Frédéric Huet, Peter N. Robinson, Guillaume Jondeau, Karin Mayer, Claire Bonithon-Kopp, Bertrand Chevallier, Uta Francke, Elodie Gautier, Laurence Faivre, Anne H. Child, Anatoli Kiotsekoglou, Christophe Béroud, Mireille Claustres, Bart Loeys, Maurizia Grasso, Gwenaëlle Collod-Béroud, Mine Arslan-Kirchner, Christine Binquet, Alice Masurel-Paulet, Catherine Boileau, Eloisa Arbustini, Julie De Backer, Anne De Paepe, Lesley C. Adès, Bert Callewaert, Dorothy Halliday, P Comeglio, Paul Coucke, Chantal Stheneur, 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), 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), 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), Center for Medical Genetics [Ghent], Ghent University Hospital, Department of Cardiological Sciences, St George's Hospital, Service de pédiatrie, urgences enfants [CHU Ambroise-Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Howard Hughes Medical Institute (HHMI), Centre for Inherited Cardiovacular Diseases, Foundation IRCCS Policlinico San Matteo, Center for Human Genetics and Laboratory Medicine, Center of Human Genetics and Laboratory Medicine, Institut für Humagenetik, Hannover Medical School [Hannover] (MHH)-Institut für Humagenetik, Department of Biochemistry [Oxford], University of Oxford [Oxford], Institut für Medizinische Genetik, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Discipline of Paediatrics and Child Health, The University of Sydney, Marfan Research Group, Westmead Hospital [Sydney], Department of Clinical Genetics, Department of Genetics [Stanford], Stanford Medicine, Stanford University-Stanford University, Service de biochimie, d'hormonologie et de génétique moléculaire [CHU Amrboise Paré], Consultation Marfan, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bichat, Service de cardiologie, Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This work was supported by a grant from the French Ministry of Health (grant Programme Hospitalier de Recherche Clinique 2004), Groupement d’Intérêt Scientifique Maladies Rares 2004, Bourse de la Société Francaise de Cardiologie, Fédération Franc¸aise de Cardiologie 2005, and ANR-05-PCOD-014. Drs Callewaert and Loeys are a research fellow and a senior clinical investigator, respectively, of the Fund for Scientific ResearchFlanders. Drs Child and Comeglio thank the Marfan Trust and the Bluff Field Charitable Fund for support., Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), COLLOD-BEROUD, Gwenaëlle, Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), University of Oxford, 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 ), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques, Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Service de pédiatrie, urgences enfants, Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, Institute of Genetic Medicine and the Howard Hugues Medical Institute, Johns Hopkins University School of Medicine, Hannover Medical School [Hannover] ( MHH ) -Institut für Humagenetik, Universitätsmedizin Charité, The University of Sydney [Sydney], The Children's Hospital at Westmead, Department of Genetics and Pediatrics, Stanford University [Stanford], Service de biochimie, d'hormonologie et de génétique moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bichat, and Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 ( UPD7 )

Subjects
Male, Proband, Marfan syndrome, Pediatrics, CI— confidence interval, Fibrillin-1, [SDV.GEN] Life Sciences [q-bio]/Genetics, 030204 cardiovascular system & hematology, MESH : Child, Preschool, PTC—premature termination codon, AAD—ascending aortic dilation, 0302 clinical medicine, MESH: Genetic Screening, MESH : Child, MESH: Child, Medicine, MESH : Female, Family history, Child, Ectopia lentis, Aortic dissection, education.field_of_study, Dural ectasia, Microfilament Proteins, MESH: Follow-Up Studies, Connective tissue disease, 3. Good health, MFS—Marfan syndrome, Child, Preschool, Female, MESH : Mutation, musculoskeletal diseases, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, MESH: Mutation, Adolescent, MESH : Microfilament Proteins, Abbreviations, MESH : Male, Population, Fibrillins, MESH: Marfan Syndrome, 03 medical and health sciences, MESH: Microfilament Proteins, MESH : Adolescent, Humans, Genetic Testing, FBN1, education, childhood, MESH : Genetic Screening, MESH: Adolescent, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH : Marfan Syndrome, MESH: Humans, business.industry, MESH : Humans, MESH: Child, Preschool, MESH : Follow-Up Studies, medicine.disease, EL— ectopia lentis, MESH: Male, Surgery, Mutation, Pediatrics, Perinatology and Child Health, international criteria, business, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, MESH: Female, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract

From a large series of 1009 probands with pathogenic FBN1 mutations, data for 320 patients

Published
2009

6. Contribution of molecular analyses in diagnosing Marfan syndrome and type I fibrillinopathies: an international study of 1009 probands

Author

Guillaume Jondeau, Mine Arslan-Kirchner, Christophe Béroud, Peter N. Robinson, Christine Binquet, Anne H. Child, J. De Backer, Paul Coucke, Eloisa Arbustini, Gwenaëlle Collod-Béroud, Elodie Gautier, Chantal Stheneur, Laurence Faivre, Mireille Claustres, Karin Mayer, Claire Bonithon-Kopp, H. Plauchu, Uta Francke, Catherine Boileau, A De Paepe, A Kiotsekoglou, Lesley C. Adès, Bart Loeys, Nicola Marziliano, Bert Callewaert, P Comeglio, Dorothy Halliday, 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), 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), 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), Department of Cardiological Sciences, St George's Hospital, Center for Medical Genetics [Ghent], Ghent University Hospital, Institute of Genetic Medicine and the Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Centre for Inherited Cardiovacular Diseases, Foundation IRCCS Policlinico San Matteo, Center for Human Genetics and Laboratory Medicine, Center of Human Genetics and Laboratory Medicine, Institut für Humagenetik, Hannover Medical School [Hannover] (MHH)-Institut für Humagenetik, Service de pédiatrie, urgences enfants [CHU Ambroise-Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Consultation Marfan, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bichat, Department of Biochemistry [Oxford], University of Oxford [Oxford], Service de Génétique, Hôtel Dieu, Institut für Medizinische Genetik, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Marfan Research Group, Westmead Hospital [Sydney], Department of Clinical Genetics, Discipline of Paediatrics and Child Health, The University of Sydney, Department of Genetics [Stanford], Stanford Medicine, Stanford University-Stanford University, Service de biochimie, d'hormonologie et de génétique moléculaire [CHU Amrboise Paré], This work was supported by a grant from the French ministry of health (PHRC 2004), GIS maladies rares 2004, Bourse de la Socie´te´ Francaise de Cardiologie, Fédération Franc¸aise de Cardiologie 2005, and ANR-05-PCOD-014. BC and BL are respectively a research fellow and a senior clinical investigator of the Fund for Scientific Research – Flanders. AC and PC thank the Marfan Trust, and the Bluff Field Charitable Fund for support., COLLOD-BEROUD, Gwenaëlle, University of Oxford, 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 ), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques, Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Hannover Medical School [Hannover] ( MHH ) -Institut für Humagenetik, Service de pédiatrie, urgences enfants, Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bichat, Universitätsmedizin Charité, The Children's Hospital at Westmead, The University of Sydney [Sydney], Department of Genetics and Pediatrics, Stanford University [Stanford], and Service de biochimie, d'hormonologie et de génétique moléculaire

Subjects
Proband, Nosology, Marfan syndrome, Male, Pediatrics, Systemic disease, MESH : International Cooperation, Fibrillin-1, International Cooperation, MESH : Aged, [SDV.GEN] Life Sciences [q-bio]/Genetics, Marfan Syndrome, MESH : Child, MESH: Child, Epidemiology, MESH : Female, Ectopia lentis, Child, Genetics (clinical), Aorta, Aortic dissection, MESH: Aged, 0303 health sciences, 030305 genetics & heredity, Microfilament Proteins, MESH: Aorta, MESH : Adult, Connective tissue disease, 3. Good health, Female, MESH : Mutation, musculoskeletal diseases, Adult, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, MESH: Mutation, MESH : Microfilament Proteins, Adolescent, MESH : Male, Fibrillins, MESH: Marfan Syndrome, 03 medical and health sciences, MESH: Microfilament Proteins, MESH : Adolescent, Genetics, medicine, Humans, 030304 developmental biology, Aged, MESH: Adolescent, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH : Marfan Syndrome, MESH: Humans, business.industry, MESH : Humans, MESH : Aorta, MESH: Adult, medicine.disease, MESH: Male, MESH: International Cooperation, Mutation, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, business, MESH: Female
Abstract

International audience; BACKGROUND: The diagnosis of Marfan syndrome (MFS) is usually initially based on clinical criteria according to the number of major and minor systems affected following international nosology. The number of FBN1 mutation carriers, at risk of aortic complications who would not be properly diagnosed based only on clinical grounds, is of growing importance owing to the increased availability of molecular screening. The aim of the study was to identify patients who should be considered for FBN1 mutation screening. METHODS: Our international series included 1009 probands with a known FBN1 mutation. Patients were classified as either fulfilling or not fulfilling "clinical" criteria. In patients with unfulfilled "clinical" criteria, we evaluated the percentage of additional patients who became positive for international criteria when the FBN1 mutation was considered. The aortic risk was evaluated and compared in patients fulfilling or not fulfilling the "clinical" international criteria. RESULTS: Diagnosis of MFS was possible on clinical grounds in 79% of the adults, whereas 90% fulfilled the international criteria when including the FBN1 mutation. Corresponding figures for children were 56% and 85%, respectively. Aortic dilatation occurred later in adults with unfulfilled "clinical criteria" when compared to the Marfan syndrome group (44% vs 73% at 40 years, p

Published
2008

7. Update of the UMD-FBN1 mutation database and creation of an FBN1 polymorphism database

Author

Saga Le Bourdelles, Bart Loeys, Maureen Boxer, James C. Hyland, Gwenaëlle Collod-Béroud, Lesley C. Adès, Leena Ala-Kokko, Katerine Holman, Leena Peltonen, Gabor Matyas, Ilkka Kaitila, Claudine Junien, Christophe Béroud, Anne H. Child, P Comeglio, Terhi Rantamäki, Anne De Paepe, Catherine Boileau, Peter N. Robinson, Patrick Booms, L Nuytinck, Beat Steinmann, Laboratoire de génétique moléculaire et chromosomique, Université Montpellier 1 (UM1) - IURC, Génétique, chromosome et cancer, Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM), Service de biochimie, d'hormonologie et de génétique moléculaire, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ) - Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Ambroise Paré, Department of medical genetics, Royal Alexandra Children's Hospital, Department of Paediatrics and Child Health, Collagen Research Unit, Biocenter and Department of Medical Biochemistry and Molecular Biology, University of Oulu, Center for Gene Therapy and Department of Medicine, Tulane University, Institut für Medizinische Genetik, Universitätsmedizin Charité, North Thames (East) Clinical Molecular Genetics Laboratory, Unit of Clinical Genetics and Fetal Medicine, Institue of Child Health, Sonalee Laboratory for Marfan syndrome and related disorders, Department of Cardiological Sciences, St. George's Hospital Medical School, Center for Medical Genetics, Ghent University Hospital, Department of Pathology and Laboratory Medicine and Center for Gene Therapy, Pediatrician and Clinical Geneticist, Clinical Genetics Unit, Helsinki University Central Hospital, Division of Metabolism and Molecular Pediatrics, University Children's Hospital, Department of Human Genetics, University of California at Los Angeles [Los Angeles] (UCLA) - UCLA School of Medicine, Department of Human Molecular Genetics, National Public Health Institute, Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de biochimie, d'hormonologie et de génétique moléculaire [CHU Amrboise Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Center for Medical Genetics [Ghent], University of California [Los Angeles] (UCLA), University of California-University of California-UCLA School of Medicine, Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), University of California (UC)-University of California (UC)-UCLA School of Medicine, and COLLOD-BEROUD, Gwenaëlle

Subjects
Fibrillin-1, database DATABASES, [SDV.GEN] Life Sciences [q-bio]/Genetics, computer.software_genre, MESH: Dogs, Mice, Genotype, Databases, Genetic, MESH: Animals, Genetics (clinical), MESH: Databases, Genetic, Genomic organization, Genetics, 0303 health sciences, Database, 030305 genetics & heredity, Microfilament Proteins, 3. Good health, Identification (information), MESH: Cattle, Mutation (genetic algorithm), Fibrillin, musculoskeletal diseases, congenital, hereditary, and neonatal diseases and abnormalities, MESH: Mutation, MESH: Rats, Biology, Fibrillins, MESH: Marfan Syndrome, 03 medical and health sciences, Chromosome 15, MESH: Microfilament Proteins, Dogs, MFS, MESH: Polymorphism, Genetic, Animals, Humans, FBN1, Gene, MESH: Mice, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Polymorphism, Genetic, MESH: Humans, fibrillinopathies, Rats, Marfan syndrome, Mutation, Human genome, Cattle, computer
Abstract

Fibrillin is the major component of extracellular microfibrils. Mutations in the fibrillin gene on chromosome 15 (FBN1) were first described in the heritable connective disorder, Marfan syndrome (MFS). FBN1 has also been shown to harbor mutations related to a spectrum of conditions phenotypically related to MFS, called "type-1 fibrillinopathies." In 1995, in an effort to standardize the information regarding these mutations and to facilitate their mutational analysis and identification of structure/function and phenotype/genotype relationships, we created a human FBN1 mutation database, UMD-FBN1. This database gives access to a software package that provides specific routines and optimized multicriteria research and sorting tools. For each mutation, information is provided at the gene, protein, and clinical levels. This tool is now a worldwide reference and is frequently used by teams working in the field; more than 220,000 interrogations have been made to it since January 1998. The database has recently been modified to follow the guidelines on mutation databases of the HUGO Mutation Database Initiative (MDI) and the Human Genome Variation Society (HGVS), including their approved mutation nomenclature. The current update shows 559 entries, of which 421 are novel. UMD-FBN1 is accessible at www.umd.be/. We have also recently developed a FBN1 polymorphism database in order to facilitate diagnostics.

Published
2003

8. Effect of Mutation Type and Location on Clinical Outcome in 1,013 Probands with Marfan Syndrome or Related Phenotypes and FBN1 Mutations: An International Study

Author

Nicola Marziliano, H. Plauchu, Peter N. Robinson, Catherine Boileau, Bert Callewaert, Uta Francke, P Comeglio, Christine Binquet, J. De Backer, Guillaume Jondeau, Dorothy Halliday, Christophe Béroud, Paul Coucke, A. De Paepe, Katherine Holman, Kenneth H. Mayer, B. Benetts, Andrew Biggin, Eloisa Arbustini, Hal Dietz, Anne H. Child, Gwenaëlle Collod-Béroud, Christine Muti, Laurence Faivre, Mireille Claustres, A Kiotsekoglou, Lesley C. Adès, Mine Arslan-Kirchner, Maggie Brett, Bart Loeys, Claire Bonithon-Kopp, Elodie Gautier, 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), 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), 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), Center for Medical Genetics [Ghent], Ghent University Hospital, Howard Hughes Medical Institute (HHMI), Sonalee Laboratory for Marfan syndrome and related disorders, Department of Cardiological Sciences, St. George's Hospital Medical School, Centre for Inherited Cardiovacular Diseases, Foundation IRCCS Policlinico San Matteo, Center for Human Genetics and Laboratory Medicine, Center of Human Genetics and Laboratory Medicine, Institut für Humagenetik, Hannover Medical School [Hannover] (MHH)-Institut für Humagenetik, Department of Biochemistry [Oxford], University of Oxford [Oxford], Consultation Marfan, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bichat, Service de Génétique, Hôtel Dieu, Institut für Medizinische Genetik, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Marfan Research Group, Westmead Hospital [Sydney], Department of Clinical Genetics, Discipline of Paediatrics and Child Health, The University of Sydney, Department of Molecular Genetics, Department of Genetics [Stanford], Stanford Medicine, Stanford University-Stanford University, Cardiological Sciences, Saint George's Hospital Medical School, Service de cardiologie, Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de biochimie, d'hormonologie et de génétique moléculaire [CHU Amrboise Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], 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 ), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques, Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Institute of Genetic Medicine and the Howard Hugues Medical Institute, Johns Hopkins University School of Medicine, Hannover Medical School [Hannover] ( MHH ) -Institut für Humagenetik, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bichat, Universitätsmedizin Charité, The Children's Hospital at Westmead, The University of Sydney [Sydney], The Children's Hospital ant Westmead, Department of Genetics and Pediatrics, Stanford University [Stanford], Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ), Service de biochimie, d'hormonologie et de génétique moléculaire, Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), University of Oxford, 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), and COLLOD-BEROUD, Gwenaëlle

Subjects
Marfan syndrome, Proband, Male, MESH: Epidermal Growth Factor, Fibrillin-1, [SDV.GEN] Life Sciences [q-bio]/Genetics, 030204 cardiovascular system & hematology, Bioinformatics, Severity of Illness Index, Marfan Syndrome, MESH: Protein Structure, Tertiary, MESH : Exons, 0302 clinical medicine, Transforming Growth Factor beta, Genotype, Missense mutation, MESH : Female, Genetics(clinical), Ectopia lentis, Genetics (clinical), MESH : Epidermal Growth Factor, Genetics, 0303 health sciences, MESH : Prognosis, Microfilament Proteins, Exons, MESH : Adult, Prognosis, 3. Good health, MESH : Phenotype, Phenotype, Mutation (genetic algorithm), MESH : Severity of Illness Index, Female, MESH : Mutation, Haploinsufficiency, MESH : Protein Structure, Tertiary, Adult, musculoskeletal diseases, congenital, hereditary, and neonatal diseases and abnormalities, MESH: Mutation, MESH : Microfilament Proteins, Adolescent, MESH : Male, Biology, MESH: Phenotype, Fibrillins, MESH: Prognosis, Article, MESH: Marfan Syndrome, MESH: Microfilament Proteins, 03 medical and health sciences, MESH : Adolescent, MESH: Severity of Illness Index, medicine, Humans, MESH: Transforming Growth Factor beta, 030304 developmental biology, MESH: Adolescent, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH : Marfan Syndrome, MESH: Humans, Epidermal Growth Factor, MESH : Humans, MESH: Adult, medicine.disease, MESH: Male, Protein Structure, Tertiary, MESH : Transforming Growth Factor beta, Inframe Mutation, Mutation, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, MESH: Exons, MESH: Female
Abstract

International audience; Mutations in the fibrillin-1 (FBN1) gene cause Marfan syndrome (MFS) and have been associated with a wide range of overlapping phenotypes. Clinical care is complicated by variable age at onset and the wide range of severity of aortic features. The factors that modulate phenotypical severity, both among and within families, remain to be determined. The availability of international FBN1 mutation Universal Mutation Database (UMD-FBN1) has allowed us to perform the largest collaborative study ever reported, to investigate the correlation between the FBN1 genotype and the nature and severity of the clinical phenotype. A range of qualitative and quantitative clinical parameters (skeletal, cardiovascular, ophthalmologic, skin, pulmonary, and dural) was compared for different classes of mutation (types and locations) in 1,013 probands with a pathogenic FBN1 mutation. A higher probability of ectopia lentis was found for patients with a missense mutation substituting or producing a cysteine, when compared with other missense mutations. Patients with an FBN1 premature termination codon had a more severe skeletal and skin phenotype than did patients with an inframe mutation. Mutations in exons 24-32 were associated with a more severe and complete phenotype, including younger age at diagnosis of type I fibrillinopathy and higher probability of developing ectopia lentis, ascending aortic dilatation, aortic surgery, mitral valve abnormalities, scoliosis, and shorter survival; the majority of these results were replicated even when cases of neonatal MFS were excluded. These correlations, found between different mutation types and clinical manifestations, might be explained by different underlying genetic mechanisms (dominant negative versus haploinsufficiency) and by consideration of the two main physiological functions of fibrillin-1 (structural versus mediator of TGF beta signalling). Exon 24-32 mutations define a high-risk group for cardiac manifestations associated with severe prognosis at all ages.

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