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8 results on '"Center of Human Genetics and Laboratory Medicine"'

1. Clinical utility gene card for: Hereditary thoracic aortic aneurysm and dissection including next-generation sequencing-based approaches

Author

Anna Dierking, Eloisa Arbustini, Guillaume Jondeau, Mine Arslan-Kirchner, Sabine Hoffjan, Philippe Charron, Julie De Backer, Karin Mayer, Anne De Paepe, Catherine Boileau, Laurence Faivre, Britta Keyser, Peter N. Robinson, Anne H. Child, Gwenaëlle Collod-Béroud, Bart Loeys, Joerg Schmidtke, Institut für Humagenetik, Hannover Medical School [Hannover] (MHH)-Institut für Humagenetik, IRCCS - Pavia, 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), Université de Montréal (UdeM), Cardiac & Vascular Sciences, St Georges, University of London, 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), Center for Medical Genetics [Ghent], Ghent University Hospital, Center for Medical Genetics, Universiteit Gent = Ghent University [Belgium] (UGENT), 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), Human Genetics, Department of Biochemistry, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Center for Human Genetics and Laboratory Medicine, Center of Human Genetics and Laboratory Medicine, Queen's University [Belfast] (QUB), Department of Clinical Genetics/EMGO Institute for Health and Care research, COLLOD-BEROUD, Gwenaëlle, 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), Universiteit Gent = Ghent University (UGENT), and 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)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Marfan syndrome, medicine.medical_specialty, Gene Expression, Dissection (medical), 030204 cardiovascular system & hematology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Loeys–Dietz syndrome, Thoracic aortic aneurysm, Sensitivity and Specificity, DNA sequencing, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Terminology as Topic, Genetics, medicine, Humans, 030212 general & internal medicine, Genetic Testing, Gene, Biology, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Genetic testing, medicine.diagnostic_test, Aortic Aneurysm, Thoracic, business.industry, High-Throughput Nucleotide Sequencing, Membrane Proteins, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Aneurysm dissecting, medicine.disease, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Chemistry, Aortic Dissection, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Clinical Utility Gene Card, Quality of Life, Cytokines, Radiology, Human medicine, Collagen, business, Biomarkers, Transcription Factors
Abstract

International audience

Published
2015

2. Cardiovascular manifestations in men and women carrying a FBN1 mutation

Author

Eloisa Arbustini, Laurence Faivre, Mine Arslan-Kirchner, Anatoli Kiotsekoglou, Christine Binquet, Claire Bonithon-Kopp, Dorothy Halliday, Christophe Béroud, Henri Plauchu, Lesley C. Adès, Julie De Backer, Bart Loeys, Catherine Boileau, Elodie Gautier, Anne H. Child, Uta Francke, Gwenaëlle Collod-Béroud, Mireille Claustres, Delphine Detaint, Peter N. Robinson, Anne De Paepe, Chantal Stheneur, Guillaume Jondeau, Karin Mayer, 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), 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), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cardiac & Vascular Sciences, St Georges, University of London, Center for Medical Genetics [Ghent], Ghent University Hospital, Lipides - Nutrition - Cancer (U866) (LNC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Institut cellule souche et cerveau (U846 Inserm - UCBL1), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), IRCCS - Pavia, 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], The Oxford Radcliffe Hospitals NHS Trust, Département de médecine d'urgence / SAMU - SMUR - CESU 21 (CHU de Dijon), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique, Hôpital de l'Hôtel Dieu [CHU-HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Sonalee Laboratory for Marfan syndrome and related disorders, Department of Cardiological Sciences, St. George's Hospital Medical School, Department of medical genetics, Royal Alexandra Children's Hospital, Department of Genetics [Stanford], Stanford Medicine, Stanford University-Stanford University, Center for Medical Genetics, Universiteit Gent = Ghent University [Belgium] (UGENT), COLLOD-BEROUD, Gwenaëlle, 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), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), 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-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Universiteit Gent = Ghent University (UGENT), Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ), 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 ), Lipides - Nutrition - Cancer (U866) ( 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-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Institut cellule souche et cerveau / Stem Cell and Brain Research Institute ( SBRI ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ), 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, Institut de génétique humaine ( IGH ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Lyon-Université de Lyon-Hôtel Dieu, Department of Genetics and Pediatrics, Stanford University [Stanford], and Ghent University [Belgium] ( UGENT )

Subjects
Male, Marfan syndrome, Fibrillin-1, Kaplan-Meier Estimate, 030204 cardiovascular system & hematology, Gene mutation, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Gastroenterology, Marfan Syndrome, 0302 clinical medicine, Mitral valve prolapse, Child, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, Aortic dissection, 0303 health sciences, Mitral Valve Prolapse, Microfilament Proteins, Middle Aged, [ SDV.MHEP.CSC ] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Connective tissue disease, Aortic Aneurysm, 3. Good health, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Phenotype, Female, Cardiology and Cardiovascular Medicine, Adult, medicine.medical_specialty, Adolescent, Genotype, [ SDV.BBM.BM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Fibrillins, Young Adult, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, medicine.artery, Internal medicine, medicine, Humans, Risk factor, 030304 developmental biology, Aorta, Vascular disease, business.industry, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Surgery, Aortic Dissection, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, business
Abstract

International audience; Aims In patients with Marfan syndrome and other type-1 fibrillinopathies, genetic testing is becoming more easily available, leading to the identification of mutations early in the course of the disease. This study evaluates the cardiovascular (CV) risk associated with the discovery of a fibrillin-1 (FBN1) mutation. Methods and results A total of 1013 probands with pathogenic FBN1 mutations were included, among whom 965 patients [median age: 22 years (11– 34), male gender 53%] had data suitable for analysis. The percentage of patients with an ascending aortic (AA) dilatation increased steadily with increasing age and reached 96% (95% CI: 94 –97%) by 60 years. The presence of aortic events (dissection or prophylactic surgery) was rare before 20 years and then increased progressively, reaching 74% (95% CI: 67–81%) by 60 years. Compared with women, men were at higher risk for AA dilatation [≤30 years: 57% (95% CI: 52– 63) vs. 50% (95% CI: 45– 55), P ¼ 0.0076] and aortic events [≤30 years: 21% (95% CI: 17–26) vs. 11% (95% CI: 8–16), P , 0.0001; adjusted HR: 1.4 (1.1 –1.8), P ¼ 0.005]. The prevalence of mitral valve (MV) prolapse [≤60 years: 77% (95% CI: 72– 82)] and MV regurgitation [≤60 years: 61% (95% CI: 53–69)] also increased steadily with age, but surgery limited to the MV remained rare [≤60 years: 13% (95% CI: 8– 21)]. No difference between genders was observed (for all P. 0.20). From 1985 to 2005 the prevalence of AA dilatation remained stable (P for trend ¼ 0.88), whereas the percentage of patients with AA dissection significantly decreased (P for trend ¼ 0.01). Conclusion The CV risk remains important in patients with an FBN1 gene mutation and is present throughout life, justifying regular aortic monitoring. Aortic dilatation or dissection should always trigger suspicion of a genetic background leading to thorough examination for extra-aortic features and comprehensive pedigree investigation.

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. The FBN2 gene: new mutations, locus-specific database (Universal Mutation Database FBN2), and genotype-phenotype correlations

Author

Christine Binquet, Christine Monino, Laurence Faivre, Gwenaëlle Collod-Béroud, Dalil Hamroun, Guillaume Jondeau, Christophe Béroud, Luitgard M. Neumann, Prateek Gupta, Catherine Boileau, Mireille Claustres, Dianna M. Milewicz, Elodie Gautier, Maurice Godfrey, Christoph Marschall, Hanns Georg Klein, Cheryl L. Maslen, Mélissa Yana Frédéric, 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 ), Center for Human Genetics and Laboratory Medicine, Center of Human Genetics and Laboratory Medicine, 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 cardiologie, Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ), Consultation Marfan, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bichat, Hémostase, bio-ingénierie et remodelage cardiovasculaires ( LBPC ), Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris 13 ( UP13 ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Galilée, Charité Campus Virchow-Klinikum (CVK), 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 ), Department of Molecular and Medical Genetics, Oregon Health and Science University, Center for Human Molecular Genetics, University of Nebraska Omaha, Department of Internal Medicine and Neurosurgery, The University of Texas Medical School, 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, UFR Paris-Ile-de-France-Ouest (PIFO), Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ), 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 Montpellier 1, INSERM, GIS-Institut des Maladies Rares 2004, Contract grant sponsor: Association Française contre les Myopathies (AFM), Grant number: AFM-R07017FF, Contract grant sponsor: Agence Nationale pour la Recherche (ANR), Grant number: ANR-05PCOD-14-02., 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 Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bichat, Hémostase, bio-ingénierie et remodelage cardiovasculaires (LBPC), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut Galilée-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Oregon Health and Science University [Portland] (OHSU), University of Nebraska System-University of Nebraska System, 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], Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), 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), COLLOD-BEROUD, Gwenaëlle, 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 Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7)-Université Paris 13 (UP13)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Galilée, and University of Nebraska [Omaha]

Subjects
Fibrillin-2, MESH : Polymorphism, Genetic, Fibrillin-1, DNA Mutational Analysis, MESH : Genotype, [SDV.GEN] Life Sciences [q-bio]/Genetics, computer.software_genre, MESH: Genotype, 0302 clinical medicine, Genotype, Databases, Genetic, Missense mutation, Congenital contractural arachnodactyly, MESH: DNA Mutational Analysis, Genetics (clinical), MESH: Databases, Genetic, Regulation of gene expression, Genetics, 0303 health sciences, Database, MESH : Gene Expression Regulation, Microfilament Proteins, Phenotype, MESH: Gene Expression Regulation, Beals-Hecht syndrome, 3. Good health, INC, MESH : Phenotype, MESH : Mutation, Fibrillin, musculoskeletal diseases, MESH: Mutation, MESH : Microfilament Proteins, database OFFICIAL JOURNAL wwwhgvsorg & 2008 WILEY-LISS, Locus (genetics), fibrillin, MESH : DNA Mutational Analysis, Biology, Fibrillins, MESH: Phenotype, MESH: Sequence Homology, Nucleic Acid, congenital contractural arachnodactyly, 03 medical and health sciences, MESH: Microfilament Proteins, Sequence Homology, Nucleic Acid, MESH: Polymorphism, Genetic, medicine, Humans, MESH : Sequence Homology, Nucleic Acid, FBN2, CCA, MESH : Databases, Genetic, Gene, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Polymorphism, Genetic, MESH: Humans, MESH : Humans, medicine.disease, Gene Expression Regulation, Mutation, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, computer, 030217 neurology & neurosurgery
Abstract

International audience; Congenital contractural arachnodactyly (CCA) is an extremely rare disease, due to mutations in the FBN2 gene encoding fibrillin-2. Another member of the fibrillin family, the FBN1 gene, is involved in a broad phenotypic continuum of connective-tissue disorders including Marfan syndrome. Identifying not only what is in common but also what differentiates these two proteins should enable us to better comprehend their respective functions and better understand the multitude of diseases in which these two genes are involved. In 1995 we created a locus-specific database (LSDB) for FBN1 mutations with the Universal Mutation Database (UMD) tool. To facilitate comparison of identified mutations in these two genes and search for specific functional areas, we created an LSDB for the FBN2 gene: the UMD-FBN2 database. This database lists 26 published and six newly identified mutations that mainly comprise missense and splice-site mutations. Although the number of described FBN2 mutations was low, the frequency of joint dislocation was significantly higher with missense mutations when compared to splice site mutations.

Published
2009

6. 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

7. 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

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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