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29 results on '"Valérie Drouin-Garraud"'

1. Clinical, laboratory and molecular findings and long-term follow-up data in 96 French patients with PMM2-CDG (phosphomannomutase 2-congenital disorder of glycosylation) and review of the literature

Author

Dominique Martin-Coignard, Olivier Pincemaille, Claire de Barace, Nathalie Boddaert, Michel Polak, Tiffany Pascreau, Nathalie Seta, Christine Francannet, Gilles Morin, Valérie Cormier-Daire, François Labarthe, Manuel Schiff, Alexis Brice, Anaïs Brassier, Arnaud Bruneel, Patrick Edery, Alina Arion, Isabelle Fontan, Brigitte Chabrol, Cyril Gitiaux, Emmanuel de Maistre, Anne de Saint-Martin, Valérie Drouin-Garraud, Maud Bidet, Magali Barth, Catherine Bloch, Thierry Dupré, Céline Roda, Nathalie Bednarek, Sandrine Vuillaumier-Barrot, Marie-Chantal Chevalier, Géraldine Viot, François Feillet, Annick Toutain, Sylvie Lamoureux, Christel Thauvin-Robinet, Marie Hully, Delphine Borgel, Cyril Mignot, Nathalie Dorison, Bernard Echenne, Agathe Roubertie, Delphine Héron, Roger Buissonnière, Marie-Lorraine Monin, and Pascale de Lonlay

Subjects
Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, Adolescent, 03 medical and health sciences, Pericarditis, Congenital Disorders of Glycosylation, 0302 clinical medicine, Tubulopathy, Hydrops fetalis, Genetics, Humans, Medicine, Hypoalbuminemia, Child, Alleles, Genetic Association Studies, Genetics (clinical), business.industry, Infant, medicine.disease, Hypotonia, Phenotype, 030104 developmental biology, Amino Acid Substitution, Phosphotransferases (Phosphomutases), Inborn error of metabolism, Child, Preschool, Mutation, Female, medicine.symptom, business, Nephrotic syndrome, Congenital disorder of glycosylation, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract

Background Phosphomannomutase 2-congenital disorder of glycosylation (PMM2-CDG) is a multisystem inborn error of metabolism. Objectives To better characterise the natural history of PMM2-CDG. Methods Medical charts of 96 patients with PMM2-CDG (86 families, 41 males, 55 females) were retrospectively reviewed. Data on clinical, laboratory and molecular parameters at diagnosis were analysed. Follow-up data at last examination were reported for 25 patients. Results The patients were born between 1963 and 2011. Diagnosis of PMM2-CDG was made at a mean (SD) age of 6.8 (8.5) years. The presenting signs were mostly neurological (hypotonia, intellectual disability, cerebellar syndrome) and observed in almost all the patients. A total of 38 patients (14 males, 24 females) exhibited, in addition to neurological signs, visceral features including at least one of these: feeding difficulty requiring a nutritional support (n=23), cardiac features (n=20; pericarditis: 14, cardiac malformation: 9, cardiomyopathy: 2), hepato-gastrointestinal features (n=12; chronic diarrhoea: 7, protein-losing enteropathy: 1, ascites: 3, liver failure: 1, portal hypertension: 1), kidney features (n=4; nephrotic syndrome: 2, tubulopathy: 2) and hydrops fetalis (n=1). Twelve patients died at a mean age of 3.8 years (especially from pericarditis and other cardiac issues). Laboratory abnormalities mostly included elevated transaminases and abnormal coagulation parameters. High thyreostimulin levels, hypocholesterolemia, hypoalbuminemia and elevated transaminases were associated with the visceral phenotype. Besides the common Arg141His PMM2 variant harboured by half of the patients, 45 different variants were observed. Conclusions PMM2-CDG clinical phenotype is heterogeneous in terms of clinical course, with no clear division between neurological and visceral presentations.

Published
2017
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2. TTC12 loss-of-function mutations cause primary Ciliary Dyskinesia and unveil distinct dynein assembly mechanisms in motile cilia versus flagella

Author

Lucie Thomas, Khaled Bouhouche, Marjorie Whitfield, Guillaume Thouvenin, Andre Coste, Bruno Louis, Claire Szymanski, Emilie Bequignon, Jean-François Papon, Manon Castelli, Michel Lemullois, Xavier Dhalluin, Valérie Drouin-Garraud, Guy Montantin, Sylvie Tissier, Philippe Duquesnoy, Bruno Copin, Florence Dastot, Sandrine Couvet, Anne-Laure Barbotin, Catherine Faucon, Isabelle Honore, Bernard Maitre, Nicole Beydon, Aline Tamalet, Nathalie Rives, France Koll, Estelle Escudier, Anne-Marie Tassin, Aminata Touré, Valérie Mitchell, Serge Amselem, Marie Legendre, Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM), Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Biogenèse et Fonction de la Structure Centriolaire et Ciliaire (BIOCIL), Département Biologie Cellulaire (BioCell), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Biomécanique & Appareil Respiratoire (BAR), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Service d'ORL [Créteil], Centre Hospitalier Intercommunal de Créteil (CHIC), IMRB - 'Biomechanics and Respiratory Apparatus' [Créteil] (U955 Inserm - UPEC), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Claude Huriez [Lille], CHU Lille, Service d’ORL et de chirurgie cervico-faciale [CHU Le Kremlin-Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Hôpital Albert Calmette, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Charles Nicolle [Rouen], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), UF de Génétique moléculaire [CHU Trousseau], CHU Trousseau [APHP], Gamétogenèse et Qualité du Gamète - ULR 4308 (GQG), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université de Lille, CHU Rouen, Normandie Université (NU), Hôpital Jeanne de Flandres, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Maladies génétiques d'expression pédiatrique (U933), Normandie Université (NU)-Normandie Université (NU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and CCSD, Accord Elsevier

Subjects
0301 basic medicine, Male, Axoneme, [SDV]Life Sciences [q-bio], primary ciliary dyskinesia, 0302 clinical medicine, hemic and lymphatic diseases, Child, Genetics (clinical), Primary ciliary dyskinesia, Cilium, Homozygote, Inner dynein arm, Middle Aged, Phenotype, Cell biology, Pedigree, [SDV] Life Sciences [q-bio], Flagella, Motile cilium, Sperm Motility, Female, CRISPR-Cas9, Ciliary Motility Disorders, Adult, dynein arm assembly, Dynein, Biology, Flagellum, Article, TTC12, 03 medical and health sciences, Young Adult, Genetics, medicine, Humans, Infertility, Male, Ciliate, cilia, Dyneins, Proteins, nutritional and metabolic diseases, biology.organism_classification, medicine.disease, sperm flagella, 030104 developmental biology, Sperm Tail, Mutation, 030217 neurology & neurosurgery
Abstract

International audience; Cilia and flagella are evolutionarily conserved organelles whose motility relies on the outer and inner dynein arm complexes (ODAs and IDAs). Defects in ODAs and IDAs result in primary ciliary dyskinesia (PCD), a disease characterized by recurrent airway infections and male infertility. PCD mutations in assembly factors have been shown to cause a combined ODA-IDA defect, affecting both cilia and flagella. We identified four loss-of-function mutations in TTC12, which encodes a cytoplasmic protein, in four independent families in which affected individuals displayed a peculiar PCD phenotype characterized by the absence of ODAs and IDAs in sperm flagella, contrasting with the absence of only IDAs in respiratory cilia. Analyses of both primary cells from individuals carrying TTC12 mutations and human differentiated airway cells invalidated for TTC12 by a CRISPR-Cas9 approach revealed an IDA defect restricted to a subset of single-headed IDAs that are different in flagella and cilia, whereas TTC12 depletion in the ciliate $Paramecium\ tetraurelia$ recapitulated the sperm phenotype. Overall, our study, which identifies TTC12 as a gene involved in PCD, unveils distinct dynein assembly mechanisms in human motile cilia versus flagella.

Published
2020
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3. Hypersociability associated with developmental delay, macrocephaly and facial dysmorphism points to CHD3 mutations

Author

François Lecoquierre, Anne Boland, Valérie Drouin-Garraud, Gaël Nicolas, Thierry Frebourg, Juliette Coursimault, Jean-François Deleuze, J. Lechevallier, Anne-Claire Brehin, and Pascale Saugier-Veber

Subjects
Male, Hypersociability, Pediatrics, medicine.medical_specialty, Developmental Disabilities, Craniofacial Abnormalities, Young Adult, Intellectual disability, Genetics, medicine, Humans, Global developmental delay, Hypertelorism, Social Behavior, Genetics (clinical), business.industry, DNA Helicases, Macrocephaly, Syndrome, General Medicine, medicine.disease, Megalencephaly, Developmental disorder, Autism spectrum disorder, Mutation, Speech delay, medicine.symptom, business, Mi-2 Nucleosome Remodeling and Deacetylase Complex
Abstract

CHD3-related syndrome, also known as Snijders Blok-Campeau syndrome, is a rare developmental disorder described in 2018, caused by de novo pathogenic variants in the CHD3 gene. This syndrome is characterized by global developmental delay, speech delay, intellectual disability, hypotonia and behavioral disorders including autism spectrum disorder (ASD). Typical dysmorphic features include macrocephaly, hypertelorism, enophthalmia, sparse eyebrows, bulging forehead, midface hypoplasia, prominent nose and pointed chin. To our knowledge, there have been no other clinical descriptions of patients since the initial publication. We report the clinical description of a 21-year-old patient harboring a pathogenic de novo variant in CHD3. We reviewed the clinical features of the 35 previously reported patients. Main features were severe intellectual disability, dysmorphic facies, macrocephaly, cryptorchidism, pectus carinatum, severe ophthalmologic abnormalities and behavioral disorders including ASD, and a frank happy demeanor. Hypersociability, which was a noticeable clinical feature in our case, despite ASD, is an uncommon behavioral feature in syndromic intellectual disabilities. Our report supports hypersociability as a suggestive feature of CHD3-related syndrome along with developmental delay, macrocephaly and a dysmorphic facies.

Published
2021
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4. Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing

Author

Estelle Colin, Christel Thauvin-Robinet, Bernard Jost, Hélène Dollfus, Marie-Ange Delrue, Dominique Bonneau, Marjolaine Willems, Christine Francannet, Claire Feger, Michèle Mathieu-Dramard, Patrick Edery, Martine Doco-Fenzy, Laurence Olivier-Faivre, Véronique Geoffroy, Jean-Louis Mandel, Muriel Philipps, Serge Vicaire, Bérénice Doray, Alice Goldenberg, Magalie Barth, Julien Thevenon, Julia Lauer, Didier Lacombe, Gaetan Lesca, David Geneviève, Angélique Quartier, Dominique Martin-Coignard, Yvan Herenger, Serge Lumbroso, Salima El-Chehadeh, Bénédicte Gérard, Mélanie Fradin, Gilles Morin, Jean Muller, Yves Alembik, Sylvie Sukno, Amélie Piton, Nicolas Haumesser, Claire Redin, Bertrand Isidor, Elisabeth Flori, Valérie Drouin-Garraud, Pierre Sarda, Alice Masurel-Paulet, Michael Dumas, Stéphanie Le Gras, and Anne Polge

Subjects
Adult, Male, Adolescent, DNA Mutational Analysis, autism, Biology, DNA sequencing, Young Adult, Intellectual disability, Genetics, medicine, Humans, Child, Genetics (clinical), ATRX, causative, Genetic heterogeneity, Infant, Newborn, high-throughput sequencing, High-Throughput Nucleotide Sequencing, Infant, Sequence Analysis, DNA, Molecular diagnostics, medicine.disease, FMR1, Molecular Diagnostic Techniques, intellectual disability, Child, Preschool, Autism, Cognitive and Behavioural Genetics, Female, CUL4B, mutation
Abstract

Background Intellectual disability (ID) is characterised by an extreme genetic heterogeneity. Several hundred genes have been associated to monogenic forms of ID, considerably complicating molecular diagnostics. Trio-exome sequencing was recently proposed as a diagnostic approach, yet remains costly for a general implementation. Methods We report the alternative strategy of targeted high-throughput sequencing of 217 genes in which mutations had been reported in patients with ID or autism as the major clinical concern. We analysed 106 patients with ID of unknown aetiology following array-CGH analysis and other genetic investigations. Ninety per cent of these patients were males, and 75% sporadic cases. Results We identified 26 causative mutations: 16 in X-linked genes (ATRX, CUL4B, DMD, FMR1, HCFC1, IL1RAPL1, IQSEC2, KDM5C, MAOA, MECP2, SLC9A6, SLC16A2, PHF8) and 10 de novo in autosomal-dominant genes (DYRK1A, GRIN1, MED13L, TCF4, RAI1, SHANK3, SLC2A1, SYNGAP1). We also detected four possibly causative mutations (eg, in NLGN3) requiring further investigations. We present detailed reasoning for assigning causality for each mutation, and associated patients’ clinical information. Some genes were hit more than once in our cohort, suggesting they correspond to more frequent ID-associated conditions (KDM5C, MECP2, DYRK1A, TCF4). We highlight some unexpected genotype to phenotype correlations, with causative mutations being identified in genes associated to defined syndromes in patients deviating from the classic phenotype (DMD, TCF4, MECP2). We also bring additional supportive (HCFC1, MED13L) or unsupportive (SHROOM4, SRPX2) evidences for the implication of previous candidate genes or mutations in cognitive disorders. Conclusions With a diagnostic yield of 25% targeted sequencing appears relevant as a first intention test for the diagnosis of ID, but importantly will also contribute to a better understanding regarding the specific contribution of the many genes implicated in ID and autism.

Published
2014

5. Novel and recurrent non-truncating mutations of the MITF basic domain: genotypic and phenotypic variations in Waardenburg and Tietz syndromes

Author

Paul J Young, Michel Goossens, Virginie Bodereau, Robyn V. Jamieson, Muriel Holder-Espinasse, Xavier Balguerie, Hélène Dollfus, Isabelle Amstutz-Montadert, Alice Goldenberg, Annick Cabot, Amanda Krause, Pascal Joly, Veronique Pingault, Clarisse Baumann, Luis Nunes, Hongsheng Chen, Sandy Léger, and Valérie Drouin-Garraud

Subjects
Adult, Genotype, Short Report, Deafness, Melanocyte, Biology, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Humans, Waardenburg Syndrome, Genetics (clinical), 030304 developmental biology, Hypopigmentation, Microphthalmia-Associated Transcription Factor, 0303 health sciences, Mutation, integumentary system, Waardenburg syndrome, Tietz syndrome, Genetic Variation, Microphthalmia-associated transcription factor, medicine.disease, Phenotype, medicine.anatomical_structure, Albinism, Oculocutaneous, Child, Preschool, 030220 oncology & carcinogenesis, Female, medicine.symptom
Abstract

The microphthalmia-associated transcription factor (MITF) is a basic helix-loop-helix leucine zipper transcription factor, which regulates melanocyte development and the biosynthetic melanin pathway. A notable relationship has been described between non-truncating mutations of its basic domain and Tietz syndrome, which is characterized by albinoid-like hypopigmentation of the skin and hair, rather than the patchy depigmentation seen in Waardenburg syndrome, and severe hearing loss. Twelve patients with new or recurrent non-truncating mutations of the MITF basic domain from six families were enrolled in this study. We observed a wide range of phenotypes and some unexpected features. All the patients had blue irides and pigmentation abnormalities that ranged from diffuse hypopigmentation to Waardenburg-like patches. In addition, they showed congenital complete hearing loss, diffuse hypopigmentation of the skin, freckling and ocular abnormalities, more frequently than patients with MITF mutations outside the basic domain. In conclusion, the non-truncating mutations of the basic domain do not always lead to Tietz syndrome but rather to a large range of phenotypes. Sun-exposed freckles are interestingly observed more frequently in Asian populations. This variability argues for the possible interaction with modifier loci.

Published
2012
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6. Molecular screening of ADAMTSL2 gene in 33 patients reveals the genetic heterogeneity of geleophysic dysplasia

Author

Yanick J. Crow, Gwendoline Pfennig, Miranda Splitt, David Geneviève, Elisabeth Flori, Carine Le Goff, Valérie Drouin-Garraud, Deborah Krakow, Andrea Superti-Furga, Jane A. Hurst, Koenraad Devriendt, Clémentine Mahaut, Sally Ann Lynch, Sahar Mansour, Arnold Munnich, Isabelle Pressac-Diebold, Sheila Unger, Nathalie Dagoneau, Martine Le Merrer, Klaske D Lichtenbelt, Denise Williams, Raoul C.M. Hennekam, Heloísa G. dos Santos, Kay D. MacDermot, Angela F. Brady, Valérie Cormier-Daire, André Mégarbané, Stanislas Lyonnet, Slimane Allali, Yasemin Alanay, University of Groningen, 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), Ankara University School of Medicine [Turkey], North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow, Genetic Medicine, University of Manchester, Manchester Academic Heath Science Centre, Department of Medical Genetics, Leuven University Hospital, Leuven, Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Department of genetics, Strasbourg hospital, Strasbourg, Service de Génétique Médicale, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Department of Pediatrics, Academic Medical Center, University of Amsterdam, Departement of Clinical Genetics, Oxford Radcliffe Hospitals, Cedars-Sinai Medical Center, University Medical Center [Utrecht], National Center for Medical Genetics, Dublin, SW Thames Regional Genetics Service, St Georgeâ™s University of London, London, Université Saint-Joseph de Beyrouth (USJ), Department of Medical Genetics , Lisboa, Institute of Human Genetics, Newcastle, Department of Pediatrics, Centre Hospitalier Universitaire, Vaudois, Lausanne, Birmingham women's hospital, Birmingham, Peer, Hal, SW Thames Regional Genetics Service, St George’s University of London, London, Unité de génétique médicale, Université Saint Joseph, Beyrouth, 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 ), Genetics Unit, Department of Pediatrics Hacettepe, University School of Medicine, Ankara, Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), Cedars Sinai Medical Center, Los Angeles, Department of Medical Genetics, University Medical Center, Utrecht, Université Saint-Joseph de Beyrouth ( USJ ), Çocuk Sağlığı ve Hastalıkları, ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, Paediatrics, and Faculteit der Geneeskunde

Subjects
Male, Pathology, WEILL-MARCHESANI-SYNDROME, ACROMICRIC DYSPLASIA, Japan, Acromicric dysplasia, Eye Abnormalities, Child, Genetics (clinical), Genetics, Inclusion Bodies, Genetics & Heredity, 0303 health sciences, Extracellular Matrix Proteins, 030305 genetics & heredity, Weill–Marchesani syndrome, 3. Good health, Pedigree, Europe, Connective Tissue, Child, Preschool, Medical genetics, Female, medicine.symptom, Adult, medicine.medical_specialty, Adolescent, Ear infection, Limb Deformities, Congenital, Dwarfism, Biology, Short stature, Article, 03 medical and health sciences, Genetic Heterogeneity, Middle East, Molecular genetics, medicine, Humans, Clinical genetics, Connective tissue disease, 030304 developmental biology, Bone Diseases, Developmental, Genetic heterogeneity, MUTATIONS, Infant, medicine.disease, Dysplasia, Mutation, Skin Abnormalities
Abstract

Background Geleophysic dysplasia (GD, OMIM 231050) is an autosomal recessive disorder characterised by short stature, small hands and feet, stiff joints, and thick skin. Patients often present with a progressive cardiac valvular disease which can lead to an early death. In a previous study including six GD families, we have mapped the disease gene on chromosome 9q34.2 and identified mutations in the A Disintegrin And Metalloproteinase with Thrombospondin repeats-like 2 gene (ADAMTSL2). Methods Following this study, we have collected the samples of 30 additional GD families, including 33 patients and identified ADAMTSL2 mutations in 14/33 patients, comprising 13 novel mutations. The absence of mutation in 19 patients prompted us to compare the two groups of GD patients, namely group 1, patients with ADAMTSL2 mutations (n=20, also including the 6 patients from our previous study), and group 2, patients without ADAMTSL2 mutations (n=19). Results The main discriminating features were facial dysmorphism and tip-toe walking, which were almost constantly observed in group 1. No differences were found concerning heart involvement, skin thickness, recurrent respiratory and ear infections, bronchopulmonary insufficiency, laryngo-tracheal stenosis, deafness, and radiographic features. Conclusions It is concluded that GD is a genetically heterogeneous condition. Ongoing studies will hopefully lead to the identification of another disease gene.

Published
2011
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7. Type I hyperprolinemia: genotype/phenotype correlations

Author

Valérie Drouin-Garraud, Simona Orcesi, Audrey Guilmatre, Caroline Espil-Taris, Lionel Van Maldergem, Luisa Bonafé, Dominique Campion, David Valle, Thierry Frebourg, Vassili Valayannopoulos, Eric Le Galloudec, Patricia Blanchet, Cyril Mignot, Vincent des Portes, Bernard Echenne, Christine Ioos, Claudia Izzi, Hélène Maurey, Gabriella Di Rosa, Solenn Legallic, Jodi D. Hoffman, Alexandra Afenjar, Alice Goldenberg, Gary Steel, Alecia Willis, Agathe Roubertie, Agnès Guët, Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Estonian Genome and Medicine, University of Tartu, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Department of Medical and Surgical Pediatrics, University Hospital, Department of Genetics, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire sur le langage, le cerveau et la cognition (L2C2), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Department of Neuro-Metabolism, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Regional Hospital, Tufts Medical Center, Università degli Studi di Brescia = University of Brescia (UniBs), Fondation 'Neurological Institute C. Mondino ', Université de Lausanne = University of Lausanne (UNIL), Beauvais Hospital, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Raymond-Poincaré Hospital, CHU Pitié-Salpêtrière [AP-HP], Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital Gui de Chauliac [CHU Montpellier], Service de neuropédiatrie, CHU Hôpital, École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Università degli Studi di Brescia [Brescia], Université de Lausanne (UNIL), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Gui de Chauliac, and Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)

Subjects
Adult, Male, Adolescent, Proline, Mutation, Missense, Biology, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Proline dehydrogenase, Genotype, Proline Oxidase, Genetics, medicine, Humans, Missense mutation, Allele, Child, Amino Acid Metabolism, Inborn Errors, Alleles, Genetic Association Studies, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Mutation, Proline oxidase, [SCCO.NEUR]Cognitive science/Neuroscience, Haplotype, Infant, Life Sciences, medicine.disease, Molecular biology, 3. Good health, Case-Control Studies, Child, Preschool, Hyperprolinemia, PRODH, type I hyperprolinemia, 22q11, POX enzymatic activity, Female, 030217 neurology & neurosurgery
Abstract

International audience; Type I hyperprolinemia (HPI) is an autosomal recessive disorder associated with cognitive and psychiatric troubles, caused by alterations of the Proline Dehydrogenase gene (PRODH) at 22q11. HPI results from PRODH deletion and/or missense mutations reducing proline oxidase (POX) activity. The goals of this study were first to measure in controls the frequency of PRODH variations described in HPI patients, second to assess the functional effect of PRODH mutations on POX activity and finally to establish genotype/enzymatic activity correlations in a new series of HPI patients. 8/14 variants occurred at polymorphic frequency in 114 controls. POX activity was determined for 6 novel mutations and 2 haplotypes. The c.1331G>A, p.G444D allele has a drastic effect whereas the c.23C>T, p.P8L allele and the c.[56C>A; 172G>A], p.[Q19P; A58T] haplotype result in a moderate decrease in activity. Among the 19 HPI patients, 10 had a predicted residual activity A, p.T275N allele, which has no detrimental effect on activity but whose frequency in controls is only 3%. Our results suggest that PRODH mutations lead to a decreased POX activity or affect other biological parameters causing hyperprolinemia.

Published
2010
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8. IRF6 Screening of Syndromic and a priori Non-Syndromic Cleft Lip and Palate Patients: Identification of a New Type of Minor VWS Sign

Author

L. Van Maldergem, Bénédicte Bayet, Valérie Drouin-Garraud, Nicole Revencu, David Geneviève, Geneviève François, Catheline Vilain, Alice Goldenberg, Romain Vanwijck, Christine Verellen-Dumoulin, Kathleen Claes, A. Gozu, Geneviève Pierquin, P. Makrythanasis, Odile Boute, Joke B. G. M. Verheij, Laurence Desmyter, Miikka Vikkula, Fiona Connell, Muriel Holder-Espinasse, M. Bouma, Sylvie Manouvrier-Hanu, Anne Dieux-Coeslier, Melissa Lees, Marie-Claude Addor, Catherine Vincent-Delorme, Sylvie Odent, U. Mcentagart, Hervé Benateau, A. Sanchez, Michèle Mathieu, Koenraad Devriendt, Yves Sznajer, Geert Mortier, Sascha Vermeer, Michella Ghassibé, Anne Moncla, and Yves Gillerot

Subjects
Orthodontics, 0303 health sciences, medicine.medical_specialty, business.industry, 030305 genetics & heredity, Lower lip, medicine.disease, Dermatology, Revised diagnosis, stomatognathic diseases, 03 medical and health sciences, Mutation (genetic algorithm), Genetics, Mutation screening, Medicine, IRF6, Van der Woude syndrome, Family history, business, Genetics (clinical), Non syndromic, 030304 developmental biology
Abstract

Van der Woude syndrome (VWS), caused by dominant IRF6 mutation, is the most common cleft syndrome. In 15% of the patients, lip pits are absent and the phenotype mimics isolated clefts. Therefore, we hypothesized that some of the families classified as having non-syndromic inherited cleft lip and palate could have an IRF6 mutation. We screened in total 170 patients with cleft lip with or without cleft palate (CL/P): 75 were syndromic and 95 were a priori part of multiplex non-syndromic families. A mutation was identified in 62.7 and 3.3% of the patients, respectively. In one of the 95 a priori non-syndromic families with an autosomal dominant inheritance (family B), new insights into the family history revealed the presence, at birth, of lower lip pits in two members and the diagnosis was revised as VWS. A novel lower lip sign was observed in one individual in this family. Interestingly, a similar lower lip sign was also observed in one individual from a 2nd family (family A). This consists of 2 nodules below the lower lip on the external side. In a 3rd multiplex family (family C), a de novo mutation was identified in an a priori non-syndromic CL/P patient. Re-examination after mutation screening revealed the presence of a tiny pit-looking lesion on the inner side of the lower lip leading to a revised diagnosis of VWS. On the basis of this data, we conclude that IRF6 should be screened when any doubt rises about the normality of the lower lip and also if a non-syndromic cleft lip patient (with or without cleft palate) has a family history suggestive of autosomal dominant inheritance.

Published
2010
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9. Heterogeneity ofNSD1alterations in 116 patients with Sotos syndrome

Author

Céline Bonnet, Valérie Cormier-Daire, Valérie Drouin-Garraud, Thierry Billette de Villemeur, Muriel Holder-Espinasse, Séverine Fehrenbach, Didier Lacombe, Dominique Bonneau, Nicolas Jeanne, Marie-France Portnoï, Joelle Roume, Valérie Malan, Marion Gérard, Christine Coubes, Lydie Burglen, Alexandra Afenjar, Delphine Héron, Clarisse Baumann, Thierry Frebourg, Albert David, and Pascale Saugier-Veber

Subjects
Adult, Male, Adolescent, Biology, Polymerase Chain Reaction, Genetic Heterogeneity, Gene duplication, Genetics, medicine, Humans, Abnormalities, Multiple, Child, Genetics (clinical), Sotos syndrome, Genetic heterogeneity, Point mutation, Infant, Newborn, Intracellular Signaling Peptides and Proteins, Macrocephaly, Infant, Nuclear Proteins, Bone age, Histone-Lysine N-Methyltransferase, Syndrome, medicine.disease, Phenotype, Child, Preschool, Overgrowth syndrome, Histone Methyltransferases, Female, medicine.symptom
Abstract

Sotos syndrome is an overgrowth syndrome characterized by distinctive facial features, learning difficulties, and macrocephaly with frequent pre- and postnatal overgrowth with advanced bone age. Here, we report on our experience in the molecular diagnostic of Sotos syndrome on 116 patients. Using direct sequencing and a quantitative multiplex PCR of short fluorescent fragments (QMPSF)-based assay allowing accurate detection of both total and partial NSD1 deletions, we identified NSD1 abnormalities in 104 patients corresponding to 102 Sotos families (90%). NSD1 point mutations were detected in 80% of the index cases, large deletions removing the NSD1 gene entirely in 14%, and intragenic NSD1 rearrangements in 6%. Among the 69 detected distinct point mutations, 48 were novel. The QMPSF assay detected an exonic duplication and a mosaic partial deletion. QMPSF mapping of the 15 large deletions revealed the heterogeneity of the deletions, which vary in size from 1 to 4.5 Mb. Clinical features of NSD1-positive Sotos patients revealed that the phenotype in patients with nontruncating mutations was less severe that in patients with truncating mutations. This study confirms the heterogeneity of NSD1 alterations in Sotos syndrome and therefore the need to complete sequencing analysis by screening for partial deletions and duplications to ensure an accurate molecular diagnosis of this syndrome.

Published
2007
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10. Whole mitochondrial genome screening in maternally inherited non-syndromic hearing impairment using a microarray resequencing mitochondrial DNA chip

Author

Didier Lacombe, Christine Francannet, Thierry Mom, Marianne Lévêque, Delphine Feldmann, Pascal Reynier, Vincent Procaccio, Marie-Madeleine Eliot, Patrizia Amati-Bonneau, Françoise Denoyelle, Hubert Journel, Denis Pierron, Sylvain Baulande, Laurence Jonard, Françoise Duriez, Christine Petit, Erea-Noel Garabedian, Hélène Catros, Valérie Drouin-Garraud, Sandrine Marlin, Rémy Couderc, Marie-Françoise Obstoy, Laurence Faivre, Hélène Dollfus, and Christian Duvillard

Subjects
Adult, Male, Mitochondrial DNA, Lineage (genetic), Hearing Loss, Sensorineural, Biology, medicine.disease_cause, DNA, Mitochondrial, Genome, Mice, Dogs, Genetics, medicine, Animals, Humans, Point Mutation, Electrophoresis, Gel, Two-Dimensional, Child, Gene, Genetics (clinical), Oligonucleotide Array Sequence Analysis, Mutation, Point mutation, Sequence Analysis, DNA, Heteroplasmy, Mitochondria, Pedigree, Rats, Genome, Mitochondrial, Cattle, Female, DNA microarray
Abstract

Mitochondrial DNA (mtDNA) mutations have been implicated in non-syndromic hearing loss either as primary or as predisposing factors. As only a part of the mitochondrial genome is usually explored in deafness, its prevalence is probably under-estimated. Among 1350 families with non-syndromic sensorineural hearing loss collected through a French collaborative network, we selected 29 large families with a clear maternal lineage and screened them for known mtDNA mutations in 12S rRNA, tRNASer(UCN) and tRNALeu(UUR) genes. When no mutation could be identified, a whole mitochondrial genome screening was performed, using a microarray resequencing chip: the MitoChip version 2.0 developed by Affymetrix Inc. Known mtDNA mutations was found in nine of the 29 families, which are described in the article: five with A1555G, two with the T7511C, one with 7472insC and one with A3243G mutation. In the remaining 20 families, the resequencing Mitochip detected 258 mitochondrial homoplasmic variants and 107 potentially heteroplasmic variants. Controls were made by direct sequencing on selected fragments and showed a high sensibility of the MitoChip but a low specificity, especially for heteroplasmic variations. An original analysis on the basis of species conservation, frequency and phylogenetic investigation was performed to select the more probably pathogenic variants. The entire genome analysis allowed us to identify five additional families with a putatively pathogenic mitochondrial variant: T669C, C1537T, G8078A, G12236A and G15077A. These results indicate that the new MitoChip platform is a rapid and valuable tool for identification of new mtDNA mutations in deafness.

Published
2007
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11. Congenital hypogonadotropic hypogonadism with split hand/foot malformation: a clinical entity with a high frequency of FGFR1 mutations

Author

Michel Polak, Carine Villanueva, Lacey Plummer, Franziska Phan-Hug, Michael Hauschild, Juliane Léger, Cheng Xu, Yisrael Sidis, Nelly Pitteloud, Taneli Raivio, Hervé Lefebvre, Elka Jacobson-Dickman, Jean-Claude Carel, Moosa Mohammadi, Dov Tiosano, Sylvie Manouvrier, Gerasimos P. Sykiotis, Pierre Bouloux, Jean-Pierre Rey, Valérie Drouin-Garraud, Youli Hu, Andrew A. Dwyer, Yang Liu, Andrew Beenken, Nicolas de Roux, Johanna Tommiska, and Marion Gérard

Subjects
Proband, Male, medicine.medical_specialty, Kallmann syndrome, MAP Kinase Signaling System, Population, Molecular Sequence Data, Limb Deformities, Congenital, Biology, medicine.disease_cause, Article, congenital hypogonadotropic hypogonadism, 03 medical and health sciences, Internal medicine, medicine, Animals, Humans, Amino Acid Sequence, Receptor, Fibroblast Growth Factor, Type 1, Phosphorylation, education, Genetics (clinical), Conserved Sequence, Genetic Association Studies, 030304 developmental biology, Genetic testing, Adaptor Proteins, Signal Transducing, 0303 health sciences, education.field_of_study, Mutation, medicine.diagnostic_test, fibroblast growth factor receptor 1, Fibroblast growth factor receptor 1, FGF receptor substrate 2α, Hypogonadism, 030305 genetics & heredity, Membrane Proteins, Micropenis, medicine.disease, 3. Good health, Pedigree, Endocrinology, split hand/foot malformation, Female, Congenital Hypogonadotropic Hypogonadism, Adaptor Proteins, Signal Transducing/metabolism, Hypogonadism/congenital, Hypogonadism/genetics, Limb Deformities, Congenital/genetics, Limb Deformities, Congenital/metabolism, Membrane Proteins/metabolism, Receptor, Fibroblast Growth Factor, Type 1/genetics, Receptor, Fibroblast Growth Factor, Type 1/metabolism
Abstract

PURPOSE: Congenital hypogonadotropic hypogonadism (CHH) and split hand/foot malformation (SHFM) are two rare genetic conditions. Here we report a clinical entity comprising the two. METHODS: We identified patients with CHH and SHFM through international collaboration. Probands and available family members underwent phenotyping and screening for FGFR1 mutations. The impact of identified mutations was assessed by sequence- and structure-based predictions and/or functional assays. RESULTS: We identified eight probands with CHH with (n = 3; Kallmann syndrome) or without anosmia (n = 5) and SHFM, seven of whom (88%) harbor FGFR1 mutations. Of these seven, one individual is homozygous for p.V429E and six individuals are heterozygous for p.G348R, p.G485R, p.Q594*, p.E670A, p.V688L, or p.L712P. All mutations were predicted by in silico analysis to cause loss of function. Probands with FGFR1 mutations have severe gonadotropin-releasing hormone deficiency (absent puberty and/or cryptorchidism and/or micropenis). SHFM in both hands and feet was observed only in the patient with the homozygous p.V429E mutation; V429 maps to the fibroblast growth factor receptor substrate 2α binding domain of FGFR1, and functional studies of the p.V429E mutation demonstrated that it decreased recruitment and phosphorylation of fibroblast growth factor receptor substrate 2α to FGFR1, thereby resulting in reduced mitogen-activated protein kinase signaling. CONCLUSION: FGFR1 should be prioritized for genetic testing in patients with CHH and SHFM because the likelihood of a mutation increases from 10% in the general CHH population to 88% in these patients.

Published
2015

12. Baraitser-Winter cerebrofrontofacial syndrome : Delineation of the spectrum in 42 cases

Author

Sara Osimani, Andrew E. Fry, Koenraad Devriendt, Débora Romeo Bertola, Marjan M. Nezarati, Han G. Brunner, Grazia M.S. Mancini, Jorge L. Juncos, Pirayeh Eftekhari, Nataliya Di Donato, Marjolijn C.J. Jongmans, Laurence Faivre, Gilles Morin, Małgorzata J.M. Nowaczyk, Didier Lacombe, Zeichi-Seide Roseli, Conny M. A. van Ravenswaaij, Daniela Melis, Julien Masliah-Planchon, William B. Dobyns, Alexander Hoischen, Hatice Koçak Eker, Marlies Kempers, Andreas Rump, Vera Uliana, Victoria Mok Siu, Fabienne Giuliano, Nicole Philip, Beate Albrecht, Omar A Abdul-Raman, Alain Verloes, Mirjam Klaus, Angela E. Lin, Massimiliano Rossi, Albert David, Bregje W.M. van Bon, Jeanette C. Ramer, Ludivine Templin, Séverine Drunat, Yves Sznajer, Vincent Procaccio, Jean-Baptiste Rivière, Mary Ella M Pierpont, Francesca Faravelli, Judith Allanson, Leina Guion Almeida, Daniela T. Pilz, Cristina Rusu, Nicolas Chassaing, Charles Marques Lourenço, Bruce H. Wainer, Valérie Drouin-Garraud, Hôpital Robert Debré, Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Universitätsklinikum Carl Gustav Carus, Université Paris Diderot - Paris 7 (UPD7), Radboud University Medical Centre [Nijmegen, The Netherlands], University of Mississippi Medical Center (UMMC), Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Children's Hospital of Eastern Ontario [Ottawa, Canada], Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Centre hospitalier universitaire de Nantes (CHU Nantes), University Hospital Gasthuisberg, Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Rouen, Normandie Université (NU), Ospedale Galliera, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Universitaire de Nice (CHU Nice), University of São Paulo (USP), Emory University School of Medicine, Emory University [Atlanta, GA], CHU Bordeaux [Bordeaux], Massachusetts General Hospital [Boston], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Università degli studi di Napoli Federico II, University of Western Ontario (UWO), CHU Amiens-Picardie, McMaster University [Hamilton, Ontario], Pennsylvania State University (Penn State), Penn State System, Hôpital de la Timone [CHU - APHM] (TIMONE), University of Minnesota [MN, USA], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Cliniques Universitaires Saint-Luc [Bruxelles], University Hospital Groningen, University Hospital of Wales [Cardiff, UK], Seattle Children’s Hospital, Clinical Genetics, UCL - SSS/IREC - Institut de recherche expérimentale et clinique, UCL - (SLuc) Centre de génétique médicale UCL, Ethical, Legal, Social Issues in Genetics (ELSI), and Clinical Cognitive Neuropsychiatry Research Program (CCNP)

Subjects
Male, Microcephaly, Pathology, Craniofacial abnormality, [SDV]Life Sciences [q-bio], Medizin, GYRAL MALFORMATIONS, Craniofacial Abnormalities, FUNCTIONAL DIVERSITY, 0302 clinical medicine, Ptosis, Gene Order, Genetics(clinical), Hypertelorism, Non-U.S. Gov't, Child, Genetics (clinical), Arthrogryposis, Dystonia, 0303 health sciences, Research Support, Non-U.S. Gov't, Anatomy, 3. Good health, Phenotype, Child, Preschool, Female, medicine.symptom, Abnormalities, Multiple, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Adult, medicine.medical_specialty, APPARENTLY UNDESCRIBED SYNDROME, Adolescent, Lissencephaly, Biology, Research Support, Article, 03 medical and health sciences, Young Adult, SDG 3 - Good Health and Well-being, medicine, Genetics, Journal Article, Humans, Abnormalities, Multiple, Preschool, 030304 developmental biology, SHALLOW ORBITS, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], GAMMA-ACTIN, Pachygyria, Facies, medicine.disease, IRIS COLOBOMA, Actins, BETA-ACTIN, Amino Acid Substitution, Genetic Loci, Mutation, FACIAL SYNDROME, 030217 neurology & neurosurgery, MENTAL-RETARDATION, GROWTH-RETARDATION
Abstract

International audience; Baraitser-Winter, Fryns-Aftimos and cerebrofrontofacial syndrome types 1 and 3 have recently been associated with heterozygous gain-of-function mutations in one of the two ubiquitous cytoplasmic actin-encoding genes ACTB and ACTG1 that encode beta- and gamma-actins. We present detailed phenotypic descriptions and neuroimaging on 36 patients analyzed by our group and six cases from the literature with a molecularly proven actinopathy (9 ACTG1 and 33 ACTB). The major clinical anomalies are striking dysmorphic facial features with hypertelorism, broad nose with large tip and prominent root, congenital non-myopathic ptosis, ridged metopic suture and arched eyebrows. Iris or retinal coloboma is present in many cases, as is sensorineural deafness. Cleft lip and palate, hallux duplex, congenital heart defects and renal tract anomalies are seen in some cases. Microcephaly may develop with time. Nearly all patients with ACTG1 mutations, and around 60% of those with ACTB mutations have some degree of pachygyria with anteroposterior severity gradient, rarely lissencephaly or neuronal heterotopia. Reduction of shoulder girdle muscle bulk and progressive joint stiffness is common. Early muscular involvement, occasionally with congenital arthrogryposis, may be present. Progressive, severe dystonia was seen in one family. Intellectual disability and epilepsy are variable in severity and largely correlate with CNS anomalies. One patient developed acute lymphocytic leukemia, and another a cutaneous lymphoma, indicating that actinopathies may be cancer-predisposing disorders. Considering the multifaceted role of actins in cell physiology, we hypothesize that some clinical manifestations may be partially mutation specific. Baraitser-Winter cerebrofrontofacial syndrome is our suggested designation for this clinical entity.European Journal of Human Genetics advance online publication, 23 July 2014; doi:10.1038/ejhg.2014.95.

Published
2015
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13. Molecular characterization of a 14q deletion in a boy with features of Holt-Oram syndrome

Author

Annick Rossi, Hélène Moirot, Valérie Drouin-Garraud, Géraldine Joly-Helas, Pascale Saugier-Veber, Saad Abu Amara, Nathalie Le Meur, Thierry Frebourg, Alice Goldenberg, Stéphane Marret, Pascale Kleinfinger, Bertrand Mace, Gérard Blaysat, and Christine Michel-Adde

Subjects
Genetics, medicine.medical_specialty, Holt–Oram syndrome, Genetic heterogeneity, Cytogenetics, Chromosome, Dysostosis, Karyotype, Radial aplasia, Locus (genetics), Biology, medicine.disease, medicine, Genetics (clinical)
Abstract

Holt-Oram syndrome, the major "heart-hand" syndrome is defined by the association of radial defects or triphalangeal thumbs and septal heart defects. The transmission is autosomal dominant and the causative gene has been shown to be TBX5, located on 12q24.1, which encodes a transcription factor. Genetic heterogeneity has been suggested by several reports. We identified a 14(q23.3 approximately 24.2q31.1) deletion in a boy presenting severe bilateral asymmetrical radial aplasia, congenital heart defects, and developmental delay. This deletion, whose size could be estimated to be 9.6-13.7 Mb, was shown to be inherited via his mother's interchromosomal insertion. This is the second report of a chromosome 14 interstitial deletion associated with clinical features of Holt-Oram syndrome. These observations suggest the existence of a new "heart-hand" locus on chromosome 14q.

Published
2005
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14. Large deletion of theGJB6gene in deaf patients heterozygous for theGJB2gene mutation: Genotypic and phenotypic analysis

Author

Jacques Leman, Catherine Calais, Valérie Drouin-Garraud, Christine Petit, Cédric Le Maréchal, Bétina Montaut, Bruno Delobel, Pierre Chauvin, Patricia Lewin, Sandrine Marlin, Didier Bouccara, Hélène Catros, Marie-Françoise Obstoy, Marie-Madeleine Eliot, Sébastien Schmerber, Hélène Dollfus, Patrice Tran Ba Huy, Jacqueline Vigneron, Delphine Feldmann, Albert David, Erea-Noel Garabedian, Alain Joannard, Françoise Duriez, Rémy Couderc, Cyril Goizet, Olivier Sterkers, Françoise Denoyelle, J. P. Delaunoy, Hubert Journel, Sylvie Odent, Jocelyne Hélias, and Florence Fellmann

Subjects
Genetics, Mutation, biology, Hearing loss, Heterozygote advantage, medicine.disease_cause, Phenotype, Gjb2 gene, Genotype, otorhinolaryngologic diseases, medicine, biology.protein, medicine.symptom, Gene, Genetics (clinical), GJB6
Abstract

Recent investigations identified a large deletion of the GJB6 gene in trans to a mutation of GJB2 in deaf patients. We looked for GJB2 mutations and GJB6 deletions in 255 French patients presenting with a phenotype compatible with DFNB1. 32% of the patients had biallelic GJB2 mutations and 6% were a heterozygous for a GJB2 mutation and a GJB6 deletion. Biallelic GJB2 mutations and combined GJB2/GJB6 anomalies were more frequent in profoundly deaf children. Based on these results, we are now assessing GJB6 deletion status in cases of prelingual hearing loss.

Published
2004
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15. Mutations in RIT1 cause Noonan syndrome with possible juvenile myelomonocytic leukemia but are not involved in acute lymphoblastic leukemia

Author

Nehla Ghedira, Nathalie Pouvreau, Yline Capri, Odile Fenneteau, Joelle Roume, Aurélie Caye, Bérénice Doray, Laurence Perrin, Odile Boute, Natacha Fillot, Aurélien Trimouille, Cédric Vignal, Yves Alembik, Patricia Blanchet, Valérie Drouin-Garraud, Bertrand Isidor, Marlène Rio, Marion Gérard, Jean-Luc Alessandri, Annick Toutain, Alain Verloes, Albert David, Hélène Cavé, Anne Dieux Coeslier, Clarisse Baumann, Olivier Dulac, Delphine Héron, Sylvie Sauvion, Catherine Vincent-Delorme, Stanislas Lyonnet, Marjorie Willems, Patrice Bouvagnet, and Didier Lacombe

Subjects
0301 basic medicine, Proband, Adult, Male, medicine.medical_specialty, Adolescent, Cardiomyopathy, Article, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Humans, Child, Genetics (clinical), Juvenile myelomonocytic leukemia, business.industry, Noonan Syndrome, Precursor Cell Lymphoblastic Leukemia-Lymphoma, medicine.disease, Pedigree, PTPN11, Leukemia, 030104 developmental biology, Phenotype, Leukemia, Myelomonocytic, Juvenile, 030220 oncology & carcinogenesis, Child, Preschool, Speech delay, Immunology, Mutation, ras Proteins, Noonan syndrome, Medical genetics, Female, medicine.symptom, business
Abstract

Noonan syndrome is a heterogeneous autosomal dominant disorder caused by mutations in at least eight genes involved in the RAS/MAPK signaling pathway. Recently, RIT1 (Ras-like without CAAX 1) has been shown to be involved in the pathogenesis of some patients. We report a series of 44 patients from 30 pedigrees (including nine multiplex families) with mutations in RIT1. These patients display a typical Noonan gestalt and facial phenotype. Among the probands, 8.7% showed postnatal growth retardation, 90% had congenital heart defects, 36% had hypertrophic cardiomyopathy (a lower incidence compared with previous report), 50% displayed speech delay and 52% had learning difficulties, but only 22% required special education. None had major skin anomalies. One child died perinatally of juvenile myelomonocytic leukemia. Compared with the canonical Noonan phenotype linked to PTPN11 mutations, patients with RIT1 mutations appear to be less severely growth retarded and more frequently affected by cardiomyopathy. Based on our experience, we estimate that RIT1 could be the cause of 5% of Noonan syndrome patients. Because mutations found constitutionally in Noonan syndrome are also found in several tumors in adulthood, we evaluated the potential contribution of RIT1 to leukemogenesis in Noonan syndrome. We screened 192 pediatric cases of acute lymphoblastic leukemias (96 B-ALL and 96 T-ALL) and 110 cases of juvenile myelomonocytic leukemias (JMML), but detected no variation in these tumoral samples, suggesting that Noonan patients with germline RIT1 mutations are not at high risk to developing JMML or ALL, and that RIT1 has at most a marginal role in these sporadic malignancies.

Published
2014

16. Neurological presentation of a congenital disorder of glycosylation CDG-Ia: Implications for diagnosis and genetic counseling

Author

Valérie Cormier-Daire, Mathilde Belgrand, Alain Hénocq, Gert Matthijs, Jean‐Nicolas Dacher, Valérie Drouin-Garraud, Pascale Saugier-Veber, Stephanie Grunewald, Thierry Frebourg, and Nathalie Seta

Subjects
Male, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Pathology, Glycosylation, Genetic counseling, Encephalopathy, Genes, Recessive, Genetic Counseling, Biology, chemistry.chemical_compound, Congenital Disorders of Glycosylation, Cerebellum, Internal medicine, Cisterna Magna, parasitic diseases, medicine, Humans, Age of Onset, Child, Genetics (clinical), Spinocerebellar Degenerations, Fourth Ventricle, Fibroblasts, medicine.disease, Endocrinology, chemistry, Phosphotransferases (Phosphomutases), Female, Cerebellar atrophy, Isoelectric Focusing, Age of onset, Congenital disorder of glycosylation, Phosphomannomutase
Abstract

The congenital disorders of glycosylation (CDG) constitute a new group of recessively inherited metabolic disorders that are characterized biochemically by defective glycosylation of proteins. Several types have been identified. CDG-Ia, the most frequent type, is a multisystemic disorder affecting the nervous system and numerous organs including liver, kidney, heart, adipose tissue, bone, and genitalia. A phosphomannomutase (PMM) deficiency has been identified in CDG-Ia patients and numerous mutations in the PMM2 gene have been identified in patients with a PMM deficiency. We report on a French family with 3 affected sibs, with an unusual presentation of CDG-Ia, remarkable for 1) the neurological presentation of the disease, and 2) the dissociation between intermediate PMM activity in fibroblasts and a decreased PMM activity in leukocytes. This report shows that the diagnosis of CDG-Ia must be considered in patients with non-regressive early-onset encephalopathy with cerebellar atrophy, and that intermediate values of PMM activity in fibroblasts do not exclude the diagnosis of CDG-Ia.

Published
2001
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17. Clinical assessment of five patients with BRWD3 mutation at Xq21.1 gives further evidence for mild to moderate intellectual disability and macrocephaly

Author

Janneke H M Schuurs-Hoeijmakers, Thierry Frebourg, Hans van Bokhoven, Sarah Grotto, Pascal Chambon, Séverine Fehrenbach, Helen Puusepp-Benazzouz, Valérie Drouin-Garraud, Pascale Saugier-Veber, Nathalie Le Meur, Arjan P.M. de Brouwer, and Katrin Õunap

Subjects
Adult, Male, Pediatrics, medicine.medical_specialty, Nonsense mutation, DNA Mutational Analysis, Cubitus valgus, Kyphosis, Other Research Donders Center for Medical Neuroscience [Radboudumc 0], Scoliosis, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Intellectual Disability, Intellectual disability, Genetics, medicine, Humans, Abnormalities, Multiple, Genetics (clinical), Exome sequencing, Genetic Association Studies, 030304 developmental biology, 0303 health sciences, Chromosomes, Human, X, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Base Sequence, business.industry, Macrocephaly, General Medicine, medicine.disease, Megalencephaly, Pedigree, Codon, Nonsense, 030220 oncology & carcinogenesis, Speech delay, medicine.symptom, business, Transcription Factors
Abstract

Item does not contain fulltext Truncating mutations of the BRWD3 gene have been reported in two distinct families with in total four patients so far. By using array-CGH, we detected a 74 Kb de novo deletion encompassing exons 11 through 41 of BRWD3 at Xq21.1 in a 20 year old boy presenting with syndromic intellectual disability. In addition, by using exome sequencing, we ascertained a family with a BRWD3 nonsense mutation, p.Tyr1131*, in four males with intellectual disability. We compared the clinical presentation of these five patients to that of the four patients already described in the literature for further delineation of the clinical spectrum in BRWD3-related intellectual disability. The main symptoms are mild to moderate intellectual disability (n = 9/9) with speech delay (n = 8/8), behavioral disturbances (n = 7/8), macrocephaly (n = 7/9), dysmorphic facial features (n = 9/9) including prominent forehead, pointed chin, deep-set eyes, abnormal ears, and broad hands and feet (n = 6/6), and skeletal symptoms (n = 7/7) like pes planus, scoliosis, kyphosis and cubitus valgus.

Published
2013

18. Complete exon sequencing of all known Usher syndrome genes greatly improves molecular diagnosis

Author

Jacques Dubin, Christine Francannet, Jacqueline Levilliers, Thierry Mom, Magali Niasme-Grare, J.-P. Hardelin, Françoise Denoyelle, Diana Zelenika, Valérie Drouin-Garraud, Didier Lacombe, Sandrine Marlin, Marc Delepine, Patrick Collignon, Alain Duvillard, Christel Thauvin, Sabine Sigaudy, Jacqueline Vigneron, Albert David, Anne Marie Frances, Christophe Vincent, Françoise Duriez, Dominique Weil, Catherine Calais, Marine Parodi, M'hamed Grati, Hélène Dollfus, Delphine Feldmann, Bruno Delobel, Laurence Jonard, Christine Petit, Marie Françoise Thuillier-Obstoy, Bettina Montaut-Verient, Crystel Bonnet, Jean Weissenbach, Aziz El-Amraoui, Georges Challe, Dominique Bonneau, Mark Lathrop, Marie Madeleine Eliot, José-Alain Sahel, Rémy Couderc, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), NIDCD, National Institutes of Health [Bethesda] (NIH), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre de Génétique, Service ORL, Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Service d'ORL et chirurgie cervico-faciale, Service d'oto-rhino-laryngologie (ORL), Hôtel-Dieu, Maternité Régionale Adolphe Pinard [Nancy], Maternité Régionale Adolphe-Pinard, Centre de Référence des Maladies Neurogénétiques, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service Oto-Rhino-Laryngologie [CHU de Dijon] (ORL [CHU de Dijon]), Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service d'ORL, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service d'ophtalmologie [Rouen], Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service ORL Pédiatrique, Normandie Université (NU)-Normandie Université (NU), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique Médicale, Hôpital intercommunal de Font-Pré, CHU Pitié-Salpêtrière [AP-HP], Institut de la Vision, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génomique métabolique (UMR 8030), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), M.G. was supported by European Commission FP6 Integrated project, EuroHear (LSHG-CT-2004-512063) and C.B. by the French Foundation 'Voir et Entendre'. This work was supported by Fondation R & G Strittmatter (under the aegis of Fondation de France), FAUN Stiftung (Suchert Foundation), ECFP7 TREATRUSH (HEALTH-F2-2010-242013), Foundation Fighting Blindness, LHW-Stiftung, Fondation Orange, The Conny-Maeva Charitable Foundation, Genoscope-CNRG project AP2005, and S'entendre Foundation., Service de génétique et embryologie médicales [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Chaire Génétique et physiologie cellulaire, Service de Biochimie et de Biologie Moléculaire [CHU Trousseau], Hôpital St-Antoine, Service d'ORL et de Chirurgie Cervicofaciale, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Normandie Université (NU)-Hôpital Charles-Nicolle, Hôpital Charles-Nicolle, Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service d'ORL pédiatrique et Chirurgie Cervico-faciale [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and BMC, Ed.

Subjects
Usher syndrome, lcsh:Medicine, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Amino Acid Sequence, medicine.disease_cause, MESH: Genotype, Exon, 0302 clinical medicine, Genotype, Genetics(clinical), Pharmacology (medical), Genetics (clinical), Exome sequencing, Medicine(all), Genetics, 0303 health sciences, Mutation, Splice site mutation, MESH: Genomics, Exons, Genomics, General Medicine, MESH: Case-Control Studies, Pedigree, 3. Good health, France, Usher Syndromes, MESH: Mutation, MESH: Pedigree, Molecular Sequence Data, Biology, 03 medical and health sciences, medicine, otorhinolaryngologic diseases, Humans, Amino Acid Sequence, MESH: Usher Syndromes, Gene, Genotyping, MESH: Genome, Human, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Molecular Sequence Data, Genome, Human, Research, lcsh:R, medicine.disease, MESH: France, Case-Control Studies, MESH: Exons, 030217 neurology & neurosurgery
Abstract

Background Usher syndrome (USH) combines sensorineural deafness with blindness. It is inherited in an autosomal recessive mode. Early diagnosis is critical for adapted educational and patient management choices, and for genetic counseling. To date, nine causative genes have been identified for the three clinical subtypes (USH1, USH2 and USH3). Current diagnostic strategies make use of a genotyping microarray that is based on the previously reported mutations. The purpose of this study was to design a more accurate molecular diagnosis tool. Methods We sequenced the 366 coding exons and flanking regions of the nine known USH genes, in 54 USH patients (27 USH1, 21 USH2 and 6 USH3). Results Biallelic mutations were detected in 39 patients (72%) and monoallelic mutations in an additional 10 patients (18.5%). In addition to biallelic mutations in one of the USH genes, presumably pathogenic mutations in another USH gene were detected in seven patients (13%), and another patient carried monoallelic mutations in three different USH genes. Notably, none of the USH3 patients carried detectable mutations in the only known USH3 gene, whereas they all carried mutations in USH2 genes. Most importantly, the currently used microarray would have detected only 30 of the 81 different mutations that we found, of which 39 (48%) were novel. Conclusions Based on these results, complete exon sequencing of the currently known USH genes stands as a definite improvement for molecular diagnosis of this disease, which is of utmost importance in the perspective of gene therapy.

Published
2011
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19. Identification of 28 novel mutations in the Bardet-Biedl syndrome genes: the burden of private mutations in an extensively heterogeneous disease

Author

Serge Vicaire, Dominique Bonneau, Pierre Bitoun, Nicholas Katsanis, Sophie Hellé, Alice Goldenberg, Valérie Drouin-Garraud, Marie-Claire Vincent, Jean Marc Danse, Vincent Marion, Sabine Sigaudy, Joelle Roume, M. Hamdani, Sylvie Odent, Christine Francannet, Erica E. Davis, Alain Verloes, V. Bennouna-Greene, Jean Muller, Josseline Kaplan, Hélène Dollfus, Virginie Laurier, Jean-Louis Mandel, André Mégarbané, Carmen C. Leitch, Jane Green, Mireille Cossée, Corinne Stoetzel, Nicole Philip, Olivier Poch, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Laboratoire de diagnostic génétique, CHU Strasbourg, Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (JHU), Unité de Génétique Médicale, Université Saint-Joseph de Beyrouth (USJ), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Hôpital 20 Août 1953, Service de Génétique et de Diagnostic Prénatal, Université de la Méditerranée - Aix-Marseille 2, Hôtel-Dieu-CHU Clermont-Ferrand-Université d'Auvergne - Clermont-Ferrand I (UdA), Service de génétique médicale, CHI Poissy-Saint-Germain, Service de Pédiatrie [Jean Verdier], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département de génétique médicale [Hôpital de la Timone - APHM], Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Service de Génétique Clinique, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-hôpital Sud, Department of Genetics, Memorial University of Newfoundland [St. John's], Center for Human Disease Modeling, Duke University [Durham], Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Unité fonctionnelle de génétique clinique, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Chaire Génétique Humaine, Collège de France (CdF (institution)), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Memorial University of Newfoundland = Université Memorial de Terre-Neuve [St. John's, Canada] (MUN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Collège de France - Chaire Génétique Humaine, De Villemeur, Hervé, Institut de Génétique et de Biologie Moléculaire et Cellulaire ( IGBMC ), Université de Strasbourg ( UNISTRA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Génétique Médicale, Université Louis Pasteur - Strasbourg I-Hôpital de Hautepierre [Strasbourg]-AVENIR-Inserm, Johns Hopkins University ( JHU ), Université Saint-Joseph de Beyrouth ( USJ ), 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 ), CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Hôtel-Dieu-CHU Clermont-Ferrand-Université d'Auvergne - Clermont-Ferrand I ( UdA ), Université Paris 13 ( UP13 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Jean Verdier, 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 ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Sud, Duke university [Durham], Université d'Angers ( UA ) -CHU Angers, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), Institut de génétique et biologie moléculaire et cellulaire ( IGBMC ), and Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS )

Subjects
BBS2, Adult, Male, congenital, hereditary, and neonatal diseases and abnormalities, BBS1, Molecular Sequence Data, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, medicine.disease_cause, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Gene Frequency, Gene Duplication, [SDV.BDD] Life Sciences [q-bio]/Development Biology, Gene duplication, Genetics, medicine, Missense mutation, Humans, [ SDV.BDD ] Life Sciences [q-bio]/Development Biology, Genetic Testing, Bardet-Biedl Syndrome, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Genetics (clinical), Chromatography, High Pressure Liquid, Polymorphism, Single-Stranded Conformational, 030304 developmental biology, Aged, 0303 health sciences, Mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, Genetic heterogeneity, 030305 genetics & heredity, Decision Trees, Homozygote, Chromosome Mapping, Sequence Analysis, DNA, Middle Aged, Disease gene identification, 3. Good health, Pedigree, BBS12, Female, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Gene Deletion, Microsatellite Repeats
Abstract

International audience; Bardet-Biedl syndrome (BBS), an emblematic disease in the rapidly evolving field of ciliopathies, is characterized by pleiotropic clinical features and extensive genetic heterogeneity. To date, 14 BBS genes have been identified, 3 of which have been found mutated only in a single BBS family each (BBS11/TRIM32, BBS13/MKS1 and BBS14/MKS4/NPHP6). Previous reports of systematic mutation detection in large cohorts of BBS families (n > 90) have dealt only with a single gene, or at most small subsets of the known BBS genes. Here we report extensive analysis of a cohort of 174 BBS families for 12/14 genes, leading to the identification of 28 novel mutations. Two pathogenic mutations in a single gene have been found in 117 families, and a single heterozygous mutation in 17 families (of which 8 involve the BBS1 recurrent mutation, M390R). We confirm that BBS1 and BBS10 are the most frequently mutated genes, followed by BBS12. No mutations have been found in BBS11/TRIM32, the identification of which as a BBS gene only relies on a single missense mutation in a single consanguineous family. While a third variant allele has been observed in a few families, they are in most cases missenses of uncertain pathogenicity, contrasting with the type of mutations observed as two alleles in a single gene. We discuss the various strategies for diagnostic mutation detection, including homozygosity mapping and targeted arrays for the detection of previously reported mutations.

Published
2010
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20. Mutation update for the CSB/ERCC6 and CSA/ERCC8 genes involved in Cockayne syndrome

Author

Hélène Dollfus, Victoria Murday, Pierre Sarda, E. Raffo, Patrick Edery, Alain Sarasin, Jacqueline Vigneron, D. Gubser-Mercati, Andrew R. Gennery, Karen Fieggen, Vincent Laugel, Valérie Drouin-Garraud, F. Sauvanaud, Dominique Martin-Coignard, Hubert Journel, Louise Brueton, John Tolmie, Marie-Claire Vincent, Alan R. Lehmann, Delphine Héron, Benoît Funalot, Stanislas Lyonnet, D. Pham, Jean-Marc Egly, Mustafa A. Salih, Sylvie Odent, U. Kristensen, E. Muñoz, Agnès Bloch-Zupan, Heather Fawcett, Edward S. Tobias, J. Sanchez del Pozo, Blanca Gener, Brigitte Chabrol, Lina M. Ramos, M. Durand, Cecile Dalloz, Zornitza Stark, K. Prescott, Laurent Pasquier, Mehrdad Noruzinia, Valérie Cormier-Daire, Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de diagnostic génétique, CHU Strasbourg, Laboratoire de génétique moléculaire et génomique médicale [CHU Rennes], CHU Pontchaillou [Rennes], Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Medical Genetics, Hospital de Cruces, Division of Developmental Medicine, Royal Hospital for Sick Children, Service de génétique, Centre Hospitalier Le Mans (CH Le Mans), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Génétique Médicale, Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA)-Hôpital Chubert, Service de Pédiatrie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Consultation de Génétique, Neurologie Pédiatrique, Hôpital neuchâtelois, Service de Neurologie [CHU Limoges], CHU Limoges, Biomolécules Thérapies anti-tumorales (EA4021), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Department of Clinical Genetics, Birmingham Women's Hospital, Centro de Biología Molecular Severo Ochoa [Madrid] (CBMSO), Universidad Autónoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Department Neurology, Hospital Clinic, Department of Pediatrics, Newcastle General Hospital, Division of Pediatric Neurology, King Saud University [Riyadh] (KSU), Department of Hematology, Tarbiat Modares University [Tehran], St James's University Hospital, Pediatric Hospital, Genetic Health Services Victoria, Groote Schuur and Red Cross Children's Hospital, Service de pédiatrie et neurologie pédiatrique, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Unité de Génétique Médicale et Foetopathologie, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Service de Génétique, Hospices Civils de Lyon (HCL), Reference Centre for Oral Manifestations of Rare Diseases, Hôpitaux Universitaires de Strasbourg, Centre for Genome Damage and Stability, University of Sussex, Génomes et cancer (GC (FRE2939)), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique et biologie moléculaire et cellulaire ( IGBMC ), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Génétique Moléculaire et Hormonologie, Hôpital Pontchaillou, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], CH Le Mans, CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Centre Hospitalier Bretagne Atlantique-Hôpital Chubert, Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Biomolécules Thérapies anti-tumorales ( EA4021 ), Université de Limoges ( UNILIM ) -Génomique, Environnement, Immunité, Santé, Thérapeutique ( GEIST FR CNRS 3503 ), Centro de Biología Molecular Severo Ochoa ( CBMSO ), Universidad Autonoma de Madrid ( UAM ) -Consejo Superior de Investigaciones Científicas [Spain] ( CSIC ), King Saud University [Riyadh] ( KSU ), Tarbiat Modares University, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Arnaud de Villeneuve, Hospices Civils de Lyon ( HCL ), Génomes et cancer ( GC (FRE2939) ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Centre National de la Recherche Scientifique ( CNRS ), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), and De Villemeur, Hervé

Subjects
Molecular Sequence Data, Prenatal diagnosis, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, medicine.disease_cause, Bioinformatics, Cockayne syndrome, 03 medical and health sciences, Structure-Activity Relationship, 0302 clinical medicine, [SDV.BDD] Life Sciences [q-bio]/Development Biology, Databases, Genetic, Genetics, medicine, Missense mutation, Coding region, Humans, Amino Acid Sequence, [ SDV.BDD ] Life Sciences [q-bio]/Development Biology, Cockayne Syndrome, Poly-ADP-Ribose Binding Proteins, Gene, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Genetics (clinical), Genetic Association Studies, 030304 developmental biology, 0303 health sciences, Mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, Polymorphism, Genetic, DNA Helicases, medicine.disease, 3. Good health, ERCC8, DNA Repair Enzymes, ERCC6, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Sequence Alignment, 030217 neurology & neurosurgery, Transcription Factors
Abstract

MMNP; International audience; Cockayne syndrome is an autosomal recessive multisystem disorder characterized principally by neurological and sensory impairment, cachectic dwarfism, and photosensitivity. This rare disease is linked to mutations in the CSB/ERCC6 and CSA/ERCC8 genes encoding proteins involved in the transcription-coupled DNA repair pathway. The clinical spectrum of Cockayne syndrome encompasses a wide range of severity from severe prenatal forms to mild and late-onset presentations. We have reviewed the 45 published mutations in CSA and CSB to date and we report 43 new mutations in these genes together with the corresponding clinical data. Among the 84 reported kindreds, 52 (62%) have mutations in the CSB gene. Many types of mutations are scattered along the whole coding sequence of both genes, but clusters of missense mutations can be recognized and highlight the role of particular motifs in the proteins. Genotype-phenotype correlation hypotheses are considered with regard to these new molecular and clinical data. Additional cases of molecular prenatal diagnosis are reported and the strategy for prenatal testing is discussed. Two web-based locus-specific databases have been created to list all identified variants and to allow the inclusion of future reports (www.umd.be/CSA/ and www.umd.be/CSB/).

Published
2010
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21. Missense mutations of conserved glycine residues in fibrillin-1 highlight a potential subtype of cb-EGF-like domains

Author

Aurélie Plancke, Anne-Françoise Roux, Gwenaëlle Collod-Béroud, Dominique Martin-Coignard, Christophe Béroud, David Baux, Mireille Claustres, Patrick Collignon, Nathalie Pallares-Ruiz, Philippe Khau Van Kien, Corinne Baudoin, Valérie Drouin-Garraud, Alain Hovnanian, Nicolas Chassaing, 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), Genetics, Centre de Référence Maladies Sensorielles Génétiques, Hôpital Gui de Chauliac [Montpellier], Service de génétique médicale, CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique, Centre Hospitalier Le Mans (CH Le Mans), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service Génétique Médicale [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), COLLOD-BEROUD, Gwenaëlle, Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Hôpital Gui de Chauliac [CHU Montpellier], and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)

Subjects
Male, Models, Molecular, Fibrillin-1, medicine.disease_cause, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Marfan Syndrome, Missense mutation, Child, Genetics (clinical), chemistry.chemical_classification, Genetics, Alanine, wwwhgvsorg, 0303 health sciences, Mutation, 030305 genetics & heredity, Microfilament Proteins, Middle Aged, Amino acid, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Pedigree, Female, Fibrillin, musculoskeletal diseases, Adult, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, Sequence analysis, Glycine, Mutation, Missense, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Fibrillins, 03 medical and health sciences, Young Adult, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, cb-EGF-like domain, medicine, Humans, Fibrillin 1 (FBN1) gene, Gene, 030304 developmental biology, Aged, Epidermal Growth Factor, fibrillinopathies, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Sequence Analysis, DNA, chemistry, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, OFFICIAL JOURNAL, Calcium
Abstract

In six index cases/families referred for Marfan syndrome (MFS) molecular diagnosis, we identified six novel mutations in the FBN1 gene: c.1753G>C (p.Gly585Arg), c.2456G>A (p.Gly819Glu), c.4981G>A (p.Gly1661Arg), c.5339G>A (p.Gly1780Glu), c.6418G>A (p.Gly2140Arg) and c.6419G>A (p.Gly2140Glu). These variants, predicted to result in Glycine substitutions are located at the third position of a 4 amino acids loop-region of calcium-binding Epidermal Growth Factor-like (cb-EGF) fibrillin-1 domains 5, 9, 24, 25 and 32. Familial segregation studies showing cosegregation with MFS manifestations or de novo inheritance in addition to in silico analyses (conservation, 3D modeling) suggest evidence for a crucial role of the respective Glycine positions. Extending these analyses to all Glycine residue at position 3 of this 4 residues loop in fibrillin-1 cb-EGF with the UMD predictor tool and alignment of 2038 available related sequences strongly support a steric strain that only allows Glycine or even Alanine residues for domain structure maintenance and for the fibrillin functions. Our data compared with those of the literature strongly suggest the existence of a cb-EGF domain subtype with implications for related diseases.

Published
2009
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22. Transcriptional explorations of CAPN3 identify novel splicing mutations, a large-sized genomic deletion and evidence for messenger RNA decay

Author

Christophe Pécheux, Christophe Béroud, Rafaëlle Bernard, Isabelle Pénisson-Besnier, Jon Andoni Urtizberea, F. Leturcq, Valérie Drouin-Garraud, Françoise Chapon, Nicolas Lévy, Pascal Laforêt, Norma B. Romero, Martin Krahn, Service de Neurologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), 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), Centre de référence des maladies rares neuromusculaires, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Laboratoire de Physique des Lasers, Atomes et Molécules - UMR 8523 (PhLAM), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 1 (UM1)-IFR3, and Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)

Subjects
Adult, Male, Adolescent, Transcription, Genetic, RNA Splicing, RNA Stability, Muscle Proteins, Biology, 03 medical and health sciences, Exon, 0302 clinical medicine, Transcription (biology), Complementary DNA, Eosinophilia, Genetics, medicine, Humans, RNA, Messenger, Muscular dystrophy, Allele, Gene, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Aged, DNA Primers, Sequence Deletion, 030304 developmental biology, 0303 health sciences, Messenger RNA, Base Sequence, Myositis, Calpain, Middle Aged, medicine.disease, Molecular biology, 3. Good health, Muscular Dystrophies, Limb-Girdle, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, RNA splicing, Female, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], 030217 neurology & neurosurgery
Abstract

Mutations in the gene encoding calpain-3 (CAPN3) cause autosomal recessive limb-girdle muscular dystrophy type 2A (LGMD2A) and idiopathic eosinophilic myositis. Accurate diagnosis and genetic counselling are based on the identification of disease-causing mutations on both alleles of CAPN3 in the patients. In the present study, we used transcriptional analysis as a complementary approach for patients suspected of being affected with LGMD2A, in whom initial denaturing high-performance liquid chromatography genomic mutation screening evidenced no or only one CAPN3 mutation obviously considered as disease causing. This allowed to identify and characterize cDNA deletions. Further genomic analysis allowed to determine the origin of these deletions, either as splicing defects caused by intronic mutations or as an internal multi-exonic deletion. In particular, we report two novel CAPN3 mutations (c.1745 + 4_1745 + 7delAGTG in IVS13 and c.2185-16A>G in IVS20) and a recurrent large-sized genomic deletion including exons 2-8 for which genomic breakpoints have been characterized. In addition, our results indicate nonsense-mediated messenger RNA decay as a mechanism for under-expression of CAPN3 associated to some specific variations.

Published
2007
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23. Involvement of hyperprolinemia in cognitive and psychiatric features of the 22q11 deletion syndrome

Author

Therese van Amelsvoort, Ann Swillen, Marie Christine Nolen, Florence Thibaut, Cyril Coizet, Valérie Drouin-Garraud, Aude Gérard-Desplanches, Michèle Carlier, Thierry Frebourg, Solenn Legallic, Jacqueline Bou, Anne Philippe, Gaëlle Opolczynski, Bernadette Hecketsweiler, Pierre Sarda, Georges-Marie M. Brévière, Emilie Bumsel, Carole Fantini, Alexandra Afenjar, Didier Hannequin, Caroline Demily, G Raux, Gabriella Di Rosa, Dominique Campion, Valérie Layet, Delphine Héron, Marie Lemarchand, Janneke Zinkstok, Michel Petit, Annick Vogels, Giuseppina Pustorino, Nicole Philip, Didier Lacombe, Yves Alembik, Sylvie Manouvrier-Hanu, ANS - Amsterdam Neuroscience, Adult Psychiatry, Laboratoire de Génétique Clinique, Hôpital Jeanne de Flandre [Lille]-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université libre de Bruxelles (ULB), Department of Medical and Surgical Pediatrics, University Hospital, Messina, Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de psychologie cognitive (LPC), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Mathématiques Jean Leray (LMJL), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Génétique, Université Montpellier 2 - Sciences et Techniques (UM2)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Department of Medical Genetics, Hôpitaux Universitaires de Strasbourg, Unité de Cytogénétique et Génétique Médicale, Groupe Hospitalier du Havre-Hôpital Gustave Flaubert, CHU Trousseau [APHP], Service de neurologie [Rouen], Normandie Université (NU)-Normandie Université (NU), Department of Genetics, University Hospital, centre hospitalier St-Jean-de-Dieu, Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (ISC-MJ), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Centre International de Hautes Études Agronomiques Méditerranéennes (CIHEAM), Unité de Psychiatrie CHU C Nicolle, Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (CNC)

Subjects
Adult, Male, Psychosis, medicine.medical_specialty, Adolescent, Proline, Chromosomes, Human, Pair 22, Biology, Catechol O-Methyltransferase, 03 medical and health sciences, 0302 clinical medicine, 22q11 Deletion Syndrome, Proline dehydrogenase, Methionine, Risk Factors, DiGeorge syndrome, Intellectual Disability, Genetics, medicine, DiGeorge Syndrome, Proline Oxidase, Humans, Genetic Predisposition to Disease, Allele, Psychiatry, Molecular Biology, Genetics (clinical), Alleles, 030304 developmental biology, 0303 health sciences, Catechol-O-methyl transferase, Epilepsy, Proline oxidase, General Medicine, Middle Aged, medicine.disease, Phenotype, Psychotic Disorders, [SCCO.PSYC]Cognitive science/Psychology, Hyperprolinemia, Female, Chromosome Deletion, 030217 neurology & neurosurgery
Abstract

International audience; Microdeletions of the 22q11 region, responsible for the velo-cardio-facial syndrome (VCFS), are associated with an increased risk for psychosis and mental retardation. Recently, it has been shown in a hyperprolinemic mouse model that an interaction between two genes localized in the hemideleted region, proline dehydrogenase (PRODH) and catechol-o-methyl-transferase (COMT), could be involved in this phenotype. Here, we further characterize in eight children the molecular basis of type I hyperprolinemia (HPI), a recessive disorder resulting from reduced activity of proline dehydrogenase (POX). We show that these patients present with mental retardation, epilepsy and, in some cases, psychiatric features. We next report that, among 92 adult or adolescent VCFS subjects, a subset of patients with severe hyperprolinemia has a phenotype distinguishable from that of other VCFS patients and reminiscent of HPI. Forward stepwise multiple regression analysis selected hyperprolinemia, psychosis and COMT genotype as independent variables influencing IQ in the whole VCFS sample. An inverse correlation between plasma proline level and IQ was found. In addition, as predicted from the mouse model, hyperprolinemic VCFS subjects bearing the Met-COMT low activity allele are at risk for psychosis (OR = 2.8, 95% CI = 1.04-7.4). Finally, from the extensive analysis of the PRODH gene coding sequence variations, it is predicted that POX residual activity in the 0-30% range results into HPI, whereas residual activity in the 30-50% range is associated either with normal plasma proline levels or with mild-to-moderate hyperprolinemia.

Published
2007
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24. Simple detection of genomic microdeletions and microduplications using QMPSF in patients with idiopathic mental retardation

Author

Thierry Frebourg, Nathalie Drouot, Valérie Drouin-Garraud, Annick Rossi, Hélène Moirot, Mario Tosi, Géraldine Joly-Helas, Brigitte Gilbert-Dussardier, Valérie Layet, Céline de La Rochebrochard, Alice Goldenberg, Pascale Saugier-Veber, and Nathalie Le Meur

Subjects
Male, Population, Polymerase Chain Reaction, Gene Duplication, Intellectual Disability, Gene duplication, Genetics, medicine, Humans, education, Genetics (clinical), In Situ Hybridization, Fluorescence, Chromosome Aberrations, Gene Rearrangement, education.field_of_study, Sotos syndrome, business.industry, Genome, Human, Intracellular Signaling Peptides and Proteins, Nuclear Proteins, Reproducibility of Results, Karyotype, Gene rearrangement, Histone-Lysine N-Methyltransferase, Telomere, medicine.disease, Subtelomere, Developmental disorder, Fragile X syndrome, Child, Preschool, Fragile X Syndrome, Histone Methyltransferases, Female, Chromosome Deletion, business, Chromosomes, Human, Pair 17
Abstract

In contrast to the numerous well-known microdeletion syndromes, only a few microduplications have been described, and this discrepancy may be due in part to methodological bias. In order to facilitate the detection of genomic microdeletions and microduplications, we developed a new assay based on QMPSF (Quantitative Multiplex PCR of Short fluorescent Fragments) able to explore simultaneously 12 candidate loci involved in mental retardation (MR) and known to be the target of genomic rearrangements. We first screened 153 patients with MR and facial dysmorphism associated with malformations, or growth anomalies, or familial history, with cytogenetically normal chromosomes, and the absence of FRAXA mutation and subtelomeric rearrangements. In this series, we found a 5q35 deletion removing the NSD1 gene in a patient with severe epilepsy, profound MR and, retrospectively, craniofacial features of Sotos syndrome. In a second series, we screened 140 patients with MR and behaviour disturbance who did not fulfil the de Vries criteria for subtelomeric rearrangements and who had a normal karyotype and no detectable FRAXA mutation. We detected a 22q11 deletion in a patient with moderate MR, obesity, and facial dysmorphism and a 4 Mb 17p11 duplication in a patient with moderate MR, behaviour disturbance, strabismus, and aspecific facial features. This new QMPSF assay can be gradually upgraded to include additional loci involved in newly recognised microduplication/microdeletion syndromes, and should facilitate wide screenings of patients with idiopathic MR and provide better estimates of the microduplication frequency in the MR population.

Published
2006

25. SLC26A4 gene is frequently involved in nonsyndromic hearing impairment with enlarged vestibular aqueduct in Caucasian populations

Author

Sebastien Albert, Pierre Bitoun, Christine Francannet, Françoise Denoyelle, Bruno Delobel, Didier Lacombe, Marie-Madeleine Eliot, Annie Sergent-Allaoui, Hélène Dollfus, Sébastien Schmerber, Alain Joannard, Pierre Chauvin, Muriel Houang, Valérie Drouin-Garraud, N. Loundon, Albert David, Erea-Noel Garabedian, Catherine Calais, Françoise Duriez, Rémy Couderc, Hélène Blons, Delphine Feldmann, Laurence Jonard, Christine Petit, Marie-Françoise Obstoy, Hélène Catros, Sandrine Marlin, Patrice Tran Ba Huy, Jacques Leman, Hubert Journel, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Génétique des Déficits Sensoriels, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), ESIM - Déterminants Sociaux de la Santé et du Recours aux Soins (DS3), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de pédiatrie, CHU Grenoble-Hôpital Michallon, Service d'ORL et de chirurgie cervicale, CHU Grenoble, CHU Saint-Antoine [AP-HP], Centre Rochin, Unité de Génétique Médicale, CHR Vannes, Centre Gabriel Deshayes, Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Service d'ORL et chirurgie cervico-faciale, Service d'oto-rhino-laryngologie (ORL), Hôtel-Dieu, Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service d'ORL, chirurgie cervico-faciale [Rouen], Hôpital Charles Nicolle [Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Service d'oto-rhino-laryngologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service d'ORL, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Hôtel-Dieu-CHU Clermont-Ferrand, Service de Pédiatrie [Jean Verdier], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Jean Verdier [AP-HP], Collège de France - Chaire Génétique et physiologie cellulaire, Collège de France (CdF (institution)), Service d'ORL pédiatrique et Chirurgie Cervico-faciale [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de Biochimie et de Biologie Moléculaire [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de médecine nucléaire pédiatrique [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Service d'ORL et de Chirurgie Cervicofaciale, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Hôpital Charles Nicolle [Rouen]-CHU Rouen, Chaire Génétique et physiologie cellulaire, Service de génétique et embryologie médicales [CHU Trousseau], Chauvin, Pierre, Neurobiologie des réseaux sensorimoteurs (NRS (U7060)), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Neurobiologie des réseaux sensorimoteurs ( NRS (U7060) ), Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Centre National de la Recherche Scientifique ( CNRS ), and Magnani, Christophe

Subjects
Male, Pediatrics, Vestibular aqueduct, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Deafness, Connexins, MESH: Membrane Transport Proteins, Cohort Studies, 0302 clinical medicine, MESH: Child, Prevalence, Medicine, Nonsyndromic deafness, Child, 030223 otorhinolaryngology, MESH: Cohort Studies, Genetics (clinical), Pendred syndrome, Genetics, Goiter, Homozygote, Syndrome, MESH: European Continental Ancestry Group, MESH: Infant, Connexin 26, medicine.anatomical_structure, Sulfate Transporters, [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Child, Preschool, 030220 oncology & carcinogenesis, Female, Sensorineural hearing loss, medicine.symptom, MESH: Homozygote, Adult, medicine.medical_specialty, MESH: Mutation, Adolescent, Hearing loss, Hearing Loss, Sensorineural, MESH: Deafness, MESH: Goiter, White People, Vestibular Aqueduct, 03 medical and health sciences, otorhinolaryngologic diseases, Humans, Alleles, MESH: Prevalence, MESH: Adolescent, MESH: Humans, business.industry, MESH: Alleles, MESH: Child, Preschool, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Infant, Membrane Transport Proteins, Congenital sensorineural hearing impairment, MESH: Adult, medicine.disease, MESH: Male, MESH: Connexins, FOXI1, MESH: Hearing Loss, Sensorineural, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Mutation, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, sense organs, business, MESH: Female, Enlarged vestibular aqueduct
Abstract

Sensorineural hearing loss is the most frequent sensory deficit of childhood and is of genetic origin in up to 75% of cases. It has been shown that mutations of the SLC26A4 (PDS) gene were involved in syndromic deafness characterized by congenital sensorineural hearing impairment and goitre (Pendred's syndrome), as well as in congenital isolated deafness (DFNB4). While the prevalence of SLC26A4 mutations in Pendred's syndrome is clearly established, it remains to be studied in large cohorts of patients with nonsyndromic deafness and detailed clinical informations. In this report, 109 patients from 100 unrelated families, aged from 1 to 32 years (median age: 10 years), with nonsyndromic deafness and enlarged vestibular aqueduct, were genotyped for SLC26A4 using DHPLC molecular screening and sequencing. In all, 91 allelic variants were observed in 100 unrelated families, of which 19 have never been reported. The prevalence of SLC26A4 mutations was 40% (40/100), with biallelic mutation in 24% (24/100), while six families were homozygous. All patients included in this series had documented deafness, associated with EVA and without any evidence of syndromic disease. Among patients with SLC26A4 biallelic mutations, deafness was more severe, fluctuated more than in patients with no mutation. In conclusion, the incidence of SLC26A4 mutations is high in patients with isolated deafness and enlarged vestibular aqueduct and could represent up to 4% of nonsyndromic hearing impairment. SLC26A4 could be the second most frequent gene implicated in nonsyndromic deafness after GJB2, in this Caucasian population.

Published
2006
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26. Clinical evidence of the nonpathogenic nature of the M34T variant in the connexin 26 gene

Author

Françoise Denoyelle, Hélène Catros, Marie-Françoise Obstoy, Dominique Weil, Lucien Moati, Natalie Loundon, Rémy Couderc, Claude Ferrec, Valérie Drouin-Garraud, Alain Joannard, Bruno Delobel, Sébastien Schmerber, Hubert Journel, Sandrine Marlin, Delphine Feldmann, Christine Petit, Erea-Noel Garabedian, and Jacques Leman

Subjects
Genetics, Male, education.field_of_study, Hearing loss, Population, Audiogram, Biology, medicine.disease, Genetic determinism, Connexins, Pedigree, Connexin 26, Genotype, Mutation, otorhinolaryngologic diseases, medicine, Humans, Sensorineural hearing loss, Female, medicine.symptom, Allele, education, Allele frequency, Genetics (clinical)
Abstract

Mutations in GJB2 are the most common cause of congenital nonsyndromic hearing loss. The controversial allele variant M34T has been hypothesized to cause autosomal dominant or recessive nonsyndromic hearing impairment and some in vitro data has been consistent with this hypothesis. In this report, we present the clinical and genotypic study of 11 families (seven familial forms of nonsyndromic sensorineural hearing loss (NSSNHL) and four sporadic cases) in which the M34T GJB2 variant has been identified. The M34T mutation did not segregate with the deafness in six of the seven familial forms of NSSNH. Eight persons with normal audiogram presented a heterozygous M34T variation and five normal hearing individuals were composite heterozygous for M34T and another GJB2 mutation. Four normal hearing individuals with a documented audiogram were M34T/35delG and one was M34T/(GJB6-D13S1830)del. Screening a French control population of 116 subjects we have found an M34T allele frequency of 1.72%. This percentage was not significatively different from the prevalence of the M34T allele in the deaf population, which was 2.12%. All these data suggest that the M34T variant is not clinically significant in human and is a frequent polymorphism in France.

Published
2003

27. ZDHHC8 Single Nucleotide Polymorphism rs175174 is not associated with psychiatric features of the 22q11 Deletion Syndrome or Schizophrenia

Author

Anne Philippe, Annick Vogels, Thierry Frebourg, Dominique Campion, Florence Thibaut, Emmanuelle Houy-Durand, Pierre Sarda, Nicole Philip, Janneke Zinkstok, Michel Petit, Jacqueline Bou, Valérie Drouin-Garraud, Sylvie Manouvrier-Hanue, Therese van Amelsvoort, Solenn Legallic, Delphine Héron, Caroline Demily, Amsterdam Neuroscience, and Adult Psychiatry

Subjects
Genetics, Zinc finger, Chromosomes, Human, Pair 22, Schizophrenia (object-oriented programming), Chromosome Mapping, Membrane Proteins, Zinc Fingers, Single-nucleotide polymorphism, Gene deletion, Biology, Disease gene identification, Polymorphism, Single Nucleotide, Psychiatry and Mental health, 22q11 Deletion Syndrome, Membrane protein, Acyltransferases, Schizophrenia, Humans, Gene Deletion, Biological Psychiatry, Genetics (clinical)
Published
2007
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28. Townes-Brocks syndrome: Detection of a SALL1 mutation hot spot and evidence for a position effect in one patient

Author

F.G. Ferraz, Alain Fourmaintraux, Nicole Philip, Rima Slim, Stéphane Blanchard, Françoise Denoyelle, Valérie Drouin-Garraud, Didier Lacombe, Jean-Edmond Toublanc, Jean-Louis Alessandri, Christine Petit, Elisa Calzolari, and Sandrine Marlin

Subjects
Male, Hearing Loss, Sensorineural, Biology, Translocation, Genetic, Frameshift mutation, Anus, Imperforate, Exon, Chromosome 16, medicine, SALL1, Genetics, Townes–Brocks syndrome, Animals, Humans, Abnormalities, Multiple, Ear, External, Frameshift Mutation, Genetics (clinical), DNA Primers, Base Sequence, Chromosome Mapping, Syndrome, medicine.disease, Penetrance, Pedigree, Position effect, Thumb, Codon, Nonsense, Mutation, Female, Haploinsufficiency, Chromosomes, Human, Pair 16, Transcription Factors
Abstract

Townes-Brocks syndrome (TBS) is an autosomal dominant developmental disorder characterized by anal and thumb malformations and by ear anomalies that can affect the three compartments and usually lead to hearing loss. The gene underlying TBS, SALL1, is a human homolog of the Drosophila spalt gene which encodes a transcription factor. A search for SALL1 mutations undertaken in 11 unrelated affected individuals (five familial and six sporadic cases) led to the detection of mutations in nine of them. One nonsense and six different novel frameshift mutations, all located in the second exon, were identified. Together with the previously reported mutations [Kohlhase et al., 1999], they establish that TBS results from haploinsufficiency. The finding of de novo mutations in the sporadic cases is consistent with the proposed complete penetrance of the disease. Moreover, the occurrence of the same 826C>T transition in a CG dimer, in three sporadic cases from the present series and three sporadic cases from the other series [Kohlhase et al., 1999] (i.e., six of the eight mutations identified in sporadic cases), reveals the existence of a mutation hotspot. Six different SALL1 polymorphisms were identified in the course of the present study, three of which are clustered in a particular region of the gene that encodes a stretch of serine residues. Finally, the chromosome 16 breakpoint of a t(5;16)(p15.3;q12.1) translocation carried by a TBS-affected individual was mapped at least 180 kb telomeric to SALL1, thus indicating that a position effect underlies the disease in this individual.

Published
1999
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29. 29 French adult patients with PMM2-congenital disorder of glycosylation: outcome of the classical pediatric phenotype and depiction of a late-onset phenotype

Author

Delphine Héron, Christel Thauvin, Emmanuel Roze, Cyril Mignot, Pascale de Lonlay, Valérie Drouin-Garraud, Catherine Lenaerts, Valérie Cormier-Daire, Bénédicte Héron, Nathalie Seta, Alice Masurel, Hélène Ogier, Perrine Charles, Marion Gérard, Alexis Brice, Michèle Mayer, Marie-Lorraine Monin, Michèle Mathieu-Dramard, Philippe Khau Van Kien, Aurélia Jacquette, Claire de Barace, Unité fonctionnelle de neurogénétique moléculaire et cellulaire, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Physiopathology and Treatment of Neurodegenerative disorders, Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe de recherche clinique 'déficience intellectuelle et autisme', Université Pierre et Marie Curie - Paris 6 (UPMC), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie pédiatriques et maladies du dévéloppement, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de génétique, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de pédiatrie, CHU Grenoble, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité de génétique médicale et cytogénétique, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Service de génétique médicale, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité d'Epileptologie Pédiatrique, Service de Neurologie Pédiatrique et des Maladies Métaboliques, AP-HP Hôpital universitaire Robert-Debré [Paris], Laboratoire de biochimie métabolique et cellulaire, Hôpital Bichat - Claude Bernard, Service de Génétique [Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP]-Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service de neuropédiatrie [Trousseau], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ) -Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble, Département des maladies du système nerveux, AP-HP, roupe hospitalier Pitié-Salpêtrière, Department of Neurology, Paris, France, CHU Pitié-Salpêtrière [APHP]-CHU Pitié-Salpêtrière [APHP], Centre Hospitalier Régional Universitaire de Nîmes ( CHRU Nîmes ), AP-HP, Hôpital Robert Debré, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Administateur, HAL Sorbonne Université

Subjects
Male, Adult, medicine.medical_specialty, Pediatrics, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, [ SDV.MHEP.PED ] Life Sciences [q-bio]/Human health and pathology/Pediatrics, Late onset, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, PMM2-CDG, Cohort Studies, Young Adult, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, Congenital Disorders of Glycosylation, Internal medicine, Retinitis pigmentosa, medicine, Humans, Genetics(clinical), Pharmacology (medical), Age of Onset, Young adult, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, Cerebellar ataxia, Genetics (clinical), Retrospective Studies, Medicine(all), [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, business.industry, Research, Congenital disorder of glycosylation, General Medicine, Middle Aged, medicine.disease, 3. Good health, Phenotype, Peripheral neuropathy, Endocrinology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Phosphotransferases (Phosphomutases), Phosphomannomutase, Female, Cerebellar atrophy, France, medicine.symptom, Age of onset, business
Abstract

International audience; PMM2-CDG (formerly known as CDG Ia) a deficiency in phosphomannomutase, is the most frequent congenital disorder of glycosylation. The phenotype encompasses a wide range of neurological and non-neurological manifestations comprising cerebellar atrophy and intellectual deficiency. The phenotype of the disorder is well characterized in children but the long term course of the disease is unknown and the phenotype of late onset forms has not been comprehensively described. We thus retrospectively collected the clinical, biological and radiological data of 29 French PMM2-CDG patients aged 15 years or more with a proven molecular diagnosis (16 females and 13 males). In addition, thirteen of these patients were reexamined at the time of the study to obtain detailed information. 27 of the 29 patients had a typical PMM2-CDG phenotype, with infantile hypotonia, strabismus, developmental delay followed by intellectual deficiency, epilepsy, retinitis pigmentosa and/or visceral manifestations. The main health problems for these patients as teenagers and in adulthood were primary ovarian insufficiency, growth retardation, coagulation anomalies and thrombotic events, skeletal deformities and osteopenia/ osteoporosis, retinitis pigmentosa, as well as peripheral neuropathy. Three patients had never walked and three lost their ability to walk. The two remaining patients had a late-onset phenotype unreported to date. All patients (n = 29) had stable cerebellar atrophy. Our findings are in line with those of previous adult PMM2-CDG cohorts and points to the need for a multidisciplinary approach to the follow up of PMM2-CDG patients to prevent late complications. Additionally, our findings add weight to the view that PMM2-CDG may be diagnosed in teenage/adult patients with cerebellar atrophy, even in the absence of intellectual deficiency or non-neurological involvement.

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