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1. Rare genetic susceptibility variants assessment in autism spectrum disorder: detection rate and practical use

Author

Thomas Husson, François Lecoquierre, Kevin Cassinari, Camille Charbonnier, Olivier Quenez, Alice Goldenberg, Anne-Marie Guerrot, Anne-Claire Richard, Valérie Drouin-Garraud, Anne-Claire Brehin, Maryam Soleimani, Romain Taton, Maud Rotharmel, Antoine Rosier, Pascal Chambon, Nathalie Le Meur, Géraldine Joly-Helas, Pascale Saugier-Veber, Anne Boland, Jean-François Deleuze, Robert Olaso, Thierry Frebourg, Gael Nicolas, Olivier Guillin, and Dominique Campion

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Abstract Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a strong genetic component whose knowledge evolves quickly. Next-generation sequencing is the only effective technology to deal with the high genetic heterogeneity of ASD in a clinical setting. However, rigorous criteria to classify rare genetic variants conferring ASD susceptibility are currently lacking. We have performed whole-exome sequencing to identify both nucleotide variants and copy number variants (CNVs) in 253 ASD patients, including 68 patients with intellectual disability (ID) and 90 diagnosed as Asperger syndrome. Using explicit criteria to classify both susceptibility genes and susceptibility variants we prioritized 217 genes belonging to the following categories: syndromic genes, genes with an excess of de novo protein truncating variants and genes targeted by rare CNVs. We obtained a susceptibility variant detection rate of 19.7% (95% CI: [15–25.2%]). The rate for CNVs was 7.1% (95% CI: [4.3–11%]) and 12.6% (95% CI: [8.8–17.4%]) for nucleotide variants. The highest rate (30.1%, 95% CI: [20.2–43.2%]) was obtained in the ASD + ID subgroup. A strong contributor for at risk nucleotide variants was the recently identified set of genes (n = 81) harboring an excess of de novo protein truncating variants. Since there is currently no evidence that the genes targeted here are necessary and sufficient to cause ASD, we recommend to avoid the term “causative of ASD” when delivering the information about a variant to a family and to use instead the term “genetic susceptibility factor contributing to ASD”.

Published
2020
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2. De novo heterozygous desmoplakin mutations leading to Naxos-Carvajal disease

Author

Dagmar I Keller, Dimitri Stepowski, Christian Balmer, Francoise Simon, Joelle Guenthard, Fabrice Bauer, Peter Itin, Nadine David, Valérie Drouin-Garraud, and Véronique Fressart

Subjects
arrythmogenic right ventricular cardiomyopathy/dysplasia, autosomal-rezessive, de novo mutations, desmoplakin gene, mutation hot spots, Naxos/Carvajal Syndrome, Medicine
Abstract

STUDY/PRINCIPLES: Arrythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an autosomal-dominantly inherited disease caused by mutations in genes encoding desmosomal proteins and is characterised by fibrofatty replacement occurring predominantly in the right ventricle and can result in sudden cardiac death. Naxos and Carvajal syndrome, autosomal recessive forms of ARVC/D, are characterised by involvement of the right and/or left ventricle in association with palmoplantar keratoderma and woolly hair. The aim of the present study has been to screen for mutations in the desmosomal protein genes of two unrelated patients with Naxos-Carvajal syndrome. METHODS AND RESULTS: Desmosomal protein genes were screened for mutations by polymerase chain reaction as well as direct sequencing approach. In each patient we identified a single heterozygous de novo mutation in the desmoplakin gene DSP, p.Leu583Pro and p.Thr564Ile, leading to severe combined cardiac/dermatological and cardiac/dermatological/dental phenotypes. The DSP missense mutations are localised in the N terminal domain of desmoplakin. CONCLUSION: The identified variations in DSP involve highly conserved residues. Moreover, the variations are de novo mutations and they are localised in critical protein domains that appear to be mutation hot spots. We assume that these heterozygous variations are causal for the mixed Naxos-Carvajal syndrome phenotype in the screened patients.

Published
2012
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3. 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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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. 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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6. 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

7. 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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8. 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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9. 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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10. 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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11. 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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12. 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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13. 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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14. Gender as a Modifying Factor Influencing Myotonic Dystrophy Type 1 Phenotype Severity and Mortality: A Nationwide Multiple Databases Cross-Sectional Observational Study.

Author

Celine Dogan, Marie De Antonio, Dalil Hamroun, Hugo Varet, Marianne Fabbro, Felix Rougier, Khadija Amarof, Marie-Christine Arne Bes, Anne-Laure Bedat-Millet, Anthony Behin, Remi Bellance, Françoise Bouhour, Celia Boutte, François Boyer, Emmanuelle Campana-Salort, Françoise Chapon, Pascal Cintas, Claude Desnuelle, Romain Deschamps, Valerie Drouin-Garraud, Xavier Ferrer, Helene Gervais-Bernard, Karima Ghorab, Pascal Laforet, Armelle Magot, Laurent Magy, Dominique Menard, Marie-Christine Minot, Aleksandra Nadaj-Pakleza, Sybille Pellieux, Yann Pereon, Marguerite Preudhomme, Jean Pouget, Sabrina Sacconi, Guilhem Sole, Tanya Stojkovich, Vincent Tiffreau, Andoni Urtizberea, Christophe Vial, Fabien Zagnoli, Gilbert Caranhac, Claude Bourlier, Gerard Riviere, Alain Geille, Romain K Gherardi, Bruno Eymard, Jack Puymirat, Sandrine Katsahian, and Guillaume Bassez

Subjects
Medicine, Science
Abstract

Myotonic Dystrophy type 1 (DM1) is one of the most heterogeneous hereditary disease in terms of age of onset, clinical manifestations, and severity, challenging both medical management and clinical trials. The CTG expansion size is the main factor determining the age of onset although no factor can finely predict phenotype and prognosis. Differences between males and females have not been specifically reported. Our aim is to study gender impact on DM1 phenotype and severity.We first performed cross-sectional analysis of main multiorgan clinical parameters in 1409 adult DM1 patients (>18 y) from the DM-Scope nationwide registry and observed different patterns in males and females. Then, we assessed gender impact on social and economic domains using the AFM-Téléthon DM1 survey (n = 970), and morbidity and mortality using the French National Health Service Database (n = 3301).Men more frequently had (1) severe muscular disability with marked myotonia, muscle weakness, cardiac, and respiratory involvement; (2) developmental abnormalities with facial dysmorphism and cognitive impairment inferred from low educational levels and work in specialized environments; and (3) lonely life. Alternatively, women more frequently had cataracts, dysphagia, digestive tract dysfunction, incontinence, thyroid disorder and obesity. Most differences were out of proportion to those observed in the general population. Compared to women, males were more affected in their social and economic life. In addition, they were more frequently hospitalized for cardiac problems, and had a higher mortality rate.Gender is a previously unrecognized factor influencing DM1 clinical profile and severity of the disease, with worse socio-economic consequences of the disease and higher morbidity and mortality in males. Gender should be considered in the design of both stratified medical management and clinical trials.

Published
2016
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15. 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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