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1. Fifteen years of research on oral–facial–digital syndromes: from 1 to 16 causal genes

Author

Bruel, Ange-Line, Franco, Brunella, Duffourd, Yannis, Thevenon, Julien, Jego, Laurence, Lopez, Estelle, Deleuze, Jean-François, Doummar, Diane, Giles, Rachel H, Johnson, Colin A, Huynen, Martijn A, Chevrier, Véronique, Burglen, Lydie, Morleo, Manuela, Desguerres, Isabelle, Pierquin, Geneviève, Doray, Bérénice, Gilbert-Dussardier, Brigitte, Reversade, Bruno, Steichen-Gersdorf, Elisabeth, Baumann, Clarisse, Panigrahi, Inusha, Fargeot-Espaliat, Anne, Dieux, Anne, David, Albert, Goldenberg, Alice, Bongers, Ernie, Gaillard, Dominique, Argente, Jesús, Aral, Bernard, Gigot, Nadège, St-Onge, Judith, Birnbaum, Daniel, Phadke, Shubha R, Cormier-Daire, Valérie, Eguether, Thibaut, Pazour, Gregory J, Herranz-Pérez, Vicente, Goldstein, Jaclyn S, Pasquier, Laurent, Loget, Philippe, Saunier, Sophie, Mégarbané, André, Rosnet, Olivier, Leroux, Michel R, Wallingford, John B, Blacque, Oliver E, Nachury, Maxence V, Attie-Bitach, Tania, Rivière, Jean-Baptiste, Faivre, Laurence, and Thauvin-Robinet, Christel

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Kidney Disease, Pediatric, 2.1 Biological and endogenous factors, Aetiology, Congenital, Abnormalities, Multiple, Ciliary Motility Disorders, Encephalocele, Face, Female, Heterozygote, Humans, Male, Mutation, Orofaciodigital Syndromes, Polycystic Kidney Diseases, Proteins, Retinitis Pigmentosa, ciliopathies, oral-facial-digital syndromes, Medical and Health Sciences, Genetics & Heredity, Clinical sciences
Abstract

Oral-facial-digital syndromes (OFDS) gather rare genetic disorders characterised by facial, oral and digital abnormalities associated with a wide range of additional features (polycystic kidney disease, cerebral malformations and several others) to delineate a growing list of OFDS subtypes. The most frequent, OFD type I, is caused by a heterozygous mutation in the OFD1 gene encoding a centrosomal protein. The wide clinical heterogeneity of OFDS suggests the involvement of other ciliary genes. For 15 years, we have aimed to identify the molecular bases of OFDS. This effort has been greatly helped by the recent development of whole-exome sequencing (WES). Here, we present all our published and unpublished results for WES in 24 cases with OFDS. We identified causal variants in five new genes (C2CD3, TMEM107, INTU, KIAA0753 and IFT57) and related the clinical spectrum of four genes in other ciliopathies (C5orf42, TMEM138, TMEM231 and WDPCP) to OFDS. Mutations were also detected in two genes previously implicated in OFDS. Functional studies revealed the involvement of centriole elongation, transition zone and intraflagellar transport defects in OFDS, thus characterising three ciliary protein modules: the complex KIAA0753-FOPNL-OFD1, a regulator of centriole elongation; the Meckel-Gruber syndrome module, a major component of the transition zone; and the CPLANE complex necessary for IFT-A assembly. OFDS now appear to be a distinct subgroup of ciliopathies with wide heterogeneity, which makes the initial classification obsolete. A clinical classification restricted to the three frequent/well-delineated subtypes could be proposed, and for patients who do not fit one of these three main subtypes, a further classification could be based on the genotype.

Published
2017

2. Do children and adolescents with type 1 diabetes suffer from a lack of resources in France? Results from a benchmark study in the New Aquitaine region

Author

B. Cammas, A. Lacoste, M. Franc, J. Chevrel, F. Compain, L. Oilleau, C. Gambert, A. Galtier, A. Tamboura, A. Fargeot-Espaliat, A. Lienhardt, L. Martineau, V. Vautier, M. Percot-Blondy, A. Valade, S. Pochelu, N. Bacheré, Pascal Barat, M.-N. Campas-Lebecque, M. Benoit, M. Carré, and C. Beau

Subjects
Blood Glucose, Male, medicine.medical_specialty, Adolescent, Health Services Accessibility, 03 medical and health sciences, 0302 clinical medicine, Multidisciplinary approach, 030225 pediatrics, Diabetes mellitus, medicine, Humans, Child, Human resources, Glycemic, Type 1 diabetes, Health Care Rationing, business.industry, Benchmarking, medicine.disease, Cross-Sectional Studies, Diabetes Mellitus, Type 1, Family medicine, Metabolic control analysis, Pediatrics, Perinatology and Child Health, Benchmark (computing), Health Resources, Female, France, business
Abstract

A benchmark study was conducted in the southwest of France, in the New Aquitaine region, to investigate metabolic outcomes and availability of resources in pediatric diabetes units. We assessed whether the level of care was in accordance with the International Society for Pediatric and Adolescent Diabetes recommendations.Demographic and clinical data were collected, as were all HbA1c tests for the 2017 calendar year. Pediatricians specialized in diabetes care were invited to complete an online survey concerning means allocated to the management of type 1 diabetes in their centers.Sixteen centers provided data for 1277 patients and 3873 clinical visits. A total of 1115 children suffering from diabetes for more than 1 year were studied. Median HbA1c was 8% (7.4-8.6) for the whole region. Only 29.2% of children had good metabolic control in accordance with the7.5% target. We identified slight but significant variation in glycemic control among centers (P=0.029). The use of an insulin pump varied greatly among centers but did not explain HbA1c differences. We did not identify a correlation between medical or paramedical time dedicated to the follow-up of diabetic patients and the mean HbA1c of each center. For 100 diabetic patients, follow-up was provided by 0.42 physicians (0.23-1.50), 0.15 nurses (0-0.56), 0.12 dietitians (0-0.48), and 0.07 psychologists (0-0.30).This study demonstrates a lack of human resources allocated to the management of type 1 diabetes in the region that is far below international recommendations. The proportion of children achieving the international glycemic target is low. There is a clear need to improve glycemic control in children, which will only be possible with improved professional practices, encouraged by benchmark studies, and by increasing the size of our multidisciplinary teams.

Published
2021
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3. Fifteen years of research on oral-facial-digital syndromes: from 1 to 16 causal genes

Author

Nadège Gigot, Anne Dieux, Yannis Duffourd, Bernard Aral, Lydie Burglen, Bérénice Doray, Olivier Rosnet, Alice Goldenberg, Martijn A. Huynen, Oliver E. Blacque, Brunella Franco, André Mégarbané, Diane Doummar, Ernie M.H.F. Bongers, Anne Fargeot-Espaliat, Clarisse Baumann, Judith St-Onge, Daniel Birnbaum, Sophie Saunier, Thibaut Eguether, Jean-François Deleuze, Estelle Lopez, Dominique Gaillard, Geneviève Pierquin, Shubha R. Phadke, Michel R. Leroux, Rachel H. Giles, Tania Attié-Bitach, Jaclyn S. Goldstein, Isabelle Desguerres, Elisabeth Steichen-Gersdorf, Brigitte Gilbert-Dussardier, Manuela Morleo, Jesús Argente, Jean Baptiste Rivière, Gregory J. Pazour, Christel Thauvin-Robinet, Julien Thevenon, Albert David, Maxence V. Nachury, Laurence Faivre, Philippe Loget, Véronique Chevrier, Bruno Reversade, Laurence Jego, Ange Line Bruel, Vicente Herranz-Pérez, Laurent Pasquier, Colin A. Johnson, John B. Wallingford, Valérie Cormier-Daire, Inusha Panigrahi, Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Institut d'Astrophysique et de Géophysique [Liège], Université de Liège, FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service: neuropédiatrie pathologie du développement, Université Pierre et Marie Curie - Paris 6 (UPMC), University Medical Center [Utrecht], University of Leeds, Radboud University [Nijmegen], Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Génétique Humaine, Université de Liège-CHU Liège, Service de Génétique, Hôpital de Hautepierre [Strasbourg], Génétique Médicale, Centre hospitalier universitaire de Poitiers (CHU Poitiers)-Centre de Référence Anomalies du Développement Ouest, Laboratory of Human Embryology and Genetics, Institute of Medical Biology, Singapore, Department of Pediatrics, Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Département de Génétique Médicale, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Advanced Pediatric Center (PGIMER), Pediatry center, Pédiatrie Neonatalogie, Centre Hospitalier Général, Brive-la-Gaillarde, Brive-la-Gaillarde, France, Service de Génétique clinique, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Dauphine Recherches en Management - MLAB (DRM - MLAB), Dauphine Recherches en Management (DRM), Université Paris Dauphine-PSL, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Dauphine-PSL, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Department of human genetics, Radboud University Medical Center [Nijmegen]-Nijmegen Centre for Molecular Life Sciences-Institute for Genetic and Metabolic Disorders, Centre de génétique et Centre de référence maladies rares et anomalies du développement et syndromes malformatifs du Centre Est, Département de Génétique et Procréation UF-Hôpital Couple Enfant de Grenoble-CHU Grenoble, Hospital Universitario La Paz, Laboratoire de Génétique Chromosomique et Moléculaire [CHU Dijon], FHU TRANSLAD, Département de Génétique, Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India, 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), Imagerie intégrative de la molécule à l'organisme, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], CHU Pontchaillou [Rennes], Neuropathies héréditaires et rein en développement, Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de génétique médicale, Université Saint-Joseph de Beyrouth (USJ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), FHU TRANSLAD, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Génétique des Anomalies du Développement ( GAD ), IFR100 - Structure fédérative de recherche Santé-STIC-Université de Bourgogne ( UB ), Centre National de Génotypage ( CNG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands, Section of Ophthalmology and Neurosciences, Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK, Radboud university [Nijmegen], Centre de Recherche en Cancérologie de Marseille ( CRCM ), Aix Marseille Université ( AMU ) -Institut Paoli-Calmettes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service de neuropédiatrie et pathologie du développement, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Service de neurométabolisme, Hôpital Necker-Enfants Malades, CHU, Paris, France, CHU de Poitiers-Centre de Référence Anomalies du Développement Ouest, Innsbruck Medical University [Austria] ( IMU ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré, Advanced Pediatric Center ( PGIMER ), Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Dauphine Recherches en Management - MLAB ( DRM - MLAB ), Dauphine Recherches en Management ( DRM ), Université Paris-Dauphine-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris-Dauphine-Centre National de la Recherche Scientifique ( CNRS ), CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -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 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -INSTITUT CURIE, Service d'anatomie et cytologie pathologiques [Rennes], Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Saint-Joseph de Beyrouth ( USJ ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Innsbruck Medical University [Austria] (IMU), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, Centre National de la Recherche Scientifique (CNRS)-Université Paris Dauphine-PSL-Centre National de la Recherche Scientifique (CNRS)-Université Paris Dauphine-PSL, Institut Curie-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 Pontchaillou-CHU Pontchaillou [Rennes], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Bruel, Ange Line, Franco, Brunella, Duffourd, Yanni, Thevenon, Julien, Jego, Laurence, Lopez, Estelle, Deleuze, Jean Françoi, Doummar, Diane, Giles, Rachel H, Johnson, Colin A, Huynen, Martijn A, Chevrier, Véronique, Burglen, Lydie, Morleo, Manuela, Desguerres, Isabelle, Pierquin, Geneviève, Doray, Bérénice, Gilbert Dussardier, Brigitte, Reversade, Bruno, Steichen Gersdorf, Elisabeth, Baumann, Clarisse, Panigrahi, Inusha, Fargeot Espaliat, Anne, Dieux, Anne, David, Albert, Goldenberg, Alice, Bongers, Ernie, Gaillard, Dominique, Argente, Jesú, Aral, Bernard, Gigot, Nadège, St Onge, Judith, Birnbaum, Daniel, Phadke, Shubha R, Cormier Daire, Valérie, Eguether, Thibaut, Pazour, Gregory J, Herranz Pérez, Vicente, Goldstein, Jaclyn S, Pasquier, Laurent, Loget, Philippe, Saunier, Sophie, Mégarbané, André, Rosnet, Olivier, Leroux, Michel R, Wallingford, John B, Blacque, Oliver E, Nachury, Maxence V, Attie Bitach, Tania, Rivière, Jean Baptiste, Faivre, Laurence, Thauvin Robinet, Christel, Bruel, Al, Franco, B, Duffourd, Y, Thevenon, J, Jego, L, Lopez, E, Deleuze, Jf, Doummar, D, Giles, Rh, Johnson, Ca, Huynen, Ma, Chevrier, V, Burglen, L, Morleo, M, Desguerres, I, Pierquin, G, Doray, B, Gilbert-Dussardier, B, Reversade, B, Steichen-Gersdorf, E, Baumann, C, Panigrahi, I, Fargeot-Espaliat, A, Dieux, A, David, A, Goldenberg, A, Bongers, E, Gaillard, D, Argente, J, Aral, B, Gigot, N, St-Onge, J, Birnbaum, D, Phadke, Sr, Cormier-Daire, V, Eguether, T, Pazour, Gj, Herranz-Perez, V, Goldstein, J, Pasquier, L, Loget, P, Saunier, S, Megarbane, A, Rosnet, O, Leroux, Mr, Wallingford, Jb, Blacque, Oe, Nachury, Mv, Attie-Bitach, T, Riviere, Jb, Faivre, L, and Thauvin-Robinet, C

Subjects
Male, 0301 basic medicine, Heterozygote, ciliopathie, Oral facial digital, [SDV]Life Sciences [q-bio], [ SDV.BBM.BM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Biology, Ciliopathies, Centriole elongation, 03 medical and health sciences, Intraflagellar transport, Genotype, Genetics, Polycystic kidney disease, medicine, Humans, Abnormalities, Multiple, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Functional studies, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Gene, oral-facial-digital syndromes, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Encephalocele, Polycystic Kidney Diseases, [ SDV ] Life Sciences [q-bio], ciliopathies, Proteins, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Orofaciodigital Syndromes, medicine.disease, 030104 developmental biology, Face, Mutation, Female, Retinitis Pigmentosa, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Ciliary Motility Disorders
Abstract

Oral–facial–digital syndromes (OFDS) gather rare genetic disorders characterised by facial, oral and digital abnormalities associated with a wide range of additional features (polycystic kidney disease, cerebral malformations and several others) to delineate a growing list of OFDS subtypes. The most frequent, OFD type I, is caused by a heterozygous mutation in theOFD1gene encoding a centrosomal protein. The wide clinical heterogeneity of OFDS suggests the involvement of other ciliary genes. For 15 years, we have aimed to identify the molecular bases of OFDS. This effort has been greatly helped by the recent development of whole-exome sequencing (WES). Here, we present all our published and unpublished results for WES in 24 cases with OFDS. We identified causal variants in five new genes (C2CD3,TMEM107,INTU,KIAA0753andIFT57) and related the clinical spectrum of four genes in other ciliopathies (C5orf42,TMEM138,TMEM231andWDPCP) to OFDS. Mutations were also detected in two genes previously implicated in OFDS. Functional studies revealed the involvement of centriole elongation, transition zone and intraflagellar transport defects in OFDS, thus characterising three ciliary protein modules: the complex KIAA0753-FOPNL-OFD1, a regulator of centriole elongation; the Meckel-Gruber syndrome module, a major component of the transition zone; and the CPLANE complex necessary for IFT-A assembly. OFDS now appear to be a distinct subgroup of ciliopathies with wide heterogeneity, which makes the initial classification obsolete. A clinical classification restricted to the three frequent/well-delineated subtypes could be proposed, and for patients who do not fit one of these three main subtypes, a further classification could be based on the genotype.

Published
2017
Full Text
View/download PDF

4. 15 years of research on Oral-Facial-Digital syndromes: from 1 to 16 causal genes

Author

Bruel, Ange-Line, Franco, Brunella, Duffourd, Yannis, Thevenon, Julien, Jego, Laurence, Lopez, Estelle, Deleuze, Jean-François, Doummar, Diane, Giles, Rachel H., Johnson, Colin A., Huynen, Martijn A., Chevrier, Véronique, Burglen, Lydie, Morleo, Manuela, Desguerres, Isabelle, Pierquin, Geneviève, Doray, Bérénice, Gilbert-Dussardier, Brigitte, Reversade, Bruno, Steichen-Gersdorf, Elisabeth, Baumann, Clarisse, Panigrahi, Inusha, Fargeot-Espaliat, Anne, Dieux, Anne, David, Albert, Goldenberg, Alice, Bongers, Ernie, Gaillard, Dominique, Argente, Jesús, Aral, Bernard, Gigot, Nadège, St-Onge, Judith, Birnbaum, Daniel, Phadke, Shubha R., Cormier-Daire, Valérie, Eguether, Thibaut, Pazour, Gregory J., Herranz-Pérez, Vicente, Lee, Jaclyn S., Pasquier, Laurent, Loget, Philippe, Saunier, Sophie, Mégarbané, André, Rosnet, Olivier, Leroux, Michel R., Wallingford, John B., Blacque, Oliver E., Nachury, Maxence V., Attie-Bitach, Tania, Rivière, Jean-Baptiste, Faivre, Laurence, and Thauvin-Robinet, Christel

Subjects
Male, Heterozygote, Polycystic Kidney Diseases, Proteins, Orofaciodigital Syndromes, Article, Face, Mutation, Humans, Abnormalities, Multiple, Female, Retinitis Pigmentosa, Ciliary Motility Disorders, Encephalocele
Abstract

Oral-facial-digital syndromes (OFDS) gather rare genetic disorders characterized by facial, oral and digital abnormalities associated with a wide range of additional features (polycystic kidney disease, cerebral malformations and several others) to delineate a growing list of OFD subtypes. The most frequent, OFD type I, is caused by a heterozygous mutation in the OFD1 gene encoding a centrosomal protein. The wide clinical heterogeneity of OFDS suggests the involvement of other ciliary genes. For 15 years, we have aimed to identify the molecular bases of OFDS. This effort has been greatly helped by the recent development of whole exome sequencing (WES). Here, we present all our published and unpublished results for WES in 24 OFDS cases. We identified causal variants in five new genes (C2CD3, TMEM107, INTU, KIAA0753, IFT57) and related the clinical spectrum of four genes in other ciliopathies (C5orf42, TMEM138, TMEM231, WDPCP) to OFDS. Mutations were also detected in two genes previously implicated in OFDS. Functional studies revealed the involvement of centriole elongation, transition zone and intraflagellar transport defects in OFDS, thus characterizing three ciliary protein modules: the complex KIAA0753-FOPNL-OFD1, a regulator of centriole elongation; the MKS module, a major component of the transition zone; and the CPLANE complex necessary for IFT-A assembly. OFDS now appear to be a distinct subgroup of ciliopathies with wide heterogeneity, which makes the initial classification obsolete. A clinical classification restricted to the three frequent/well-delineated subtypes could be proposed, and for patients who do not fit one of these 3 main subtypes, a further classification could be based on the genotype.

Published
2017

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