2. Academic Validation
  3. Fifteen years of research on oral-facial-digital syndromes: from 1 to 16 causal genes

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

  • J Med Genet. 2017 Jun;54(6):371-380. doi: 10.1136/jmedgenet-2016-104436.
Ange-Line Bruel 1 2,  Brunella Franco 3 4,  Yannis Duffourd 1 2,  Julien Thevenon 1 2 5,  Laurence Jego 1 2,  Estelle Lopez 2,  Jean-François Deleuze 6,  Diane Doummar 7,  Rachel H Giles 8,  Colin A Johnson 9,  Martijn A Huynen 10,  Véronique Chevrier 11 12 13 14,  Lydie Burglen 7,  Manuela Morleo 2 3,  Isabelle Desguerres 15,  Geneviève Pierquin 16,  Bérénice Doray 17,  Brigitte Gilbert-Dussardier 18,  Bruno Reversade 19,  Elisabeth Steichen-Gersdorf 20,  Clarisse Baumann 21,  Inusha Panigrahi 22,  Anne Fargeot-Espaliat 23,  Anne Dieux 24,  Albert David 25,  Alice Goldenberg 26,  Ernie Bongers 27,  Dominique Gaillard 28,  Jesús Argente 29 30 31,  Bernard Aral 32,  Nadège Gigot 1 2 32,  Judith St-Onge 1 2,  Daniel Birnbaum 11 12 13 14,  Shubha R Phadke 33,  Valérie Cormier-Daire 3 34 35,  Thibaut Eguether 36,  Gregory J Pazour 36,  Vicente Herranz-Pérez 37 38,  Jaclyn S Goldstein 39,  Laurent Pasquier 40,  Philippe Loget 41,  Sophie Saunier 42 43,  André Mégarbané 44,  Olivier Rosnet 11 12 13 14,  Michel R Leroux 45 46,  John B Wallingford 47 48,  Oliver E Blacque 49,  Maxence V Nachury 39,  Tania Attie-Bitach 34 35 43,  Jean-Baptiste Rivière 1 2 32,  Laurence Faivre 1 2 5,  Christel Thauvin-Robinet 1 2 5
Affiliations

Affiliations

  • 1 FHU-TRANSLAD, Université de Bourgogne/CHU Dijon, Dijon, France.
  • 2 Équipe EA42271 GAD, Université de Bourgogne, Dijon, France.
  • 3 Department of Translational Medicine, Medical Genetics Ferderico II University of Naples, Naples, Italy.
  • 4 Telethon Institute of Genetics and Medicine-TIGEM, Naples, Italy.
  • 5 Centre de Référence maladies rares « Anomalies du Développement et syndrome malformatifs » de l'Est et Centre de Génétique, Hôpital d'Enfants, CHU, Dijon, France.
  • 6 Centre National de Génotypage, Evry, France.
  • 7 APHP, hôpital TROUSSEAU, Centre de référence des malformations et maladies congénitales du cervelet et département de génétique, Paris, France.
  • 8 Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands.
  • 9 Section of Ophthalmology and Neurosciences, Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK.
  • 10 Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
  • 11 Centre de Recherche en Cancérologie de Marseille, Marseille, France.
  • 12 Institut Paoli-Calmettes, Marseille, France.
  • 13 CNRS U7258, Marseille, France.
  • 14 Aix-Marseille Université, Marseille, France.
  • 15 Service de neurométabolisme, Hôpital Necker-Enfants Malades, CHU, Paris, France.
  • 16 Service de Génétique, CHU, Liège, Belgium.
  • 17 Service de Génétique Médicale, Hôpital de Hautepierre, CHU, Strasbourg, France.
  • 18 Centre de Référence Maladies Rares, Université de Poitiers, Poitiers, France.
  • 19 Laboratory of Human Embryology and Genetics, Institute of Medical Biology, Singapore.
  • 20 Department of Pediatrics I, Innsbruck Medical University, Innsbruck, Austria.
  • 21 Département de Génétique, Unité Fonctionelle de Génétique Clinique, Hôpital Robert Debré, CHU, Paris, France.
  • 22 Genetic-Metabolic Unit, Department of Pediatrics, Advanced Pediatric Centre, PGIMER, Chandigarh, India.
  • 23 Pédiatrie Neonatalogie, Centre Hospitalier Général, Brive-la-Gaillarde, Brive-la-Gaillarde, France.
  • 24 Centre de Référence CLAD NdF, Service de Génétique Clinique, Hôpital Jeanne de Flandre, CHRU, Lille, France.
  • 25 Service de Génétique Médicale, Unité de Génétique Clinique, Hôpital Mère-Enfant, CHU, Nantes, France.
  • 26 Service de Génétique, CHU de Rouen, Centre Normand de Génomique Médicale et Médecine Personnalisée, Rouen, France.
  • 27 Department of Human Genetics, Radboud University, Nijmegen, The Netherlands.
  • 28 Service de Génétique, Hôpital Maison Blanche, CHRU, Reims, France.
  • 29 Department of Pediatrics & Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.
  • 30 Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain.
  • 31 CIBEROBN de fisiopatología de la obesidad y nutrición, Instituto de Salud Carlos III, Madrid, Spain.
  • 32 Laboratoire de Génétique Moléculaire, PTB, CHU, Dijon, France.
  • 33 Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India.
  • 34 INSERM UMR1163, Université de Paris-Descartes-Sorbonne Paris Cité, Institut IMAGINE, Hôpital Necker-Enfants Malades, Paris, France.
  • 35 Service de génétique médicale, Hôpital Universitaire Necker-Enfants Malades, AP-HP, Institut Imagine, Paris, France.
  • 36 Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
  • 37 Laboratorio de Neurobiología Comparada, Instituto Cavanilles, Universitat de València, CIBERNED, Valencia, Spain.
  • 38 Unidad mixta de Esclerosis Múltiple y Neurorregeneración, IIS Hospital La Fe-UVEG, Valencia, Spain.
  • 39 Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California, USA.
  • 40 Centre de Référence Maladies Rares, Unité Fonctionnelle de Génétique Médicale, CHU, Rennes, France.
  • 41 Laboratoire d'Anatomie-Pathologie, CHU Rennes, Rennes, France.
  • 42 INSERM U983, Institut IMAGINE, Hôpital Necker-Enfants Malades, Paris, France.
  • 43 Département de Génétique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
  • 44 Institut Jérôme Lejeune, Paris, France.
  • 45 Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
  • 46 Centre for Cell Biology, Development and Disease, Simon Fraser University, Burnaby, British Columbia, Canada.
  • 47 Department of Molecular Biosciences, Center for Systems and Synthetic Biology, University of Texas at Austin, Austin, Texas, USA.
  • 48 Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, Texas, USA.
  • 49 School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland.
PMID: 28289185 DOI: 10.1136/jmedgenet-2016-104436
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.

Keywords

ciliopathies; oral-facial-digital syndromes.

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