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Fifteen years of research on oral–facial–digital syndromes: from 1 to 16 causal genes
  1. Ange-Line Bruel1,2,
  2. Brunella Franco3,4,
  3. Yannis Duffourd1,2,
  4. Julien Thevenon1,2,5,
  5. Laurence Jego1,2,
  6. Estelle Lopez2,
  7. Jean-François Deleuze6,
  8. Diane Doummar7,
  9. Rachel H Giles8,
  10. Colin A Johnson9,
  11. Martijn A Huynen10,
  12. Véronique Chevrier11,12,13,14,
  13. Lydie Burglen7,
  14. Manuela Morleo2,3,
  15. Isabelle Desguerres15,
  16. Geneviève Pierquin16,
  17. Bérénice Doray17,
  18. Brigitte Gilbert-Dussardier18,
  19. Bruno Reversade19,
  20. Elisabeth Steichen-Gersdorf20,
  21. Clarisse Baumann21,
  22. Inusha Panigrahi22,
  23. Anne Fargeot-Espaliat23,
  24. Anne Dieux24,
  25. Albert David25,
  26. Alice Goldenberg26,
  27. Ernie Bongers27,
  28. Dominique Gaillard28,
  29. Jesús Argente29,30,31,
  30. Bernard Aral32,
  31. Nadège Gigot1,2,32,
  32. Judith St-Onge1,2,
  33. Daniel Birnbaum11,12,13,14,
  34. Shubha R Phadke33,
  35. Valérie Cormier-Daire3,34,35,
  36. Thibaut Eguether36,
  37. Gregory J Pazour36,
  38. Vicente Herranz-Pérez37,38,
  39. Jaclyn S Goldstein39,
  40. Laurent Pasquier40,
  41. Philippe Loget41,
  42. Sophie Saunier42,43,
  43. André Mégarbané44,
  44. Olivier Rosnet11,12,13,14,
  45. Michel R Leroux45,46,
  46. John B Wallingford47,48,
  47. Oliver E Blacque49,
  48. Maxence V Nachury39,
  49. Tania Attie-Bitach34,35,43,
  50. Jean-Baptiste Rivière1,2,32,
  51. Laurence Faivre1,2,5,
  52. Christel Thauvin-Robinet1,2,5
  1. 1 FHU-TRANSLAD, Université de Bourgogne/CHU Dijon, Dijon, France
  2. 2 Équipe EA42271 GAD, Université de Bourgogne, Dijon, France
  3. 3 Department of Translational Medicine, Medical Genetics Ferderico II University of Naples, Naples, Italy
  4. 4 Telethon Institute of Genetics and Medicine-TIGEM, Naples, Italy
  5. 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. 6 Centre National de Génotypage, Evry, France
  7. 7 APHP, hôpital TROUSSEAU, Centre de référence des malformations et maladies congénitales du cervelet et département de génétique, Paris, France
  8. 8 Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands
  9. 9 Section of Ophthalmology and Neurosciences, Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK
  10. 10 Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
  11. 11 Centre de Recherche en Cancérologie de Marseille, Marseille, France
  12. 12 Institut Paoli-Calmettes, Marseille, France
  13. 13 CNRS U7258, Marseille, France
  14. 14 Aix-Marseille Université, Marseille, France
  15. 15 Service de neurométabolisme, Hôpital Necker-Enfants Malades, CHU, Paris, France
  16. 16 Service de Génétique, CHU, Liège, Belgium
  17. 17 Service de Génétique Médicale, Hôpital de Hautepierre, CHU, Strasbourg, France
  18. 18 Centre de Référence Maladies Rares, Université de Poitiers, Poitiers, France
  19. 19 Laboratory of Human Embryology and Genetics, Institute of Medical Biology, Singapore
  20. 20 Department of Pediatrics I, Innsbruck Medical University, Innsbruck, Austria
  21. 21 Département de Génétique, Unité Fonctionelle de Génétique Clinique, Hôpital Robert Debré, CHU, Paris, France
  22. 22 Genetic-Metabolic Unit, Department of Pediatrics, Advanced Pediatric Centre, PGIMER, Chandigarh, India
  23. 23 Pédiatrie Neonatalogie, Centre Hospitalier Général, Brive-la-Gaillarde, Brive-la-Gaillarde, France
  24. 24 Centre de Référence CLAD NdF, Service de Génétique Clinique, Hôpital Jeanne de Flandre, CHRU, Lille, France
  25. 25 Service de Génétique Médicale, Unité de Génétique Clinique, Hôpital Mère-Enfant, CHU, Nantes, France
  26. 26 Service de Génétique, CHU de Rouen, Centre Normand de Génomique Médicale et Médecine Personnalisée, Rouen, France
  27. 27 Department of Human Genetics, Radboud University, Nijmegen, The Netherlands
  28. 28 Service de Génétique, Hôpital Maison Blanche, CHRU, Reims, France
  29. 29 Department of Pediatrics & Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain
  30. 30 Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain
  31. 31 CIBEROBN de fisiopatología de la obesidad y nutrición, Instituto de Salud Carlos III, Madrid, Spain
  32. 32 Laboratoire de Génétique Moléculaire, PTB, CHU, Dijon, France
  33. 33 Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
  34. 34 INSERM UMR1163, Université de Paris-Descartes-Sorbonne Paris Cité, Institut IMAGINE, Hôpital Necker-Enfants Malades, Paris, France
  35. 35 Service de génétique médicale, Hôpital Universitaire Necker-Enfants Malades, AP-HP, Institut Imagine, Paris, France
  36. 36 Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA
  37. 37 Laboratorio de Neurobiología Comparada, Instituto Cavanilles, Universitat de València, CIBERNED, Valencia, Spain
  38. 38 Unidad mixta de Esclerosis Múltiple y Neurorregeneración, IIS Hospital La Fe-UVEG, Valencia, Spain
  39. 39 Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California, USA
  40. 40 Centre de Référence Maladies Rares, Unité Fonctionnelle de Génétique Médicale, CHU, Rennes, France
  41. 41 Laboratoire d’Anatomie-Pathologie, CHU Rennes, Rennes, France
  42. 42 INSERM U983, Institut IMAGINE, Hôpital Necker-Enfants Malades, Paris, France
  43. 43 Département de Génétique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
  44. 44 Institut Jérôme Lejeune, Paris, France
  45. 45 Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada
  46. 46 Centre for Cell Biology, Development and Disease, Simon Fraser University, Burnaby, British Columbia, Canada
  47. 47 Department of Molecular Biosciences, Center for Systems and Synthetic Biology, University of Texas at Austin, Austin, Texas, USA
  48. 48 Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, Texas, USA
  49. 49 School of Biomolecular and Biomedical Science, University College Dublin, Dublin, Ireland
  1. Correspondence to Ange-Line Bruel, Genetics of Developmental Disorders, Bât B3, Université de Bourgogne-Franche Comté, 15 Boulevard Maréchal Delattre de Tassigny, 21070 Dijon, France; ange-line.bruel{at}


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.

  • oral-facial-digital syndromes
  • ciliopathies

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  • Contributor BF, DD, RHG, CAJ, LB, MM, ID, GP, BD, BG-D, BR, ES-G, CB, IP, AF-E, AD, AD, AG, EB, DG, JA, DB, SRP, VCD, GJP, VH-P, LP, PL, SS, AM, TA-B, LF and CT-R ascertained the family and delineated OFD syndromes.

    A-LB, JT, LJ, EL, MAH, VC, BA, NG, JSO, TE, JSL, OR, MRL, JBW, OEB, MVN, JBR performed molecular analysis, interpretation of results in these families and characterised ciliopathy proteins.

    YD, J-FD, J-BR, A-LB performed the bioinformatic analysis of the data.

    All the authors participated to the writing and reviewing processes of the manuscript.

  • Funding This work was supported by grants from the GIS-Institut des Maladies Rares (HTS), the French Foundation for Rare Diseases, the French Ministry of Health (PHRC national 2010-A01 014–35 and 2013) and the Regional Council of Burgundy.

  • Competing interests None declared.

  • Patient consent Pictures of patients described in this publication have previously been published.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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