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Journal Articles Journal of Medical Genetics Year : 2017

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

1 Equipe GAD (LNC - U1231)
2 Institut d'Astrophysique et de Géophysique [Liège]
4 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
5 LNC - Lipides - Nutrition - Cancer (U866)
6 GAD - Génétique des Anomalies du Développement
7 CNG - Centre National de Génotypage
8 Service: neuropédiatrie pathologie du développement
9 UMCU - University Medical Center [Utrecht]
10 University of Leeds
11 Radboud University [Nijmegen]
12 CRCM - Centre de Recherche en Cancérologie de Marseille
13 CHU Trousseau [APHP]
14 Hôpital Necker - Enfants Malades [AP-HP]
15 Centre de Génétique Humaine
16 Service de Génétique
17 Génétique Médicale
18 Laboratory of Human Embryology and Genetics, Institute of Medical Biology, Singapore
19 Department of Pediatrics
20 Département de Génétique Médicale
21 PGIMER - Advanced Pediatric Center
22 Pédiatrie Neonatalogie, Centre Hospitalier Général, Brive-la-Gaillarde, Brive-la-Gaillarde, France
23 Service de Génétique clinique
24 DRM - MLAB - Dauphine Recherches en Management - MLAB
25 Service de génétique [Rouen]
26 Department of human genetics
27 Centre de génétique et Centre de référence maladies rares et anomalies du développement et syndromes malformatifs du Centre Est
28 Hospital Universitario La Paz
29 Laboratoire de Génétique Chromosomique et Moléculaire [CHU Dijon]
30 FHU TRANSLAD, Département de Génétique
31 Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
32 Inserm U781 - Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement
33 Imagerie intégrative de la molécule à l'organisme
34 Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes]
35 Neuropathies héréditaires et rein en développement
36 Unité de génétique médicale
37 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
Ange-Line Bruel
  • Function : Author
  • PersonId : 994768
Yannis Duffourd
  • Function : Author
  • PersonId : 994654
Estelle Lopez
Jean-François Deleuze
  • Function : Author
  • PersonId : 1015006
Lydie Burglen
Brigitte Gilbert-Dussardier
Elisabeth Steichen-Gersdorf
  • Function : Author
  • PersonId : 886494
Ernie Bongers
  • Function : Author
  • PersonId : 906792
Gregory Pazour
  • Function : Author
Vicente Herranz-Pérez
Jaclyn Goldstein
  • Function : Author
Laurent Pasquier
  • Function : Author
  • PersonId : 1014327
André Mégarbané
Michel Leroux
  • Function : Author
John Wallingford
  • Function : Author
Oliver Blacque
  • Function : Author
Maxence Nachury
  • Function : Author
Jean-Baptiste Rivière
  • Function : Author
  • PersonId : 994656


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.
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Dates and versions

hal-01789377 , version 1 (18-06-2024)



Ange-Line Bruel, Brunella Franco, Yannis Duffourd, Julien Thévenon, Laurence Jego, et al.. Fifteen years of research on oral–facial–digital syndromes: from 1 to 16 causal genes. Journal of Medical Genetics, 2017, 54 (6), pp.371 - 380. ⟨10.1136/jmedgenet-2016-104436⟩. ⟨hal-01789377⟩
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