Orofacio-digital syndromes

Orofacial-digital syndromes (OFD) are rare and characterized by the presence of oral, facial and digital manifestations. Its incidence is estimated at between 1/50000 and 1/250000 births with a higher frequency of OFD type I. Their initial classification in 14 sub-types, was principally based on their mode of inheritance and the associated clinical signs (cerebral and renal malformation, bone dysplasia, retinal involvement,…) principally with OFD I syndrome (polycystic kidney disease, agenesis of the corpus callosum), OFD IV (tibial dysplasia), OFD VI (vermian hypoplasia with the molar tooth sign, central polydactyly) and OFD IX (retinal involvement). Apart from OFD I, which has X-linked dominant inheritance and is fatal in male offspring, autosomal recessive inheritance is suspected for most of the other sub-types. Until now, only the OFD1 gene, responsible for type I OFD and coding for a centrosomal protein and the basal body, was principally known, suggesting involvement of the primary cilia in OFD syndromes. Mutations in the genes TMEM216 and DDX59 were recently reported, in one or two patients.

Syndromes oro-facio-digitaux

Over the last 15 years, we have built up an international cohort of more than 150 patients with OFD syndrome, who have been finely phenotyped, and among whom about half carry a mutation of the OFD1 gene.

In order to identify new genes implicated in these syndromes, we are using the high-throughput exome/genome sequencing strategy in des rare forms of orofacial-digital syndromes. Bioinformatics analysis of genomic data focuses on rare variations, preferentially present in ciliary genes and with an autosomal recessive mode of inheritance. These projects are funded by several national calls for projects (national PHRC, rare GIS diseases, Rare Diseases Foundation).

This strategy has already allowed us to identify 5 new genes (C2CD3, TMEM107, INTU, KIAA0753, IFT57) and to extend to OFD syndromes the clinical spectrum of 4 genes already known in other ciliopathies (C5orf42, TMEM138, TMEM231, WDPCP). Functional analyses (cellular models, zebrafish models, zenope, …) are being done by our team (IFT57) or in collaboration with international teams with renown in the field, such as the teams of Pr. M. Nachury in Stanford (C2CD3), Dr. O. Blacque in Dublin (TMEM107) Pr. J. Wallingford in Austin (INTU, WDPCP, C5orf42), Pr. M. Leroux in Vancouver (TMEM138, TMEM231), and Dr. O. Rosnet in Marseille (KIAA0753). These different studies have shown the implication of centriole growth, the transition zone and intraflagellar transport, notably with the characterization of 3 principal protein complexes: the ternary complex KIAA0753/OFD1/FOPNL, which regulates centriole growth, the MKS complex (TMEM107, TMEM231, TMEM138, TMEM216), which is active in the  transition zone and the CPLANE complex (INTU/FUZ/WDPCP), which fosters assembly of the peripheral proteins of the intraflagellar transport complex (IFTA). 

syndromes oro-facio-digitaux

Over the last 5 years, these major scientific results have led to:

  • 7 publications in international peer-reviewed journals, including prestigious journals such as Nature Genetics, Nature Cell Biology and PLos Biology
  • 2 invited conferences
  • 5 conferences following selection of abstracts, including one at the Congress of the American Society of Human Genetics (ASHG 2015)
  • 11 posters

Cette stratégie se poursuit de façon prospective pour continuer le démembrement de l’hétérogénéité clinique et génétique des syndromes OFD. De la classification clinique initiale de 14 sous-types totalement obsolète, l’équipe a largement participé à la caractérisation de 3 complexes protéiques principaux. 

Publications on the theme

TMEM107 recruits ciliopathy proteins to subdomains of the ciliary transition zone and causes Joubert syndrome
Lambacher* NJ, Bruel AL*, van Dam TJP, Szymańska K, Slaats GG, et al. TMEM107 recruits ciliopathy proteins to anchored periodic subdomains of the ciliary transition zone membrane and is mutated in Joubert syndrome. Nat Cell Biol 2015 Nov 23. * equally contributor

The oral-facial-digital syndrome gene C2CD3 encodes a positive regulator of centriole elongation
C. Thauvin-Robinet*, J.S. Lee*, E. Lopez, V. Herranz-Pérez, J.B. Rivière, et al. The Oral-Facial-Digital Syndrome Gene C2CD3 Promotes Centriole Elongation. Nat Genet. 2014;46: 905-11. * equally contributor

C5orf42 is the major gene responsible for OFD syndrome type VI
E.Lopez*, C. Thauvin-Robinet*, B. Reversade, N. El Khartoufi, L. Devisme, et al. C5orf42 is the major gene responsible for OFD syndrome type VI. Hum Genet 2014;133:367-77. * equally contributor

OFD1 mutations in males: phenotypic spectrum and ciliary basal body docking impairment
C. Thauvin-Robinet, S. Thomas, M. Sinico, B. Aral, L. Burglen, N. et al. OFD1 mutations in males: Phenotypic spectrum and basal bodies docking impairment. Clin Genet 2013 Jul;84:86-90.

TCTN3 mutations cause Mohr-Majewski syndrome
S. Thomas, M. Legendre, S. Saunier, B. Bessières, C. Alby, et al. TCTN3 Mutations Cause Mohr-Majewski Syndrome. Am J Hum Genet 2012;91:372-8.