Molecular Genetics of Oral‐Facial‐Digital Syndromes


Oral‐facial‐digital syndromes (OFDS) identify a group of rare and genetically heterogeneous disorders. Typical features include abnormalities of the face, oral cavity and digits with frequent involvement of the central nervous system and of visceral organs. OFD type I was first described in 1941 and to date, several different forms have been reported. It is still unclear whether all the described subtypes do exist, and only next‐generation sequencing approaches will clarify the number of different OFDS. Sixteen genes have been found mutated to date and all of them localise to the primary cilium, a microtubule‐based organelle conserved across species protruding from the cell surface of vertebrate cells. These transcripts contribute to primary cilia structure/formation/maintenance and/or function thus ascribing this condition to the number of disorders due to cilia dysfunction called ‘ciliopathies.’

Key Concepts

  • OFDS are rare and highly heterogeneous from a genetic point of view.
  • NGS approaches will eventually define the exact number of different OFDS.
  • A multiallelic mode of inheritance may modify the phenotype in OFDS patients.
  • Most of the OFDS are due to dysfunction of primary cilia.
  • The majority of genes responsible for OFDs are localized to primary cilia.

Keywords: OFDS; ciliopathies; primary cilia; cilia dysfunction; pleiotropic disorders; genetic heterogeneity

Figure 1. Localisation of proteins encoded by the 16 oral‐facial‐digital (OFD) genes in primary cilia. Causative genes are illustrated in light blue and are localised to different portion of the primary cilium. Ange‐Line Bruel et al. . Reproduced with permission of BMJ Publishing Group Limited.
Figure 2. Clinical pictures, X‐rays and brain MRI of cases with oral‐facial‐digital syndromes. Patient with mutation in TMEM107 (K), patient with mutation in TMEM107 (L), patient with mutation in C2CD3 (B, N, V), patient with mutation in INTU (κ), patient with homozygous mutation in IFT57 (A, R, S, T, U), patient with homozygous mutation in IFT57 (F, Y, Z, α β), patient with mutation in C5orf42 (G), patient with mutation in C5orf42 (E, L, Q, ϵ, ζ ι, κ), patient with mutation in WDPCP (J, Y), patient with mutation in KIAA0753 (O), OFD case in which no mutations have been identified yet (D, I, K), OFD case in which no mutations have been identified yet (E), OFD case in which no mutations have been identified yet (ϵ), patient with mutation in C5orf42 (λ, μ), patient with mutation in C5orf42 (D, X, ζ), patient with mutation in C5orf42 (P, ν, O, π) patient with mutation in C5orf42 (Q, ρ, ς), patient with mutation in C2CD3 (υ, φ) with facial dysmorphism (A–D) including low‐set ears, median pseudo‐cleft of upper lip (F), missing incisors (A) or severe microcephaly (B), abnormal frenulae (E), cleft palate (I), lobulated tongue or hamartoma (G, H, J), pre and postaxial polydactyly of hands and feet (R, S, V, W, ϵ, ζ, ι, κ‐υ), broad duplicated and/or deviated hallux (T, U, V, ϵ, ζ, η, θ, μ, ν, υ), Y‐shaped metacarpal abnormality (κ, π), hypothalamic hamartoma (P), cerebellar hypoplasia (Q), brain MRI with MTS (K–O). Ange‐Line Bruel et al. . Reproduced with permission of BMJ Publishing Group Limited.
Figure 3. Distribution of mutated genes in genotypes oral‐facial‐digital cases. Ange‐Line Bruel et al. . Reproduced with permission of BMJ Publishing Group Limited.


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Further Reading

Franco B (2008) The Molecular basis of Oral‐Facial‐Digital type I (OFDI) syndrome. In: Epstein JC, Erickson RP and Wynshaw‐Boris A (eds) Inborn Errors of Development, pp 1379–1386. New York: Oxford University Press.

Franco B (2016) Oral‐facial‐digital type 1 syndrome. In: Turner N, Lameire N, Goldsmith DJ, et al. (eds) Oxford Textbook of Clinical Nephrology, pp 2685–2687. Oxford: Oxford University Press.

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Franco, Brunella(Nov 2019) Molecular Genetics of Oral‐Facial‐Digital Syndromes. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0027354]