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

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 Here, we present all our published and unpublished results for WES in 24 cases with OFDS.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.

Figure 1. Clinical pictures, X-rays and brain MRI of OFD cases

Case 3a (K), case 3b (L), case 4 (B, N, V), case 5 (κ), case 6a (A, R, S, T, U), case 6b (F, Y, Z, α, β), case 7 (G), case 8 (E, L, Q, ε, ζ, ι, κ), case 10 (J, Y), case 11 (O), case 17 (D, I, K), case 19 (E), case 22 (ε), case 25 (λ, μ), case 26b (D, X, ζ), case 27 (P, ν, ο, π) case 28b (Q, ρ, ς), case 29 (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-sharped metacarpal abnormality (κ, π), hypothalamic hamartoma (P), cerebellar hypoplasia (Q), brain MRI with MTS (K-O).

Figure 2

Strategy for exome analysis

Figure 3. Localization of proteins encoded by the 16 OFD genes in primary cilia

5 new OFD genes (in red), 4 genes previously implicated in other ciliopathies (in green), 7 genes previously reported in OFD - 2 with presented mutations (blue) and 5 others (white).

Figure 4

Distribution of mutated genes in genotyped OFD cases reported in this study and in the literature.