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 characterized 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 OFD 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 Here, we present all our published and unpublished results for WES in 24 OFDS cases. We identified causal variants in five new genes (C2CD3, TMEM107, INTU, KIAA0753, IFT57) and related the clinical spectrum of four genes in other ciliopathies (C5orf42, TMEM138, TMEM231, 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 characterizing three ciliary protein modules: the complex KIAA0753-FOPNL-OFD1, a regulator of centriole elongation; the MKS 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 3 main subtypes, a further classification could be based on the genotype.

INTU‐related oral‐facial‐digital syndrome type VI: A confirmatory report

“…Our patient shares a congenital heart defect and digital abnormalities with the previous patient, but despite a mildly abnormal CNS MRI, has no major neurodevelopmental difficulties or deafness, although his young age still precludes firm conclusions. Brain MRI disclosed the molar tooth sign, a cardinal feature of ciliopathies, usually associated with OFD syndrome type VI but also reported in a few other unclassified OFD syndrome cases . the molar tooth sign has not been previously reported in the INTU phenotypic spectrum because no CNS imaging is available for the single published case.…”

“…Brain MRI disclosed the molar tooth sign, a cardinal feature of ciliopathies, usually associated with OFD syndrome type VI 7 but also reported in a few other unclassified OFD syndrome cases. 2,8 the molar tooth sign has not been previously reported in the INTU phenotypic spectrum because no CNS imaging is available for the single published case. The association of a lingual hamartoma with a molar tooth sign leads us to propose INTU as a new causal gene for OFD syndrome type VI, as the present case fits the diagnostic criteria for OFD syndrome type VI, that is the molar tooth sign and one or more of the following: (1) tongue hamartoma(s) and/or multiple frenula and/or upper lip notch;…”

“…Pathogenic mutations in the other CPLANE subunits, notably in C5orf42 and WDPCP genes, have also previously been reported in OFD syndromes. 2 Recessive mutations in C5orf42 cause OFD syndrome type VI characterized by the molar tooth sign on brain MRI and postaxial polydactyly. The WDPCP gene is responsible for unclassified OFD syndromes with heart malformations and deafness.…”

“…NGS has challenged this clinically based typology: OFD syndromes are now known to belong to the ciliopathy family, as causal genes encode proteins involved in ciliogenesis, the ciliary basal body, primary cilium or post‐ciliary microtubule function functions. At least 20 different genes have been identified in patients within the OFD spectrum, with C5orf42 being the most common. The clinical classification of OFD syndromes has thus lost most of its pertinence (except for OFD syndrome types I, IV and VI), considering the imperfect correlation between clinical and molecular nosologies, and the overlap of “OFD genes” with genes involved in other ciliopathies such as Bardet‐Biedl, Meckel or Joubert syndromes.…”

“…Recently, a single patient was reported with a homozygous truncating variant in the INTU gene (patient #5 in Reference ). INTU encodes a basal body protein that is a subunit of the CPLANE complex (ciliogenesis and planar polarity effectors).…”