Dataset Information

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 Here, we present all our published and unpublished results for WES in 24 cases with OFDS.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

SUBMITTER: Bruel AL

PROVIDER: S-EPMC5557276 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Bruel Ange-Line AL Franco Brunella B Duffourd Yannis Y Thevenon Julien J Jego Laurence L Lopez Estelle E Deleuze Jean-François JF Doummar Diane D Giles Rachel H RH Johnson Colin A CA Huynen Martijn A MA Chevrier Véronique V Burglen Lydie L Morleo Manuela M Desguerres Isabelle I Pierquin Geneviève G Doray Bérénice B Gilbert-Dussardier Brigitte B Reversade Bruno B Steichen-Gersdorf Elisabeth E Baumann Clarisse C Panigrahi Inusha I Fargeot-Espaliat Anne A Dieux Anne A David Albert A Goldenberg Alice A Bongers Ernie E Gaillard Dominique D Argente Jesús J Aral Bernard B Gigot Nadège N St-Onge Judith J Birnbaum Daniel D Phadke Shubha R SR Cormier-Daire Valérie V Eguether Thibaut T Pazour Gregory J GJ Herranz-Pérez Vicente V Goldstein Jaclyn S JS Pasquier Laurent L Loget Philippe P Saunier Sophie S Mégarbané André A Rosnet Olivier O Leroux Michel R MR Wallingford John B JB Blacque Oliver E OE Nachury Maxence V MV Attie-Bitach Tania T Rivière Jean-Baptiste JB Faivre Laurence L Thauvin-Robinet Christel C

Journal of medical genetics 20170313 6

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 <i>OFD1</i> gene encoding a centrosomal protein. The wide clinical heterogeneity of OFDS suggests the involvement of other ciliary ge ...[more]

PMID: 28289185

Similar Datasets

Project description:Oral-Facial-Digital Syndrome type VI (OFD VI) represents a rare phenotypic subtype of Joubert syndrome and related disorders (JSRD). In the original report polydactyly, oral findings, intellectual disability, and absence of the cerebellar vermis at post-mortem characterized the syndrome. Subsequently, the molar tooth sign (MTS) has been found in patients with OFD VI, prompting the inclusion of OFD VI in JSRD. We studied the clinical, neurodevelopmental, neuroimaging, and genetic findings in a cohort of 16 patients with OFD VI. We derived the following inclusion criteria from the literature: 1) MTS and one oral finding and polydactyly, or 2) MTS and more than one typical oral finding. The OFD VI neuroimaging pattern was found to be more severe than in other JSRD subgroups and includes severe hypoplasia of the cerebellar vermis, hypoplastic and dysplastic cerebellar hemispheres, marked enlargement of the posterior fossa, increased retrocerebellar collection of cerebrospinal fluid, abnormal brainstem, and frequently supratentorial abnormalities that occasionally include characteristic hypothalamic hamartomas. Additionally, two new JSRD neuroimaging findings (ascending superior cerebellar peduncles and fused thalami) have been identified. Tongue hamartomas, additional frenula, upper lip notch, and mesoaxial polydactyly are specific findings in OFD VI, while cleft lip/palate and other types of polydactyly of hands and feet are not specific. Involvement of other organs may include ocular findings, particularly colobomas. The majority of the patients have absent motor development and profound cognitive impairment. In OFD VI, normal cognitive functions are possible, but exceptional. Sequencing of known JSRD genes in most patients failed to detect pathogenetic mutations, therefore the genetic basis of OFD VI remains unknown. Compared with other JSRD subgroups, the neurological findings and impairment of motor development and cognitive functions in OFD VI are significantly worse, suggesting a correlation with the more severe neuroimaging findings. Based on the literature and this study we suggest as diagnostic criteria for OFD VI: MTS and one or more of the following: 1) tongue hamartoma(s) and/or additional frenula and/or upper lip notch; 2) mesoaxial polydactyly of one or more hands or feet; 3) hypothalamic hamartoma.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets