title: 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 theOFD1gene 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 Here, we present all our published and unpublished results for WES in 24 cases with OFDS.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,KIAA0753andIFT57) and related the clinical spectrum of four genes in other ciliopathies (C5orf42,TMEM138,TMEM231andWDPCP) 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.
authors.affiliation: FHU-TRANSLAD, Université de Bourgogne/CHU Dijon, Dijon, France.|Équipe EA42271 GAD, Université de Bourgogne, Dijon, France.
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authors.affiliation: Department of Translational Medicine, Medical Genetics Ferderico II University of Naples, Naples, Italy.|Telethon Institute of Genetics and Medicine-TIGEM, Naples, Italy.
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authors.affiliation: FHU-TRANSLAD, Université de Bourgogne/CHU Dijon, Dijon, France.|Équipe EA42271 GAD, Université de Bourgogne, Dijon, France.
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authors.affiliation: FHU-TRANSLAD, Université de Bourgogne/CHU Dijon, Dijon, France.|Équipe EA42271 GAD, Université de Bourgogne, Dijon, France.|Centre de Référence maladies rares « Anomalies du Développement et syndrome malformatifs » de l'Est et Centre de Génétique, Hôpital d'Enfants, CHU, Dijon, France.
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authors.affiliation: FHU-TRANSLAD, Université de Bourgogne/CHU Dijon, Dijon, France.|Équipe EA42271 GAD, Université de Bourgogne, Dijon, France.
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authors.affiliation: Équipe EA42271 GAD, Université de Bourgogne, Dijon, France.
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authors.affiliation: Centre National de Génotypage, Evry, France.
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authors.affiliation: Centre de Recherche en Cancérologie de Marseille, Marseille, France.|Institut Paoli-Calmettes, Marseille, France.|CNRS U7258, Marseille, France.|Aix-Marseille Université, Marseille, France.
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authors.affiliation: Équipe EA42271 GAD, Université de Bourgogne, Dijon, France.|Department of Translational Medicine, Medical Genetics Ferderico II University of Naples, Naples, Italy.
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authors.affiliation: FHU-TRANSLAD, Université de Bourgogne/CHU Dijon, Dijon, France.|Équipe EA42271 GAD, Université de Bourgogne, Dijon, France.|Laboratoire de Génétique Moléculaire, PTB, CHU, Dijon, France.
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authors.affiliation: FHU-TRANSLAD, Université de Bourgogne/CHU Dijon, Dijon, France.|Équipe EA42271 GAD, Université de Bourgogne, Dijon, France.
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authors.affiliation: Centre de Recherche en Cancérologie de Marseille, Marseille, France.|Institut Paoli-Calmettes, Marseille, France.|CNRS U7258, Marseille, France.|Aix-Marseille Université, Marseille, France.
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authors.affiliation: Department of Translational Medicine, Medical Genetics Ferderico II University of Naples, Naples, Italy.|INSERM UMR1163, Université de Paris-Descartes-Sorbonne Paris Cité, Institut IMAGINE, Hôpital Necker-Enfants Malades, Paris, France.|Service de génétique médicale, Hôpital Universitaire Necker-Enfants Malades, AP-HP, Institut Imagine, Paris, France.
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authors.affiliation: FHU-TRANSLAD, Université de Bourgogne/CHU Dijon, Dijon, France.|Équipe EA42271 GAD, Université de Bourgogne, Dijon, France.|Laboratoire de Génétique Moléculaire, PTB, CHU, Dijon, France.
authors.forename: Jean-Baptiste
authors.initials: JB
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authors.affiliation: FHU-TRANSLAD, Université de Bourgogne/CHU Dijon, Dijon, France.|Équipe EA42271 GAD, Université de Bourgogne, Dijon, France.|Centre de Référence maladies rares « Anomalies du Développement et syndrome malformatifs » de l'Est et Centre de Génétique, Hôpital d'Enfants, CHU, Dijon, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Faivre
authors.affiliation: FHU-TRANSLAD, Université de Bourgogne/CHU Dijon, Dijon, France.|Équipe EA42271 GAD, Université de Bourgogne, Dijon, France.|Centre de Référence maladies rares « Anomalies du Développement et syndrome malformatifs » de l'Est et Centre de Génétique, Hôpital d'Enfants, CHU, Dijon, France.
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mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D002925:Ciliary Motility Disorders / Q000235:genetics; D004677:Encephalocele / Q000235:genetics; D005145:Face / Q000002:abnormalities*; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics; D009958:Orofaciodigital Syndromes / Q000235:genetics*; D007690:Polycystic Kidney Diseases / Q000235:genetics; D011506:Proteins / Q000235:genetics; D012174:Retinitis Pigmentosa
chemical_list: D011506:Proteins
keywords: ciliopathies; oral-facial-digital syndromes