title: Autosomal recessive IFT57 hypomorphic mutation cause ciliary transport defect in unclassified oral-facial-digital syndrome with short stature and brachymesophalangia.
abstract: The 13 subtypes of oral-facial-digital syndrome (OFDS) belong to the heterogeneous group of ciliopathies. Disease-causing genes encode for centrosomal proteins, components of the transition zone or proteins implicated in ciliary signaling. A unique consanguineous family presenting with an unclassified OFDS with skeletal dysplasia and brachymesophalangia was explored. Homozygosity mapping and exome sequencing led to the identification of a homozygous mutation in IFT57, which encodes a protein implicated in ciliary transport. The mutation caused splicing anomalies with reduced expression of the wild-type transcript and protein. Both anterograde ciliary transport and sonic hedgehog signaling were significantly decreased in subjects' fibroblasts compared with controls. Sanger sequencing of IFT57 in 13 OFDS subjects and 12 subjects with Ellis-Van Creveld syndrome was negative. This report identifies the implication of IFT57 in human pathology and highlights the first description of a ciliary transport defect in OFDS, extending the genetic heterogeneity of this subgroup of ciliopathies.
authors.affiliation: FHU-TRANSLAD, Université de Bourgogne/CHU Dijon, Dijon, France.|Equipe EA4271 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: J
authors.identifier: 0000-0001-9271-3961
authors.initials: J
authors.lastname: Thevenon
authors.affiliation: FHU-TRANSLAD, Université de Bourgogne/CHU Dijon, Dijon, France.|Equipe EA4271 GAD, Université de Bourgogne, Dijon, France.
authors.forename: L
authors.initials: L
authors.lastname: Duplomb
authors.affiliation: Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India.
authors.forename: S
authors.initials: S
authors.lastname: Phadke
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Eguether
authors.affiliation: Laboratoire de Génétique Médicale, CHU - Hopitaux de Brabois, Vandoeuvre les Nancy cedex, France.
authors.forename: A
authors.initials: A
authors.lastname: Saunier
authors.affiliation: FHU-TRANSLAD, Université de Bourgogne/CHU Dijon, Dijon, France.|Equipe EA4271 GAD, Université de Bourgogne, Dijon, France.
authors.forename: M
authors.initials: M
authors.lastname: Avila
authors.affiliation: FHU-TRANSLAD, Université de Bourgogne/CHU Dijon, Dijon, France.|Equipe EA4271 GAD, Université de Bourgogne, Dijon, France.
authors.forename: V
authors.initials: V
authors.lastname: Carmignac
authors.affiliation: FHU-TRANSLAD, Université de Bourgogne/CHU Dijon, Dijon, France.|Equipe EA4271 GAD, Université de Bourgogne, Dijon, France.
authors.forename: A-L
authors.initials: AL
authors.lastname: Bruel
authors.affiliation: FHU-TRANSLAD, Université de Bourgogne/CHU Dijon, Dijon, France.|Equipe EA4271 GAD, Université de Bourgogne, Dijon, France.|Laboratoire de Génétique Moléculaire, PTB, CHU Dijon, Dijon, France.
authors.forename: J
authors.initials: J
authors.lastname: St-Onge
authors.affiliation: FHU-TRANSLAD, Université de Bourgogne/CHU Dijon, Dijon, France.|Equipe EA4271 GAD, Université de Bourgogne, Dijon, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Duffourd
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: G J
authors.initials: GJ
authors.lastname: Pazour
authors.affiliation: Telethon Institute of Genetics and Medicine, Naples, Italy.|Medical Genetics, Department of Medical Translational Sciences, University of Napoli Federico II, Naples, Italy.|Department of Medical Translational Sciences, Division of Pediatrics, Federico II University of Naples, Naples, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Franco
authors.affiliation: Service de Génétique, Hôpital Necker-Enfants Malades, APHP, Institut Imagine, INSERM UMR1163, University Sorbonne-Paris-Cité, Paris, France.
authors.forename: T
authors.initials: T
authors.lastname: Attie-Bitach
authors.affiliation: FHU-TRANSLAD, Université de Bourgogne/CHU Dijon, 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: A
authors.initials: A
authors.lastname: Masurel-Paulet
authors.affiliation: FHU-TRANSLAD, Université de Bourgogne/CHU Dijon, Dijon, France.|Equipe EA4271 GAD, Université de Bourgogne, Dijon, France.|Laboratoire de Génétique Moléculaire, PTB, CHU Dijon, Dijon, France.
authors.forename: J-B
authors.initials: JB
authors.lastname: Rivière
authors.affiliation: Service de Génétique, Hôpital Necker-Enfants Malades, APHP, Institut Imagine, INSERM UMR1163, University Sorbonne-Paris-Cité, Paris, France.
authors.forename: V
authors.initials: V
authors.lastname: Cormier-Daire
authors.affiliation: Laboratoire de Génétique Médicale, CHU - Hopitaux de Brabois, Vandoeuvre les Nancy cedex, France.
authors.forename: C
authors.initials: C
authors.lastname: Philippe
authors.affiliation: FHU-TRANSLAD, Université de Bourgogne/CHU Dijon, Dijon, France.|Equipe EA4271 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: L
authors.initials: L
authors.lastname: Faivre
authors.affiliation: FHU-TRANSLAD, Université de Bourgogne/CHU Dijon, Dijon, France.|Equipe EA4271 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: C
authors.initials: C
authors.lastname: Thauvin-Robinet
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000072661:Ciliopathies / Q000235:genetics* / Q000503:physiopathology; D003241:Consanguinity; D019465:Craniofacial Abnormalities / Q000235:genetics* / Q000503:physiopathology; D004392:Dwarfism / Q000235:genetics* / Q000503:physiopathology; D004423:Ear / Q000002:abnormalities* / Q000503:physiopathology; D004613:Ellis-Van Creveld Syndrome / Q000235:genetics / Q000503:physiopathology; D059472:Exome / Q000235:genetics; D005260:Female; D018740:Genetic Heterogeneity; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D008297:Male; D009154:Mutation; D009333:Neck / Q000002:abnormalities* / Q000503:physiopathology; D009958:Orofaciodigital Syndromes / Q000235:genetics* / Q000503:physiopathology; D010641:Phenotype; D013909:Thorax / Q000002:abnormalities* / Q000503:physiopathology; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C499179:IFT57 protein, human
keywords: IFT57; ciliopathy; exome sequencing; oral-facial-digital syndrome