2. Academic Validation
  3. Autosomal recessive IFT57 hypomorphic mutation cause ciliary transport defect in unclassified oral-facial-digital syndrome with short stature and brachymesophalangia

Autosomal recessive IFT57 hypomorphic mutation cause ciliary transport defect in unclassified oral-facial-digital syndrome with short stature and brachymesophalangia

  • Clin Genet. 2016 Dec;90(6):509-517. doi: 10.1111/cge.12785.
J Thevenon 1 2 3,  L Duplomb 1 2,  S Phadke 4,  T Eguether 5,  A Saunier 6,  M Avila 1 2,  V Carmignac 1 2,  A-L Bruel 1 2,  J St-Onge 1 2 7,  Y Duffourd 1 2,  G J Pazour 5,  B Franco 8 9 10,  T Attie-Bitach 11,  A Masurel-Paulet 1 3,  J-B Rivière 1 2 7,  V Cormier-Daire 11,  C Philippe 6,  L Faivre 1 2 3,  C Thauvin-Robinet 1 2 3
Affiliations

Affiliations

  • 1 FHU-TRANSLAD, Université de Bourgogne/CHU Dijon, Dijon, France.
  • 2 Equipe EA4271 GAD, Université de Bourgogne, Dijon, France.
  • 3 Centre de Référence maladies rares "Anomalies du Développement et syndrome malformatifs" de l'Est et Centre de Génétique, Hôpital d'Enfants, CHU, Dijon, France.
  • 4 Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India.
  • 5 Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
  • 6 Laboratoire de Génétique Médicale, CHU - Hopitaux de Brabois, Vandoeuvre les Nancy cedex, France.
  • 7 Laboratoire de Génétique Moléculaire, PTB, CHU Dijon, Dijon, France.
  • 8 Telethon Institute of Genetics and Medicine, Naples, Italy.
  • 9 Medical Genetics, Department of Medical Translational Sciences, University of Napoli Federico II, Naples, Italy.
  • 10 Department of Medical Translational Sciences, Division of Pediatrics, Federico II University of Naples, Naples, Italy.
  • 11 Service de Génétique, Hôpital Necker-Enfants Malades, APHP, Institut Imagine, INSERM UMR1163, University Sorbonne-Paris-Cité, Paris, France.
PMID: 27060890 DOI: 10.1111/cge.12785
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.

Keywords

IFT57; ciliopathy; exome sequencing; oral-facial-digital syndrome.

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