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

Julien Thevenon (1, 2) , Laurence Duplomb Jego (1, 2) , A. Saunier (3) , M. Avila (1) , Virginie Carmignac (1) , Ange-Line Bruel (1) , Judith Saint-Onge (1, 2) , Yannis Duffourd (1) , B. Franco (4) , Tania Attie-Bitach (5, 6) , Alice Masurel-Paulet (2) , Laurence Olivier-Faivre (1, 2) , Christel Thauvin-Robinet (2, 1)

1 GAD - Génétique des Anomalies du Développement
2 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
3 Service de Génétique Médicale [CHRU Nancy]
4 Institut d'Astrophysique et de Géophysique [Liège]
5 Hôpital Necker - Enfants Malades [AP-HP]
6 IMAGINE - U1163 - Imagine - Institut des maladies génétiques

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.

Mots clés: IFT57; ciliopathy; exome sequencing; oral-facial-digital syndrome

Domaines: Médecine humaine et pathologie

Julien Thevenon, Laurence Duplomb Jego, A. Saunier, M. Avila, Virginie Carmignac, et al.. Autosomal recessive IFT57 hypomorphic mutation cause ciliary transport defect in unclassified oral-facial-digital syndrome with short stature and brachymesophalangia. Clinical Genetics, 2016, 90 (6), pp.509 - 517. ⟨10.1111/cge.12785⟩. ⟨hal-01404457⟩