The Development of a European Registry for Facial Dysostosis Syndromes: A Delphi-Guided Approach

Abstract

Acrofacial dysostosis; Delphi technique; Miller syndrome

Disostosis acrofacial; Técnica Delphi; Síndrome de Miller

Disostosi acrofacial; Tècnica Delphi; Síndrome de Miller

Craniosynostosis is a multigenic congenital condition in which one or more calvarial sutures have prematurely fused during the development of the fetus. Pathogenic variants in FGFR2 are associated with the development of syndromic craniosynostosis, such as Crouzon, Apert and Pfeifer syndromes. Investigation of FGFR2-linked craniosynostosis is hindered by the lack of appropriate in vitro models. Patient-derived human induced pluripotent stem cell (hiPSC) in vitro disease models provide the opportunity to investigate the disease, identify molecular targets for pharmaceutical treatments, and enable the generation of autologous pluripotent stem cell catalogues. Here, we report three patient-derived hiPSC lines carrying the C342Y, S252W or E565G FGFR2 pathogenic variant. The patient hiPSC lines express characteristic pluripotency markers and display distinct phosphorylation profiles under unstimulated conditions. FGFR2C342Y showed autophosphorylation in the absence of bFGF ligand, although downstream docking proteins PLCγ and FRS2α were not phosphorylated. FGFR2S252W and FGFR2E565G hiPSCs showed increased phosphorylation of docking proteins PLCγ and FRS2α, whereas FGFR2 was not phosphorylated. These patient hiPSC lines provide molecular and cellular options to investigate FGFR2-linked craniosynostosis in the patient-specific genomic context and develop therapeutic modalities.

The present study was partially funded by the European Reference Network for rare and/or complex craniofacial anomalies and ear, nose, and throat (ENT) disorders (ERN CRANIO) in terms of personnel costs of the first author. ERN CRANIO is funded by the European Union.