Chitayat Syndrome: Hyperphalangism, Characteristic Facies, Hallux Valgus And Bronchomalacia Results From A Recurrent C.266a > G P.(Tyr89cys) Variant In The Erf Gene

Background In 1993, Chitayat et al., reported a newborn with hyperphalangism, facial anomalies, and bronchomalacia. We identified three additional families with similar findings. Features include bilateral accessory phalanx resulting in shortened index fingers; hallux valgus; distinctive face; respiratory compromise.Objective(s) To identify the genetic aetiology of Chitayat syndrome and identify a unifying cause for this specific form of hyperphalangism.Methods Through ongoing collaboration, we had collected patients with strikingly-similar phenotype. Triobased exome sequencing was first performed in Patient 2 through Deciphering Developmental Disorders study. Proband-only exome sequencing had previously been independently performed in Patient 4. Following identification of a candidate gene variant in Patient 2, the same variant was subsequently confirmed from exome data in Patient 4. Sanger sequencing was used to validate this variant in Patients 1, 3; confirm paternal inheritance in Patient 5.Results A recurrent, novel variant NM_ 006494.2: c. 266A > G p.(Tyr89Cys) in ERF was identified in five affected individuals: de novo (patient 1, 2 and 3) and inherited from an affected father (patient 4 and 5). p. Tyr89Cys is an aromatic polar neutral to polar neutral amino acid substitution, at a highly conserved position and lies within the functionally important ETS-domain of the protein. The recurrent ERF c. 266A > C p.(Tyr89Cys) variant causes Chitayat syndrome.Discussion ERF variants have previously been associated with complex craniosynostosis. In contrast, none of the patients with the c. 266A > G p.(Tyr89Cys) variant have craniosynostosis.Conclusions We report the molecular aetiology of Chitayat syndrome and discuss potential mechanisms for this distinctive phenotype associated with the p. Tyr89Cys substitution in ERF.