PT  - JOURNAL ARTICLE
AU  - M Balasubramanian
AU  - H Lord
AU  - S Levesque
AU  - H Guturu
AU  - F Thuriot
AU  - G Sillon
AU  - A M Wenger
AU  - D L Sureka
AU  - T Lester
AU  - D S Johnson
AU  - J Bowen
AU  - A R Calhoun
AU  - D H Viskochil
AU  - DDD Study
AU  - G Bejerano
AU  - J A Bernstein
AU  - D Chitayat
TI  - Chitayat syndrome: hyperphalangism, characteristic facies, hallux valgus and bronchomalacia results from a recurrent c.266A>G p.(Tyr89Cys) variant in the <em>ERF</em> gene
AID  - 10.1136/jmedgenet-2016-104143
DP  - 2017 Mar 01
TA  - Journal of Medical Genetics
PG  - 157--165
VI  - 54
IP  - 3
4099  - http://jmg.bmj.com/content/54/3/157.short
4100  - http://jmg.bmj.com/content/54/3/157.full
SO  - J Med Genet2017 Mar 01; 54
AB  - 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. Trio-based 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.