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.
- Chitayat syndrome
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JAB and DC joint senior authors.
Contributors MB planned the study, recruited patient 2 to DDD and wrote manuscript. HL, HG, AMW and TL undertook sequencing and analyses. SL, FT and GS recruited patient 1, JAB and DLS recruited patients 4 and 5. HG, AMW and GB conducted analysis of exome sequencing data for patient 4. DSJ and JB provided clinical care of patient 2. ARC and DHV recruited patient 3. DDD Study undertook exome sequencing of patient 2. JAB and DC senior authors conceived the study, assembled the patient cohort and prepared the manuscript; all authors reviewed and contributed to the manuscript.
Funding Patient 2: The Deciphering Developmental Disorders (DDD) study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). The views expressed in this publication are those of the authors and not necessarily those of the Wellcome Trust or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12 granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network. Patient 4: This work was supported by the Stanford Department of Pediatrics, Stanford Discovery Fund, DARPA, and an NIH U01 MH105949 Grant (GB).
Competing interests None declared.
Patient consent Obtained.
Ethics approval Cambridge South REC.
Provenance and peer review Not commissioned; externally peer reviewed.