title: Chitayat syndrome: hyperphalangism, characteristic facies, hallux valgus and bronchomalacia results from a recurrent c.266A>G p.(Tyr89Cys) variant in theERFgene.
abstract: In 1993, Chitayatet 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.
  
  
  
  To identify the genetic aetiology of Chitayat syndrome and identify a unifying cause for this specific form of hyperphalangism.
  
  
  
  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.
  
  
  
  A recurrent, novel variant NM_006494.2:c.266A>G p.(Tyr89Cys) inERFwas 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 recurrentERFc.266A>C p.(Tyr89Cys) variant causes Chitayat syndrome.
  
  
  
  ERFvariants have previously been associated with complex craniosynostosis. In contrast, none of the patients with the c.266A>G p.(Tyr89Cys) variant have craniosynostosis.
  
  
  
  We report the molecular aetiology of Chitayat syndrome and discuss potential mechanisms for this distinctive phenotype associated with the p.Tyr89Cys substitution inERF.
authors.affiliation: Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK.
authors.forename: M
authors.identifier: 0000-0003-1488-3695
authors.initials: M
authors.lastname: Balasubramanian
authors.affiliation: Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, The Churchill Hospital, Oxford, UK.
authors.forename: H
authors.initials: H
authors.lastname: Lord
authors.affiliation: Department of Pediatrics, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Levesque
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: H
authors.initials: H
authors.lastname: Guturu
authors.affiliation: Department of Pediatrics, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: F
authors.initials: F
authors.lastname: Thuriot
authors.affiliation: Department of Medical Genetics, McGill University Health Center, Montreal, Quebec, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Sillon
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Wenger
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Sureka
authors.affiliation: Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, The Churchill Hospital, Oxford, UK.
authors.forename: T
authors.initials: T
authors.lastname: Lester
authors.affiliation: Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK.
authors.forename: D S
authors.initials: DS
authors.lastname: Johnson
authors.affiliation: Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK.
authors.forename: J
authors.initials: J
authors.lastname: Bowen
authors.affiliation: Division of Genetics and Metabolism, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: A R
authors.initials: AR
authors.lastname: Calhoun
authors.affiliation: School of Medicine, Pediatric Genetics, Salt Lake City, Utah, USA.
authors.forename: D H
authors.initials: DH
authors.lastname: Viskochil
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA.|Department of Computer Science, Stanford University, Stanford, California, USA.|Department of Developmental Biology, Stanford University, Stanford, California, USA.
authors.forename: G
authors.initials: G
authors.lastname: Bejerano
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Bernstein
authors.affiliation: The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, Toronto, Ontario, Canada.|Division of Clinical Genetics and Metabolism, Department of Pediatrics, The Hospital for Sick Children; University of Toronto, Toronto, Ontario, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Chitayat
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000503:physiopathology; D055091:Bronchomalacia / Q000235:genetics / Q000503:physiopathology; D003616:Dandy-Walker Syndrome / Q000235:genetics* / Q000503:physiopathology; D002658:Developmental Disabilities / Q000235:genetics* / Q000503:physiopathology; D059472:Exome / Q000235:genetics; D005145:Face / Q000503:physiopathology; D005147:Facial Bones / Q000002:abnormalities* / Q000503:physiopathology; D005260:Female; D006215:Hallux Valgus / Q000235:genetics / Q000503:physiopathology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D010641:Phenotype; D012097:Repressor Proteins / Q000235:genetics*
chemical_list: C107465:ERF protein, human; D012097:Repressor Proteins
keywords: Bronchomalacia; Chitayat syndrome; Craniosynostosis; ERF; Hyperphalangism