title: Mutations inMYT1, encoding the myelin transcription factor 1, are a rare cause of OAVS.
abstract: BACKGROUND
  Oculo-auriculo-vertebral spectrum (OAVS) is a developmental disorder involving first and second branchial arches derivatives, mainly characterised by asymmetric ear anomalies, hemifacial microsomia, ocular defects and vertebral malformations. Although numerous chromosomal abnormalities have been associated with OAVS, no causative gene has been identified so far.
  
  
  OBJECTIVE
  We aimed to identify the first causative gene for OAVS.
  
  
  METHODS
  As sporadic cases are mostly described in Goldenhar syndrome, we have performed whole exome sequencing (WES) on selected affected individuals and their unaffected parents, looking for de novo mutations. Candidate gene was tested through transient knockdown experiment in zebrafish using a morpholino-based approach. A functional test was developed in cell culture in order to assess deleterious consequences of mutations.
  
  
  RESULTS
  By WES, we identified a heterozygous nonsense mutation in one patient in the myelin transcription factor 1 (MYT1) gene. Further, we detected one heterozygous missense mutation in another patient among a cohort of 169 patients with OAVS. This gene encodes theMYT1. Functional studies by transient knockdown ofmyt1a, homologue ofMYT1in zebrafish, led to specific craniofacial cartilage alterations. Treatment with all-trans retinoic acid (RA), a known teratogenic agent causing OAVS, led to an upregulation of cellular endogenousMYT1expression. Additionally, cellular wild-typeMYT1overexpression induced a downregulation of RA receptor β (RARB), whereas mutatedMYT1did not.
  
  
  CONCLUSIONS
  We reportMYT1as the first gene implicated in OAVS, within the RA signalling pathway.
authors.affiliation: University of Bordeaux, Maladies Rares: Génétique et Métabolisme (MRGM), U 1211 INSERM, Bordeaux, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Lopez
authors.affiliation: University of Bordeaux, Maladies Rares: Génétique et Métabolisme (MRGM), U 1211 INSERM, Bordeaux, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Berenguer
authors.affiliation: University of Bordeaux, Maladies Rares: Génétique et Métabolisme (MRGM), U 1211 INSERM, Bordeaux, France.
authors.forename: Angèle
authors.initials: A
authors.lastname: Tingaud-Sequeira
authors.affiliation: Département de Génétique, Hôpital Universitaire Necker-Enfants-Malades, Centre de Référence des Surdités Génétiques, Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marlin
authors.affiliation: Service de Génétique, Hôpital Bretonneau, Centre Hospitalier Universitaire, Tours, France.
authors.forename: Annick
authors.initials: A
authors.lastname: Toutain
authors.affiliation: Service d'ORL pédiatrique et de chirurgie cervicofaciale, Hôpital Universitaire Necker-Enfants-Malades, Centre de Référence des malformations ORL rares, Paris, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Denoyelle
authors.affiliation: Service de chirurgie maxillo-faciale, Hôpital Universitaire Necker-Enfants Malades, Paris, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Picard
authors.affiliation: University of Bordeaux, Maladies Rares: Génétique et Métabolisme (MRGM), U 1211 INSERM, Bordeaux, France.
authors.forename: Sabine
authors.initials: S
authors.lastname: Charron
authors.affiliation: University of Bordeaux, Maladies Rares: Génétique et Métabolisme (MRGM), U 1211 INSERM, Bordeaux, France.
authors.forename: Guilaine
authors.initials: G
authors.lastname: Mathieu
authors.affiliation: University of Bordeaux, Maladies Rares: Génétique et Métabolisme (MRGM), U 1211 INSERM, Bordeaux, France.
authors.forename: Harmony
authors.initials: H
authors.lastname: de Belvalet
authors.affiliation: University of Bordeaux, Maladies Rares: Génétique et Métabolisme (MRGM), U 1211 INSERM, Bordeaux, France.|Service de Génétique Médicale, CHU de Bordeaux, Centre de Référence Anomalies du Développement et Syndromes Malformatifs, Bordeaux, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Arveiler
authors.affiliation: University of Bordeaux, Maladies Rares: Génétique et Métabolisme (MRGM), U 1211 INSERM, Bordeaux, France.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Babin
authors.affiliation: University of Bordeaux, Maladies Rares: Génétique et Métabolisme (MRGM), U 1211 INSERM, Bordeaux, France.|Service de Génétique Médicale, CHU de Bordeaux, Centre de Référence Anomalies du Développement et Syndromes Malformatifs, Bordeaux, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Lacombe
authors.affiliation: University of Bordeaux, Maladies Rares: Génétique et Métabolisme (MRGM), U 1211 INSERM, Bordeaux, France.|Service de Génétique Médicale, CHU de Bordeaux, Centre de Référence Anomalies du Développement et Syndromes Malformatifs, Bordeaux, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Rooryck
keywords: Goldenhar syndrome; MYT1; OAVS; RARB; Retinoic acid