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Original research
OTX2 duplications: a recurrent cause of oculo-auriculo-vertebral spectrum
  1. Tristan Celse1,2,3,
  2. Angèle Tingaud-Sequeira4,
  3. Klaus Dieterich1,5,
  4. Geraldine Siegfried6,
  5. Cédric Lecaignec7,8,
  6. Laurence Bouneau7,
  7. Madeleine Fannemel9,
  8. Gaelle Salaun10,11,
  9. Fanny Laffargue10,
  10. Guillaume Martinez1,2,3,
  11. Véronique Satre1,2,3,
  12. Gaelle Vieville3,
  13. Marie Bidart1,2,12,
  14. Cecilia Soussi Zander13,
  15. Ann-Charlotte Turesson13,
  16. Miranda Splitt14,
  17. Dorothee Reboul15,
  18. Jean Chiesa16,17,
  19. Philippe Khau Van Kien16,17,
  20. Manon Godin18,
  21. Nicolas Gruchy18,
  22. Himanshu Goel19,20,
  23. Elizabeth Palmer21,22,
  24. Kalliope Demetriou21,
  25. Carolyn Shalhoub21,22,
  26. Caroline Rooryck4,23,
  27. Charles Coutton1,2,3
  1. 1 Universite Grenoble Alpes, Saint-Martin-d'Heres, France
  2. 2 Genetics Epigenetics and Therapies of Infertility, Institute for Advanced Biosciences, INSERM 1209, CNRS UMR 5309, Grenoble, France
  3. 3 Service de Génétique, Génomique et Procréation, CHU Grenoble Alpes, Grenoble, France
  4. 4 Univ. Bordeaux, Maladies Rares : Génétique et Métabolisme (MRGM), INSERM U1211, Bordeaux, France
  5. 5 Inserm, U1216, GIN, Grenoble, France
  6. 6 Xenofish Platform U1312 – BRIC, Inserm, Univ. Bordeaux, Bordeaux, France
  7. 7 Génétique médicale, Institut Fédératif de Biologie (IFB), CHU de Toulouse - Hôpital Purpan, Toulouse, France
  8. 8 Toulouse NeuroImaging Center, Inserm, UPS, Université de Toulouse, Toulouse, France
  9. 9 Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
  10. 10 Cytogénétique Médicale, CHU Estaing, Clermont-Ferrand, France
  11. 11 Université Clermont Auvergne, INSERM, U1240 Imagerie Moléculaire et Stratégies Théranostiques, Clermont-Ferrand, France
  12. 12 CHU Grenoble Alpes, Laboratoire de Génétique Moléculaire: Maladies Héréditaires et Oncologie, Grenoble, France
  13. 13 Department of Immunology, Genetics and Pathology, Science for Life Laboratory Uppsala, Uppsala University, Uppsala, Sweden
  14. 14 Northern Genetics Service, Institute of Genetic Medicine, Newcastle, UK
  15. 15 Hôpital Carémeau, CHU Nîmes, Laboratoire de Cytologie Clinique et Cytogénétique, Nimes, France
  16. 16 UF de Génétique Médicale et Cytogénétique, Centre Hospitalier Régional Universitaire de Nîmes, Nimes, France
  17. 17 Faculté de Médecine Montpellier-Nîmes, Laboratoire d'Histologie-Embryologie-Cytogénétique, Institut des Biomolécules Max Mousseron (IBMM), CNRS UMR5247, Nimes, France
  18. 18 Normandy University, UNICAEN, Caen University Hospital, Department of Genetics, Reference Center of Rare Diseases of Developmental Anomalies and Malformation Syndromes, Caen, France
  19. 19 Hunter Genetics, Waratah, New South Wales, Australia
  20. 20 University of Newcastle, Callaghan, NSW 2308, Australia
  21. 21 Centre for Clinical Genetics, Sydney Children's Hospitals Network Randwick, Randwick, NSW 2031, Australia
  22. 22 School of Clinical Medicine, Discipline of Paediatrics and Child Health, Faculty of Medicine and Health, NSW 2031, Australia
  23. 23 21 CHU Bordeaux, Service de Génétique Médicale, Bordeaux, France
  1. Correspondence to Professor Charles Coutton, Génétique et Procréation, Université Grenoble Alpes, Saint-Martin-d'Heres, France; CCoutton{at}


Background Oculo-auriculo-vertebral spectrum (OAVS) is the second most common cause of head and neck malformations in children after orofacial clefts. OAVS is clinically heterogeneous and characterised by a broad range of clinical features including ear anomalies with or without hearing loss, hemifacial microsomia, orofacial clefts, ocular defects and vertebral abnormalities. Various genetic causes were associated with OAVS and copy number variations represent a recurrent cause of OAVS, but the responsible gene often remains elusive.

Methods We described an international cohort of 17 patients, including 10 probands and 7 affected relatives, presenting with OAVS and carrying a 14q22.3 microduplication detected using chromosomal microarray analysis. For each patient, clinical data were collected using a detailed questionnaire addressed to the referring clinicians. We subsequently studied the effects of OTX2 overexpression in a zebrafish model.

Results We defined a 272 kb minimal common region that only overlaps with the OTX2 gene. Head and face defects with a predominance of ear malformations were present in 100% of patients. The variability in expressivity was significant, ranging from simple chondromas to severe microtia, even between intrafamilial cases. Heterologous overexpression of OTX2 in zebrafish embryos showed significant effects on early development with alterations in craniofacial development.

Conclusions Our results indicate that proper OTX2 dosage seems to be critical for the normal development of the first and second branchial arches. Overall, we demonstrated that OTX2 genomic duplications are a recurrent cause of OAVS marked by auricular malformations of variable severity.

  • Gene Duplication
  • Genomics
  • Human Genetics
  • Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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  • Correction notice The article has been corrected since it was published Online First. Caroline Rooryck's name has been amended. Furthermore, the title has been corrected: 'OTX2' has been set in italic type.

  • Contributors All authors of this manuscript fulfil the criteria of authorship. TC, KDi, CL, LB, MF, GS, FL, VS, CSZ, A-CT, MS, DR, JC, PKVK, MG, NG, CC, HG, EP, KDe and CS recruited patients and collected clinical and biological information. AT-S, GS and CR-T performed zebrafish experiments. TC, GV, GM, MB, AT-S, GS, CR-T and CC performed data analysis and interpretation. TC, CC, AT-S, GS, CR-T and CC designed the study and wrote the manuscript. CC: guarantor

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.