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OTX2 mutations contribute to the otocephaly-dysgnathia complex
  1. Nicolas Chassaing1,2,3,
  2. Susanna Sorrentino4,
  3. Erica E Davis5,6,7,
  4. Dominique Martin-Coignard8,
  5. Anthony Iacovelli4,
  6. William Paznekas4,
  7. Bryn D Webb4,9,
  8. Ona Faye-Petersen10,
  9. Férechté Encha-Razavi11,
  10. Leopoldine Lequeux12,
  11. Adeline Vigouroux1,
  12. Ahmet Yesilyurt13,
  13. Simeon A Boyadjiev14,
  14. Hülya Kayserili15,
  15. Philippe Loget16,
  16. Dominique Carles17,
  17. Consolato Sergi18,19,
  18. Surasak Puvabanditsin20,
  19. Chih-Ping Chen21,22,23,
  20. Heather C Etchevers2,24,
  21. Nicholas Katsanis5,6,7,
  22. Catherine L Mercer25,
  23. Patrick Calvas1,2,3,
  24. Ethylin Wang Jabs4,9,26
  1. 1Department of Medical Genetics, Purpan Hospital, CHU Toulouse, Toulouse, France
  2. 2GR2DE Team, Toulouse III Paul-Sabatier University, Toulouse, France
  3. 3INSERM, Centre de Physiopathologie de Toulouse Purpan, Toulouse, France
  4. 4Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, USA
  5. 5Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina, USA
  6. 6Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA
  7. 7Department of Cell Biology, Duke University Medical Center, Durham, North Carolina, USA
  8. 8Department of Medical Genetics, CH Le Mans, Le Mans, France
  9. 9Department of Pediatrics, Mount Sinai School of Medicine, New York, USA
  10. 10Department of Pathology, University of Alabama, Birmingham, Alabama, USA
  11. 11Department of Histology-Embryology, Hôpital Necker, Paris, France
  12. 12Department of Ophthalmology, Purpan Hospital, CHU Toulouse, Toulouse, France
  13. 13Genetic Center, Dr Zekai Tahir Burak Women Health Training and Research Hospital, Ankara, Turkey
  14. 14Section of Genetics, Department of Pediatrics, University of California Davis, Sacramento, California, USA
  15. 15Department of Medical Genetics, Istanbul Medical Faculty, Istanbul, Turkey
  16. 16Department of Pathology, University Hospital of Rennes, Rennes, France
  17. 17Pathology Laboratory, Bordeaux University Hospital, Bordeaux, France
  18. 18Department of Laboratory Medicine and Pathology, University of Alberta Hospital, Edmonton, Canada
  19. 19Institute of Pathology, Medical University of Innsbruck, Innsbruck, Austria
  20. 20Department of Pediatrics, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, USA
  21. 21Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan
  22. 22Department of Biotechnology, Asia University, Taichung, Taiwan
  23. 23School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan
  24. 24INSERM, Université de la Méditerranée Faculté de Médecine, Marseille, France
  25. 25Academic Unit of Genetic Medicine, Division of Human Genetics, University of Southampton, Southampton, UK
  26. 26Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, USA
  1. Correspondence to Dr Nicolas Chassaing, Service de Génétique Médicale, Pavillon Lefebvre, CHU Purpan, Place du Dr Baylac, Toulouse 31059, Cedex 9, France; chassaing.n{at}


Background Otocephaly or dysgnathia complex is characterised by mandibular hypoplasia/agenesis, ear anomalies, microstomia, and microglossia; the molecular basis of this developmental defect is largely unknown in humans.

Methods and results This study reports a large family in which two cousins with micro/anophthalmia each gave birth to at least one child with otocephaly, suggesting a genetic relationship between anophthalmia and otocephaly. OTX2, a known microphthalmia locus, was screened in this family and a frameshifting mutation was found. The study subsequently identified in one unrelated otocephalic patient a sporadic OTX2 mutation. Because OTX2 mutations may not be sufficient to cause otocephaly, the study assayed the potential of otx2 to modify craniofacial phenotypes in the context of known otocephaly gene suppression in vivo. It was found that otx2 can interact genetically with pgap1, prrx1, and msx1 to exacerbate mandibular and midline defects during zebrafish development. However, sequencing of these loci in the OTX2-positive families did not unearth likely pathogenic lesions, suggesting further genetic heterogeneity and complexity.

Conclusion Identification of OTX2 involvement in otocephaly/dysgnathia in humans, even if loss of function mutations at this locus does not sufficiently explain the complex anatomical defects of these patients, suggests the requirement for a second genetic hit. Consistent with this notion, trans suppression of otx2 and other developmentally related genes recapitulate aspects of the otocephaly phenotype in zebrafish. This study highlights the combined utility of genetics and functional approaches to dissect both the regulatory pathways that govern craniofacial development and the genetics of this disease group.

  • Otocephaly
  • agnathia
  • microphthalmia
  • OTX2
  • MSX1
  • PRRX1
  • genetics
  • clinical genetics
  • molecular genetics
  • visual development
  • development
  • embryology
  • genetic screening/counselling
  • genome-wide
  • diabetes
  • epigenetics
  • cytogenetics
  • dermatology
  • microarray
  • congenital heart disease

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  • NC, SS contributed equally to this work.

  • Funding This work was supported by grants from the Clinical Research Hospital Program from the French Ministry of Health (PHRC 09 109 01), Retina France, and from National Institutes of Health (5 R01 DE13849 and -09 S1).

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Ethics approval was provided by the Comité de Protection des Personnes Sud-Ouest et Outre-Mer II.

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