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Heterogeneity of mutational mechanisms and modes of inheritance in auriculocondylar syndrome
  1. Christopher T Gordon1,
  2. Alice Vuillot1,
  3. Sandrine Marlin2,
  4. Erica Gerkes3,
  5. Alex Henderson4,
  6. Adila AlKindy5,
  7. Muriel Holder-Espinasse6,
  8. Sarah S Park7,
  9. Asma Omarjee1,
  10. Mateo Sanchis-Borja1,
  11. Eya Ben Bdira1,
  12. Myriam Oufadem1,
  13. Birgit Sikkema-Raddatz3,
  14. Alison Stewart8,
  15. Rodger Palmer9,
  16. Ruth McGowan10,
  17. Florence Petit6,
  18. Bruno Delobel11,
  19. Michael R Speicher12,
  20. Paul Aurora13,
  21. David Kilner13,
  22. Philippe Pellerin14,
  23. Marie Simon15,
  24. Jean-Paul Bonnefont15,
  25. Edward S Tobias16,
  26. Sixto García-Miñaúr17,
  27. Maria Bitner-Glindzicz18,
  28. Pernille Lindholm19,
  29. Brigitte A Meijer20,
  30. Véronique Abadie21,
  31. Françoise Denoyelle22,
  32. Marie-Paule Vazquez23,24,25,
  33. Christa Rotky-Fast26,
  34. Vincent Couloigner27,
  35. Sébastien Pierrot27,
  36. Yves Manach27,
  37. Sylvain Breton28,29,
  38. Yvonne M C Hendriks30,
  39. Arnold Munnich1,15,
  40. Linda Jakobsen19,
  41. Peter Kroisel12,
  42. Angela Lin31,
  43. Leonard B Kaban32,
  44. Lina Basel-Vanagaite33,34,35,
  45. Louise Wilson9,
  46. Michael L Cunningham7,36,
  47. Stanislas Lyonnet1,15,
  48. Jeanne Amiel1,15
  1. 1INSERM U781, Hôpital Necker-Enfants Malades and Université Paris Descartes–Sorbonne Paris Cité, Institut Imagine, Paris, France
  2. 2Centre de référence des surdités génétiques, Service de génétique médicale, Hôpital d'Enfants Armand-Trousseau AP-HP, Paris, France
  3. 3Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
  4. 4Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
  5. 5Department of Genetics, Sultan Qaboos University Hospital, Muscat, Oman
  6. 6Service de Génétique Clinique, Hôpital Jeanne de Flandre, CHRU Lille, France
  7. 7Center for Tissue and Cell Sciences, Seattle Children's Research Institute, Seattle, USA
  8. 8West Midlands Regional Genetics Service, Birmingham, UK
  9. 9North East Thames Regional Genetics Service, Great Ormond Street Hospital, London, UK
  10. 10North Scotland Regional Genetics Service, Ashgrove House, Aberdeen, UK
  11. 11Laboratoire de génétique chromosomique, Hôpital St Vincent de Paul, Lille, France
  12. 12Institute of Human Genetics, Medical University of Graz, Graz, Austria
  13. 13Respiratory Medicine, Great Ormond Street Hospital, London, UK
  14. 14Centre de Référence des Malformations Cranio-maxillo-faciales Rares, CHRU Lille, France
  15. 15AP-HP, Département de Génétique, Hôpital Necker-Enfants Malades, Paris, France
  16. 16School of Medicine, University of Glasgow, Yorkhill Hospital, Glasgow, UK
  17. 17Institute for Medical and Molecular Genetics, La Paz University Hospital, Madrid, Spain
  18. 18Clinical and Molecular Genetics, Institute of Child Health, UCL, London, UK
  19. 19Department of Plastic and Reconstructive Surgery, Copenhagen University Hospital, Rigshospitalet, Denmark
  20. 20Department of Oral and Maxillofacial Surgery, Kennemer Gasthuis, Haarlem, The Netherlands
  21. 21Service de Pédiatrie Générale, Université Paris Descartes, Hôpital Necker-Enfants Malades, Paris, France
  22. 22INSERM UMR-S587 and Pediatric Otolaryngology Department, Armand-Trousseau Children's Hospital, AP-HP, Paris 6 University, Paris, France
  23. 23Service de Chirurgie Maxillo-Faciale et Plastique, CRMR des Malformations de la Face et de la Cavité Buccale, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
  24. 24Université Paris 5, UFR de Médecine Paris-Descartes, Paris, France
  25. 25Centre de Recherche des Cordeliers, UMR S 872, Paris, France
  26. 26Department of Pediatrics and Adolescence Medicine, Medical University of Graz, Graz, Austria
  27. 27Service d'ORL Pediatrique, Hôpital Necker-Enfants Malades, AP-HP, Université Paris 5, Paris, France
  28. 28AP-HP, Service d'Imagerie Pédiatrique, Hôpital Necker-Enfants Malades, Paris, France
  29. 29Laboratoire d'Anatomie, Université Paris-Descartes, Paris, France
  30. 30Department of Clinical Genetics, Free University Medical Center, Amsterdam, The Netherlands
  31. 31Genetics Unit, MassGeneral Hospital for Children, Boston, Massachusetts, USA
  32. 32Department of Oral and Maxillofacial Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
  33. 33Pediatric Genetics, Schneider Children's Medical Center of Israel and Raphael Recanati Genetics Institute, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel
  34. 34Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel;
  35. 35Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva, Israel
  36. 36Department of Pediatrics, University of Washington and Seattle Children's Hospital Craniofacial Center, Seattle, Washington, USA
  1. Correspondence to Dr Christopher T Gordon and Professor Jeanne Amiel, INSERM U781, Tour Lavoisier 2ème étage, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, Paris 75015, France; chris.gordon{at}, jeanne.amiel{at}


Background Auriculocondylar syndrome (ACS) is a rare craniofacial disorder consisting of micrognathia, mandibular condyle hypoplasia and a specific malformation of the ear at the junction between the lobe and helix. Missense heterozygous mutations in the phospholipase C, β 4 (PLCB4) and guanine nucleotide binding protein (G protein), α inhibiting activity polypeptide 3 (GNAI3) genes have recently been identified in ACS patients by exome sequencing. These genes are predicted to function within the G protein-coupled endothelin receptor pathway during craniofacial development.

Results We report eight additional cases ascribed to PLCB4 or GNAI3 gene lesions, comprising six heterozygous PLCB4 missense mutations, one heterozygous GNAI3 missense mutation and one homozygous PLCB4 intragenic deletion. Certain residues represent mutational hotspots; of the total of 11 ACS PLCB4 missense mutations now described, five disrupt Arg621 and two disrupt Asp360. The narrow distribution of mutations within protein space suggests that the mutations may result in dominantly interfering proteins, rather than haploinsufficiency. The consanguineous parents of the patient with a homozygous PLCB4 deletion each harboured the heterozygous deletion, but did not present the ACS phenotype, further suggesting that ACS is not caused by PLCB4 haploinsufficiency. In addition to ACS, the patient harbouring a homozygous deletion presented with central apnoea, a phenotype that has not been previously reported in ACS patients.

Conclusions These findings indicate that ACS is not only genetically heterogeneous but also an autosomal dominant or recessive condition according to the nature of the PLCB4 gene lesion.

  • PLCB4
  • GNAI3
  • auriculocondylar syndrome
  • question mark ear
  • micrognathia

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