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EFTUD2 haploinsufficiency leads to syndromic oesophageal atresia
  1. Christopher T Gordon1,
  2. Florence Petit2,3,
  3. Myriam Oufadem1,
  4. Charles Decaestecker2,
  5. Anne-Sophie Jourdain3,
  6. Joris Andrieux4,
  7. Valérie Malan5,
  8. Jean-Luc Alessandri6,
  9. Geneviève Baujat5,
  10. Clarisse Baumann7,
  11. Odile Boute-Benejean2,
  12. Roseline Caumes5,
  13. Bruno Delobel8,
  14. Klaus Dieterich9,
  15. Dominique Gaillard10,
  16. Marie Gonzales11,
  17. Didier Lacombe12,
  18. Fabienne Escande3,
  19. Sylvie Manouvrier-Hanu2,
  20. Sandrine Marlin13,
  21. Michèle Mathieu-Dramard14,
  22. Sarju G. Mehta15,
  23. Ingrid Simonic15,
  24. Arnold Munnich1,5,
  25. Michel Vekemans1,5,
  26. Nicole Porchet3,
  27. Loïc de Pontual1,16,
  28. Sabine Sarnacki17,
  29. Tania Attie-Bitach1,5,
  30. Stanislas Lyonnet1,5,
  31. Muriel Holder-Espinasse2,
  32. Jeanne Amiel1,5
  1. 1Unité INSERM U781, Faculté Paris-Descartes, Institut IMAGINE, Paris, France
  2. 2Service de Génétique Clinique, Hôpital Jeanne de Flandre, CHRU Lille, France
  3. 3Laboratoire de Biologie Moléculaire, Centre de Biologie Pathologie, CHRU Lille, France
  4. 4Laboratoire de Génétique Médicale, Hôpital Jeanne de Flandre, CHRU Lille, France
  5. 5Département de Génétique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
  6. 6Pole Enfants, Hôpital Felix Guyon, CHRU de La Réunion, France
  7. 7Département de génétique, Hôpital Robert Debré, Paris, France
  8. 8Laboratoire de génétique chromosomique, Hôpital St Vincent de Paul, Lille, France
  9. 9Département de Génétique et Procréation, Hôpital Couple Enfant, CHU Grenoble, and Unité INSERM U836, Grenoble Institut des Neurosciences, Grenoble, France
  10. 10Service de génétique, Hôpital Maison Blanche, CHRU Reims, France
  11. 11Service de génétique et embryologie médicales, Hôpital d'Enfants Armand-Trousseau, CHU Paris Est, France
  12. 12Service de Génétique, CHU Bordeaux, Laboratoire MRGM, Université de Bordeaux, Bordeaux, France
  13. 13Centre de référence des surdités génétiques, service de génétique médicale, Hôpital Armand Trousseau, APHP, Paris, France
  14. 14Unité de génétique clinique, Hôpital Nord, CHU Amiens, France
  15. 15East Anglian Medical Genetics Service, Addenbrookes Hospital, Cambridge, UK
  16. 16Service de Pédiatrie, Hôpital Jean Verdier, Université Paris XIII, AP-HP, Bondy, France
  17. 17Service de chirurgie viscérale pédiatrique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
  1. Correspondence to Professor Jeanne Amiel, Service de Génétique et INSERM U781, Hôpital Necker, Tour Lavoisier 2ème étage, 149 rue de Sèvres, Paris 75015, France; Jeanne.amiel{at}


Background: Oesophageal atresia (OA) and mandibulofacial dysostosis (MFD) are two congenital malformations for which the molecular bases of syndromic forms are being identified at a rapid rate. In particular, the EFTUD2 gene encoding a protein of the spliceosome complex has been found mutated in patients with MFD and microcephaly (MIM610536). Until now, no syndrome featuring both MFD and OA has been clearly delineated.

Results: We report on 10 cases presenting with MFD, eight of whom had OA, either due to de novo 17q21.31 deletions encompassing EFTUD2 and neighbouring genes or de novo heterozygous EFTUD2 loss-of-function mutations. No EFTUD2 deletions or mutations were found in a series of patients with isolated OA or isolated oculoauriculovertebral spectrum (OAVS).

Conclusions: These data exclude a contiguous gene syndrome for the association of MFD and OA, broaden the spectrum of clinical features ascribed to EFTUD2 haploinsufficiency, define a novel syndromic OA entity, and emphasise the necessity of mRNA maturation through the spliceosome complex for global growth and within specific regions of the embryo during development. Importantly, the majority of patients reported here with EFTUD2 lesions were previously diagnosed with Feingold or CHARGE syndromes or presented with OAVS plus OA, highlighting the variability of expression and the wide range of differential diagnoses.

  • Mandibulofacial dysostosis
  • esophageal atresia
  • microcephaly
  • 17q21.31 deletion
  • EFTUD2

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