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Cleft lip/palate and CDH1/E-cadherin mutations in families with hereditary diffuse gastric cancer
  1. T Frebourg1,
  2. C Oliveira2,
  3. P Hochain3,
  4. R Karam4,
  5. S Manouvrier5,
  6. C Graziadio6,
  7. M Vekemans7,
  8. A Hartmann8,
  9. S Baert-Desurmont1,
  10. C Alexandre6,
  11. S Lejeune Dumoulin5,
  12. C Marroni9,
  13. C Martin1,
  14. S Castedo10,
  15. M Lovett11,
  16. J Winston11,
  17. J C Machado12,
  18. T Attié7,
  19. E W Jabs13,
  20. J Cai13,
  21. Ph Pellerin14,
  22. J P Triboulet15,
  23. M Scotte16,
  24. F Le Pessot17,
  25. A Hedouin1,
  26. F Carneiro12,
  27. M Blayau18,
  28. R Seruca12
  1. 1Department of Genetics, Rouen University Hospital, Rouen, France
  2. 2Institute of Molecular Pathology and Immunology, University of Porto (IPATIMUP), Porto, Portugal
  3. 3Centre Médico-Chirurgical du Cèdre, Bois-Guillaume, France
  4. 4IPATIMUP, Porto, Portugal and Department of Genetics, Fundação Faculdade Federal de Ciências Médicas de Porto Alegre (FFFCMPA), Porto Alegre, Brazil
  5. 5Department of Genetics, Lille University Hospital, Lille, France
  6. 6Department of Genetics, FFFCMPA, Porto Alegre, Brazil
  7. 7Department of Genetics, Inserm U393, Necker, Paris, France
  8. 8Department of Pathology, FFFCMPA, Porto Alegre, Brazil
  9. 9Department of Gastroenterology, FFFCMPA, Porto Alegre, Brazil
  10. 10Department of Genetics, Faculty of Medicine, University of Porto, Porto, Portugal
  11. 11Department of Genetics, Washington University School of Medicine, St Louis, MO, USA
  12. 12IPATIMUP and Department of Pathology, Faculty of Medicine, University of Porto, Porto, Portugal
  13. 13Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA
  14. 14Department of Plastic Surgery, Lille University Hospital, Lille, France
  15. 15Department of Surgery, Lille University Hospital, Lille, France
  16. 16Department of Surgery, Rouen University Hospital, Rouen, France
  17. 17Department of Pathology, Rouen University Hospital, Rouen, France
  18. 18Molecular Genetics Laboratory, Rennes University Hospital, Rennes, France
  1. Correspondence to:
 Dr T Frebourg
 Inserm U614, Faculty of Medicine, 22 Boulevard Gambetta, 76183 Rouen, France; Frebourg{at}
 Dr R Seruca
 IPATIMUP, Rua Dr. Roberto Frias, s/n, 4200-465 Porto, Portugal; rseruca{at}


We report the association of CDH1/E-cadherin mutations with cleft lip, with or without cleft palate (CLP), in two families with hereditary diffuse gastric cancer (HDGC). In each family, the CDH1 mutation was a splicing mutation generating aberrant transcripts with an in-frame deletion, removing the extracellular cadherin repeat domains involved in cell-cell adhesion. Such transcripts might encode mutant proteins with trans-dominant negative effects. We found that CDH1 is highly expressed at 4 and 5 weeks in the frontonasal prominence, and at 6 weeks in the lateral and medial nasal prominences of human embryos, and is therefore expressed during the critical stages of lip and palate development. These findings suggest that alteration of the E-cadherin pathway can contribute to human clefting.

  • CL, cleft lip
  • CLP, cleft lip with or without cleft palate
  • COGENE, Craniofacial and Oral Gene Expression Network Consortium
  • HDGC, hereditary diffuse gastric cancer
  • NMD, nonsense mediated decay
  • CDH1/E-cadherin
  • cleft lip/palate
  • gastric cancer

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  • This work was supported by l’Association pour la Recherche sur le Cancer, La Ligue Nationale Contre le Cancer, and in part by grants from the National Institute of Health (N01 DE92630 to EWJ).

  • Competing interests: none declared