SHORT REPORT

Cleft lip/palate and CDH1/E-cadherin mutations in families with hereditary diffuse gastric cancer

T Frebourg¹, C Oliveira², P Hochain³, R Karam⁴, S Manouvrier⁵, C Graziadio⁶, M Vekemans⁷, A Hartmann⁸, S Baert-Desurmont¹, C Alexandre⁶, S Lejeune Dumoulin⁵, C Marroni⁹, C Martin¹, S Castedo¹⁰, M Lovett¹¹, J Winston¹¹, J C Machado¹², T Attié⁷, E W Jabs¹³, J Cai¹³, Ph Pellerin¹⁴, J P Triboulet¹⁵, M Scotte¹⁶, F Le Pessot¹⁷, A Hedouin¹, F Carneiro¹², M Blayau¹⁸, R Seruca¹²

¹ Department of Genetics, Rouen University Hospital, Rouen, France
² Institute of Molecular Pathology and Immunology, University of Porto (IPATIMUP), Porto, Portugal
³ Centre Médico-Chirurgical du Cèdre, Bois-Guillaume, France
⁴ IPATIMUP, Porto, Portugal and Department of Genetics, Fundação Faculdade Federal de Ciências Médicas de Porto Alegre (FFFCMPA), Porto Alegre, Brazil
⁵ Department of Genetics, Lille University Hospital, Lille, France
⁶ Department of Genetics, FFFCMPA, Porto Alegre, Brazil
⁷ Department of Genetics, Inserm U393, Necker, Paris, France
⁸ Department of Pathology, FFFCMPA, Porto Alegre, Brazil
⁹ Department of Gastroenterology, FFFCMPA, Porto Alegre, Brazil
¹⁰ Department of Genetics, Faculty of Medicine, University of Porto, Porto, Portugal
¹¹ Department of Genetics, Washington University School of Medicine, St Louis, MO, USA
¹² IPATIMUP and Department of Pathology, Faculty of Medicine, University of Porto, Porto, Portugal
¹³ Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA
¹⁴ Department of Plastic Surgery, Lille University Hospital, Lille, France
¹⁵ Department of Surgery, Lille University Hospital, Lille, France
¹⁶ Department of Surgery, Rouen University Hospital, Rouen, France
¹⁷ Department of Pathology, Rouen University Hospital, Rouen, France
¹⁸ Molecular Genetics Laboratory, Rennes University Hospital, Rennes, France

Correspondence to:
Dr T Frebourg
Inserm U614, Faculty of Medicine, 22 Boulevard Gambetta, 76183 Rouen, France; Frebourg{at}chu-rouen.fr
Dr R Seruca
IPATIMUP, Rua Dr. Roberto Frias, s/n, 4200-465 Porto, Portugal; rseruca{at}ipatimup.pt

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.

Keywords: CDH1/E-cadherin; cleft lip/palate; gastric cancer

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