The CDH1 gene encodes the E-cadherin, a cell adhesion molecule. To be active, E-cadherin needs to be bound to calcium. All identified mutations in Blepharocheilodontic (BCD) syndrome lead to amino-acid substitution or partial deletion of the protein. Two mutational hotspots have been found, involving calcium binding sites and deletion of exon 9. Changes in calcium binding sites possibly disrupt the electrostatic interactions between E-cadherin and calcium ions. Biological consequences of exon 9 deletion, as well as the other variants are less clear. However, functional tests show that all variants cause reduction of the expression of the protein and modification of its cellular localization.
Concerning cleft lip/palate (CLP), mutations partially overlap with BCD syndrome. Variant p.(Asp254Asn) has been identified in two large families and in a sporadic case, corresponding to 19 patients. Variant p.(Asn256Lys) has been identified in 4 individuals from 1 large family. Mutations resulting in premature stop codon have been identified in 9 patients from 3 families. All the remaining patients carry a missense variant in different functional domains of the protein. There is no genotype/phenotype correlation to explain why a patient would present Non-Syndromic Cleft Lip with or without cleft Palate (NSCLP) or BCD syndrome or develop hereditary diffuse gastric cancer (HDGC).