All CDH1 variations identified in BCD syndrome lead to amino-acid substitution or exon 9 skipping. Two mutational hotspots have been found, involving calcium binding sites located in EC1 and EC2 domains of E-cadherin protein, and in exon 9. Indeed, 11 patients from 7 families carry p.(Asp254Asn), p.(Asp254Tyr), p.(Asn256Lys) or p.(Asp257Val), and 9 patients from 7 families carry exon 9 skipping i.e. p.(Tyr380_Lys440del). The remaining patients carry p.(Asp288His), p.(Pro373Arg), p.(Val454del) and p.(Asp676Glu). Variants involving the conserved Asp254-Gln255-Asn256-Asp257 sequence possibly disrupt the electrostatic interactions between EC1–EC2 linker and calcium ions. Biological consequences of the other variants are less clear. However, functional tests show that all variants cause reduction in the expression of the protein and modification of its subcellular localization. Assays in zebrafish suggest dominant negative effect of the mutated protein.
Concerning Non-Syndromic Cleft Lip with or without cleft Palate (NSCLP), the mutational spectrum partially overlaps with BCD syndrome. Variant p.(Asp254Asn) has been identified in 18 patients from two large families and in a sporadic case. Variant p.(Asn256Lys) has been identified in 4 individuals from 1 large family. Protein-truncating variants have been identified in 9 patients from 3 families. 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 NSCLP or BCD syndrome or develop hereditary diffuse gastric cancer (HDGC).