A Novel <i>CDH1</i> Mutation Causing Reduced E-Cadherin Dimerization Is Associated with Nonsyndromic Cleft Lip With or Without Cleft Palate

Abstract

<b><i>Aims:</i></b> Cleft lip with or without cleft palate (CL/P) is a common birth defect with an average prevalence of 1/700 to 1/1000. Almost 70% of CL/P cases are nonsyndromic CL/P (NSCL/P). The aim of this study was to identify the underlying cause of a four-generation Chinese family with autosomal dominant NSCL/P. <b><i>Methods:</i></b> Genomic DNA was extracted from peripheral blood leukocytes, and whole-exome sequencing was carried out to identify the underlying genetic cause of the disorder. The mutation was confirmed by Sanger sequencing and polymerase chain reaction-restriction fragment length polymorphism methods. Western blotting and coimmunoprecipitation were used to analyze the protein expression level and adhesive dimerization of the <i>CDH1</i> mutants. Slow aggregation assays were conducted to investigate the cell-cell adhesion ability. <b><i>Results:</i></b> A novel missense mutation (c.468G>C/p.Trp156Cys) of <i>CDH1</i> was identified in the proband and the mutation was shown to cosegregate with the phenotype in the family. Furthermore, we found that the p.Trp156Cys mutation led to decreased E-cadherin dimerization and cell-cell adhesion ability. <b><i>Conclusions:</i></b> Our findings identified a novel <i>CDH1</i> variant (c.468G>C/p.Trp156Cys) responsible for NSCL/P in a Chinese family, which expanded the mutational spectrum of the <i>CDH1</i> gene and may contribute to understanding the molecular basis of NSCL/P.