The Recurrent E-Cadherin (CDH1) Mutation c.760G>A Causes Orofacial Clefts but Does Not Predispose to Hereditary Cancer

<b>Objective</b>: Congenital, non-syndromic orofacial clefts (CL/P) are infrequently monogenic in etiology. However, heterozygous pathogenic <i>CDH1</i> germline variants were reported in a few non-syndromic CL/P families, as well as in one syndromic form of CL/P: the blepharocheilodontic syndrome. <i>CDH1</i> encodes epithelial cadherin (E-cadherin), and close to 300 different pathogenic <i>CDH1</i> variants are listed in the ClinVar mutation database. The majority of <i>CDH1</i> germline variants are implicated in hereditary diffuse gastric cancer (HDGC) susceptibility. The purpose of this study was to classify the <i>CDH1</i> c.760G>A (p.Asp254Asn) mutation with respect to its resulting phenotype. <b>Methods</b>: Exome sequencing and targeted Sanger sequencing were performed in a family segregating CL/P. A review of pathogenic <i>CDH1</i> variants in ClinVar and those identified in a PubMed/MEDLINE search was performed. <b>Results</b>: We identified a family with six individuals, who were 35-77 years old (mean 56 years) at their last examination, uniformly affected with bilateral CL/P. The <i>CDH1</i> c.760G>A variant segregated with CL/P. This variant had been reported in 21 individuals, most often children and young adults, from six families. We determined a significant sex preponderance for this variant regarding CL/P: all 16 male and 5 of 11 female heterozygotes presented with CL/P. Furthermore, none of the heterozygous individuals in seven families reported any gastrointestinal tumors. <b>Conclusions</b>: The recurrent <i>CDH1</i> c.760G>A mutation confers a high risk for CL/P, with strong male preponderance. This review of 27 mutation carriers, including 3 who were 68, 70, and 77 years of age, indicates that c.760G>A does not confer an increased risk for HDGC. The relevance of differentiating craniofacial from cancer phenotypes in mutation carriers is substantial for precision medicine and for counseling families.