Blepharocheilodontic syndrome is a CDH1 pathway–related disorder due to mutations in CDH1 and CTNND1

Abstract

Mutations in CDH1 encoding the E-cadherin were previously reported in hereditary diffuse gastric cancer as well as in nonsyndromic cleft lip/palate. Mutations in CTNND1 have never been reported before. The encoded protein, p120ctn, prevents E-cadherin endocytosis and stabilizes its localization at the cell surface. Conditional deletion of Cdh1 and Ctnnd1 in various animal models induces features reminiscent of BCD syndrome and underlines critical role of the E-cadherin-p120ctn interaction in eyelid, craniofacial, and tooth development. Our data assert BCD syndrome as a CDH1 pathway-related disorder due to mutations in CDH1 and CTNND1 and widen the phenotypic spectrum of E-cadherin anomalies.Genet Med advance online publication 09 March 2017.

De-novovariants inXIRP1associated with polydactyly and polysyndactyly in Holstein cattle

“…Further, CTNNB1 operates in SHH polarization in hair morphogenesis (G at et al 1998). Mutations in the CTNND1 and cadherin 1 ( CDH1 ) are highly associated causing blepharocheilodontic syndrome (BCD) in human (G houmid et al 2017). The phenotype of this syndrome included dominant features as eyelid malformations, cleft lip or palate and ectodermal dysplasia.…”

“…The phenotype of this syndrome included dominant features as eyelid malformations, cleft lip or palate and ectodermal dysplasia. Furthermore, malformation or absence of the thyroid gland, atresia ani, neural tube defects, syndactyly or complex limb reduction defects are reported (G orlin et al 1976; W eaver et al 2010; A babneh et al 2014; G houmid et al 2017). Both calves showed parts of these phenotypic variations.…”

CDH1 germline mutations: different syndromes, same management?

“…4 They performed exome sequencing in five families and targeted sequencing in the remainder, and found in all of them pathogenic or likely pathogenic germline mutations in either CDH1 or CTNND1. Overall, the association is convincing, even though in vitro experiments, in addition to the in silico simulations and expression studies already performed, would be needed to prove beyond reasonable doubt the pathogenicity of the three missense CDH1 mutations (there is little doubt that the splice-site CDH1 and truncating CTNND1 mutations are pathogenic).…”

“…5,6 In addition, CDH1 is an established susceptibility gene for nonsyndromic CLP, with, for example, 4/81 (5%) affected cases carrying a germline mutation in a Dutch study. 7 The medical relevance of the findings reported by Ghoumid et al 4 would be limited to the possibility of preimplantation or prenatal testing for BCD patients planning to conceive, were it not for hereditary diffuse gastric cancer (HDGC), a complex and fascinating cancer susceptibility syndrome. Like BCD, HDGC is caused by germline CDH1 mutations.…”

“…Furthermore, there is obvious overlap between HDGC, BCD and nonsyndromic CLP. For example, in the paper by Ghoumid et al 4 , the mother of a BCD case died at the age of 35 of gastric cancer, most likely of the diffuse type, while CLP has been reported in at least six HDGC families so far. 6,13,14 Admittedly, four out of five CDH1 families reported by Ghoumid et al 4 had no history of DGC, and this is why the authors do not envisage risk-reducing gastrectomies at this stage.…”