Molecular Genetic Analysis Of A Chinese Family With Nonsyndromic Cleft Lip With Or Without Cleft Palate

Cleft lip with or without cleft palate(CL/P) is a common birth defect characterized by an opening in the upper lip or palate, with a prevalence of 1/1000 to 7/1000. The occurrence of cleft lip may be associated with cleft palate, the cleft palate can also occur alone. CL/P is divided into two types, non-syndromic CL/P(NSCL/P) and syndromic CL/P(SCL/P). According to epidemiology, almost 70% of CL/P cases are non-syndromes,and the prevalence of NSCL/P in China is 1.13/1000 to 1.30/1000. The incidence of NSCL/P is affected by genetic and environment factors. The NSCL/P has genetic heterogeneity. So far, the mutations of some genes, including MAFB, FOXE1, IRF6,CDH1 et al., have been associated with NSCL/P. However, the pathogenic mechanism of NSCL/P is unknown. Genetic studies from CL/P families may reveal the causative gene of CL/P, which is important to elucidate the pathogenic mechanism of CL/P.In this study, a Han family from Henan province with autosomal dominant inherited NSCLP was collected and identified. This NSCLP family was studied by whole exome sequencing and sanger sequencing and identified the causative gene. The results are shown as follows:The results of exome sequencing revealed a novel mutation of a G to C transversion at nucleotide 468 of(c.468 G>C) of CDH1, which was detected in two affected family members. This mutation leads to a substitution of a highly conserved amino acid residue Tryptophan with a Cysteine residue at 156(p.W156C). Sanger sequencing showed that c.468G>C variant fully segregated with the CL/P phenotype in this family. RFLP analysis certified that this variation was not detected in 211 normal Han controls. CDH1 encodes E-cadherin, a calcium dependent cell adhesion protein. The tryptophan at codon 156 locates in the highly conservative region of E-cadherin, the p.W156 C mutation was predicted to be damaging to protein function both by Polyphen-2 and Mutation Taster.In the previous studies, the change of Trp156 damaged the dimerization of E-cadherin,which in turn had negative impact on cell adhesion. In this study, we found that the c.468G>C(p.W156C) mutation should be responsible for the CL/P phenotype of this family. However, how p.W156 C mutation cause CL/P is still unclear, and needs for further study.