Maternal inflammation as a risk factor for cleft lip and palate development in individuals with CDH1 loss of function

• Grant number: 22/07972-7
• Support Opportunities: Scholarships in Brazil - Master
• Start date: December 01, 2022
• End date: August 31, 2024
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Maria Rita dos Santos e Passos Bueno
• Grantee: Diogo Andrade Nani
• Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center, AP.CEPID

Abstract

Cleft lip and palate (CLP) are craniofacial malformations characterized by the discontinuity of lip and/or palate tissues. CLP is a multifactorial inherited disease which has been related to smoking, alcohol consumption and inflammation during pregnancy, as well as common and rare genetic variants. Our group has recently observed that pathogenic variants leading to loss of function in the CDH1 gene segregate in families of non syndromic CLP patients with incomplete penetrance. It was also observed a positive correlation between methylation of the CDH1 promoter region and CLP occurrence. Interestingly, it is well established that levels of CDH1 promoter methylation relates to hereditary diffuse gastric cancer. CDH1 encodes for E-cadherins and it is known that proinflammatory factors can induce its hypermethylation and reduce the protein abundance. E-cadherins are essential for cell-cell adhesion, which are necessary for the fusion of palatal shelves and prospective upper lip prominences. They are also important for cell signalization in craniofacial development. Therefore, our main hypothesis is that maternal inflammation is a factor of risk for the development of CLP in individuals with CDH1 loss of function. To test this hypothesis, we propose to functionally investigate the role of cdh1 and inflammation in CLP development. We pretend to contribute with a better understanding of how environmental and genetic factors can lead to CLP cases. Such knowledge is important for preventing new cases and also has an impact on public health policies and genetic counseling.