Unraveling the genetic architecture of non-syndromic cleft lip and palate associated with dental agenesis: genomic mapping.

• Grant number: 24/18278-0
• Support Opportunities: Regular Research Grants
• Start date: August 01, 2025
• End date: July 31, 2028
• Field of knowledge: Health Sciences - Dentistry
• Principal Investigator: Lucimara Teixeira das Neves
• Grantee: Lucimara Teixeira das Neves
• Host Institution: Hospital de Reabilitação de Anomalias Craniofaciais (HRAC). Universidade de São Paulo (USP). Bauru , SP, Brazil
• Associated researchers: Ariadne Letra ; Ricardo Della Coletta

Abstract

Nonsyndromic cleft lip and palate (NSCLP) is a congenital craniofacial anomaly affecting the oral cavity and more than 130,000 babies worldwide yearly. The global rehabilitation protocol requires a series of procedures involving numerous areas, generating social, emotional and financial burdens, impacting the quality of life of individuals and their families and the public health system. Clinically, among the numerous phenotypes that have been associated with NSCLP, dental agenesis stands out. When present together, these two phenotypes, NSCLP and dental agenesis, characterize a condition of multiple anomalies, and both have a complex multifactorial aetiology in which genetic, environmental and epigenetic factors interact with their occurrence. The epidemiological data on prevalence and the close embryological relationship between NSCL and dental agenesis support the hypothesis that these phenotypes in association may share a similar genetic background. To date, no study has analyzed this association of phenotypes (NSCLP dental agenesis) as a specific condition through Whole Genome Sequencing (WGS). Thus, there is a gap in understanding the genetic aetiology of this association of phenotypes, which is very prevalent in clinical practice and impacts the complexity of the oral rehabilitation process. In this context, WGS has been effective in discovering new genes related to the genetic architecture of complex conditions, making it possible to broaden the understanding of possible genetic susceptibility factors. Thus, the main objective of this project is to unravel the genetic architecture of NSCLP in association with dental agenesis, investigating and identifying genetic variants involved in the aetiology of this specific condition through WGS. For this, a study design based on families, with and without recurrence, in a Brazilian population will be used. After WGS, the data will be processed and aligned to the reference genome, followed by identifying and annotating genetic variants. Then, using numerous bioinformatics tools, the functional interpretation of the variants will be performed to relate these variants to the phenotypes and their potential clinical implications. This study aims to make an important contribution to the field, as it will allow us to identify markers of genetic predisposition to risk, also enabling new insights to understand the molecular pathways and the specific signalling cascade in the occurrence of both phenotypes. Moreover, from the results, we seek to establish a polygenic risk score that can be included in the analysis and risk management, supporting more accurate genetic counselling. In addition, the results may also guide new preventive strategies within the scope of public policies, aiming to reduce the clinical impact of these conditions. (AU)