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Etiology of the nonsyndromic oral clefts

Renato Assis Machado, PhD

The nonsyndromic oral cleft (NSOC) is the most common orofacial birth defect with a prevalence of 1:500-2,500 live births. NSOC has complex etiology, which is related to environmental and genetic risk factors.

In recent years there has been an evolution in the understanding of causal factors, with the identification of new genetic variants, environmental risk factors and how environmental factors interact with genetics. This knowledge should eventually result in better prevention, treatment and prognosis for the affected individuals [5,16,10]. 

Studies with differentiated approaches have been carried out with the aim of identifying the genes involved with the NSOC etiology. Part of the candidate genes was suggested through studies with experimental models in:

  • Knockout mice [9];
  • Cytogenetics [4,8];
  • Studies of oral cleft associated with Mendelian syndromes [11,23];
  • Analysis of gene expression in embryonic tissues [6,19].

The most recent approaches are based on genome-wide association studies (GWAS), in which polymorphisms distributed by the genome are analyzed simultaneously in patients affected or not by NSOC. Six GWAS [1,3,7,12,15,21] and 1 meta-analysis of 2 of these GWAS [14] were performed with NSOC samples, identifying 15 genetic risk regions. 

In 2017, a new GWAS with a large Chinese population and a validation group with samples from patients from European populations was published, revealing 14 new loci and confirming another 12 [22]. In addition, 3 loci were identified in studies validating the results of GWAS [2,13] and in association with studies of linkage and analysis of candidate genes, which confirmed the participation of IRF6 (Interferon Regulatory Factor 6) [20,23] and the 9q22 locus that contains the FOXE1 gene (forkhead box E1) [17,18].  Thus, 34 loci are currently associated with NSOC, however, differences in ancestry determine the genetic predisposition, where regions that are strongly associated with one population may not be with others. 

An example of this is noted in the last two GWAS that identified the 17q23 region in individuals of European descent [12] or with the new regions identified in the Chinese population (4q28.1, 5p12, 9q22.32, 12q21. 1 and 14q32.13) and European (4p16.2, 8p11.23, 12q13.13, 12q13.2 and 17q21.32) [22]. Thus, as the Brazilian population, for example, is highly miscegenated, based mainly in European, African and Amerindian ancestry, other regions/genes may be associated with NSOC etiology and validation studies need to be carried out in more populations.

About the author: Renato Assis Machado has a degree in Dentistry, a master’s and a doctorate in Stomatopathology (FOP/Unicamp). He currently works as a Postdoctoral Researcher at the Hospital for Rehabilitation of Craniofacial Anomalies at USP and as a collaborator in the Department of Oral Diagnosis (FOP/UNICAMP).

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