RESUMEN
Nonsyndromic orofacial cleft (NSOFC) is a severe birth defect that occurs early in embryonic development and includes the subtypes cleft palate only (CPO), cleft lip only (CLO) and cleft lip with cleft palate (CLP). Given a lack of specific genetic factor analysis for CPO and CLO, the present study aimed to dissect the landscape of genetic factors underlying the pathogenesis of these two subtypes using 6,986 cases and 10,165 controls. By combining a genome-wide association study (GWAS) for specific subtypes of CPO and CLO, as well as functional gene network and ontology pathway analysis, we identified 18 genes/loci that surpassed genome-wide significance (P < 5 × 10-8) responsible for NSOFC, including nine for CPO, seven for CLO, two for both conditions and four that contribute to the CLP subtype. Among these 18 genes/loci, 14 are novel and identified in this study and 12 contain developmental transcription factors (TFs), suggesting that TFs are the key factors for the pathogenesis of NSOFC subtypes. Interestingly, we observed an opposite effect of the genetic variants in the IRF6 gene for CPO and CLO. Moreover, the gene expression dosage effect of IRF6 with two different alleles at the same single-nucleotide polymorphism (SNP) plays important roles in driving CPO or CLO. In addition, PAX9 is a key TF for CPO. Our findings define subtypes of NSOFC using genetic factors and their functional ontologies and provide a clue to improve their diagnosis and treatment in the future.
Asunto(s)
Encéfalo/anomalías , Labio Leporino/genética , Fisura del Paladar/genética , Factores Reguladores del Interferón/genética , Factor de Transcripción PAX9/genética , Alelos , Encéfalo/fisiopatología , Labio Leporino/fisiopatología , Fisura del Paladar/fisiopatología , Dosificación de Gen/genética , Regulación de la Expresión Génica/genética , Redes Reguladoras de Genes/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
In esthetic rehabilitation, methods used to enhance the margin quality have always been the focus and difficulty of improving the level of diagnosis and treatment, prevention and treatment of complications, and collaboration between clinicians and technicians. However, it is impeded by the ambiguous definition and classification of margin, unstandardized tooth preparation, manufacturing process of restoration, and lack of reliable means of checking the quantitative requirements of preparation or restoration. The digital technologies that are increasingly applied, such as intra-oral scanner, impression scanner, and computerized numerical control cutting machine, have strict requirements about margin quality. Failure of recognizing margins by these scanners will hinder the digital process of diagnosis and treatment. Even if these sharp and narrow margins are successfully scanned, they cannot be milled accurately. To overcome these problems, this article demonstrated the clear and complete definition of preparation margin and restoration margin, as well as their subclassifications, by analyzing the target restoration space from a geometric perspective. Practical approaches to measuring the margin width and inspecting the margin quality were proposed. The new and full understanding and proposal about preparation margin and restoration margin characterized by measurements will effectively support the thoroughly digitalized process of esthetic rehabilitation using porcelain in fixed prosthodontics, which is based on the guidance of values.