Orofacial Cleft and Mandibular Prognathism-Human Genetics and Animal Models.
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ABSTRACT:
SUBMITTER: Jaruga A
PROVIDER: S-EPMC8779325 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Mandibular prognathism is assumed to be a polygenic trait in the vast majority of cases. In a few families, this phenotype and perhaps a syndrome with a broader spectrum of facial anomalies seems to be determined by a single dominant gene of very low frequency (McKusick No *176700). The phenotype is known to have occurred independently in several European noble families. We constructed a pedigree comprising 13 of these families with 409 members in 23 generations in which mandibular prognathism has been segregating. Obviously, the presumed dominant gene is not fully penetrant in the heterozygous state. Pedigree analysis using the Elston-Stewart algorithm yields a maximum likelihood estimate (MLE) of p = 0.955 (SE 0.038) of the penetrance parameter.
| S-EPMC1016265 | biostudies-literature
Project description:Orofacial clefting is considered one of the commonest birth defects worldwide. It presents as cleft lip only, isolated cleft palate or cleft lip and palate. The condition has a diverse genetic background influenced by gene-gene and gene-environment interaction, resulting in two main types, syndromic and nonsyndromic orofacial clefts. Orofacial clefts lead to significant physiological difficulties that affect feeding, speech and language development and other developmental aspects, which results in an increased social and financial burden on the affected individuals and their families. The management of cleft lip and palate is solely based on following a multidisciplinary team approach. In this narrative review article, we briefly summarize the different genetic causes of orofacial clefts and discuss some of the common syndromes and the approach to the management of orofacial clefts.
| S-EPMC10454293 | biostudies-literature
Project description:Cleft lip or palate (CL/P) is a common facial defect present in 1?:?700 live births and results in substantial burden to patients. There are more than 500 CL/P syndromes described, the causes of which may be single-gene mutations, chromosomopathies, and exposure to teratogens. Part of the most prevalent syndromic CL/P has known etiology. Nonsyndromic CL/P, on the other hand, is a complex disorder, whose etiology is still poorly understood. Recent genome-wide association studies have contributed to the elucidation of the genetic causes, by raising reproducible susceptibility genetic variants; their etiopathogenic roles, however, are difficult to predict, as in the case of the chromosomal region 8q24, the most corroborated locus predisposing to nonsyndromic CL/P. Knowing the genetic causes of CL/P will directly impact the genetic counseling, by estimating precise recurrence risks, and the patient management, since the patient, followup may be partially influenced by their genetic background. This paper focuses on the genetic causes of important syndromic CL/P forms (van der Woude syndrome, 22q11 deletion syndrome, and Robin sequence-associated syndromes) and depicts the recent findings in nonsyndromic CL/P research, addressing issues in the conduct of the geneticist.
| S-EPMC3503281 | biostudies-literature
Project description:ObjectiveThe current study aimed to identify and analyze missense single nucleotide polymorphisms (SNPs) that can potentially cause mandibular prognathism.MethodsAfter reviewing the articles, 56 genes associated with mandibular prognathism were identified and their missense SNPs were retrieved from the NCBI website. Several web-based tools including CADD, PolyPhen-2, PROVEAN, SNAP2, PANTHER, FATHMM, and PON-P2 were used to filter out harmful SNPs. Additionally, ConSurf determined the level of evolutionary conservation at positions where SNPs occur. I-Mutant2 and MUpro predicted the effect of SNPs on protein stability. Furthermore, to investigate the structural and functional changes of proteins, HOPE and LOMETS tools were utilized.ResultsBased on predictions in at least four web-based tools, the results indicated that PLXNA2-rs4844658, DUSP6-rs2279574, and FBN3-rs33967815 are harmful. These SNPs are located at positions with variable or average conservation and have the potential to reduce the stability of their respective proteins. Moreover, they may impair protein activity by causing structural and functional changes.ConclusionsIn this study, we identified PLXNA2-rs4844658, DUSP6-rs2279574, and FBN3-rs33967815 as potential risk factors for mandibular prognathism using several web-based tools. According to the possible roles of PLXNA2, DUSP6, and FBN3 proteins in ossification pathways, we recommend that these SNPs be investigated further in experimental research. Through such studies, we hope to gain a better understanding of the molecular mechanisms involved in mandible formation.
| S-EPMC10203774 | biostudies-literature
Project description:IntroductionSeveral candidate loci have been suggested as influencing mandibular prognathism (1p22.1, 1p22.2, 1p36, 3q26.2, 5p13-p12, 6q25, 11q22.2-q22.3, 12q23, 12q13.13, and 19p13.2). The goal of this study was to replicate these results in a well-characterized homogeneous sample set.MethodsThirty-three single nucleotide polymorphisms spanning all candidate regions were studied in 44 prognathic and 35 Class I subjects from the University of Pittsburgh School of Dental Medicine Dental Registry and DNA Repository. The 44 subjects with mandibular prognathism had an average age of 18.4 years; 31 were female and 13 male; and 24 were white, 15 African American, 2 Hispanic, and 3 Asian. The 36 Class I subjects had an average age of 17.6 years; 27 were female and 9 male; and 27 were white, 6 African American, 1 Hispanic, and 2 Asian. Skeletal mandibular prognathism diagnosis included cephalometric values indicative of Class III such as an ANB smaller than 2°, a negative Wits appraisal, and a positive A-B plane. Additional mandibular prognathism criteria included negative overjet and visually prognathic (concave) profile as determined by the subject's clinical evaluation. Orthognathic subjects without jaw deformations were used as the comparison group. The mandibular prognathic and orthognathic subjects were matched by race, sex, and age. Genetic markers were tested by polymerase chain reaction with TaqMan chemistry. Chi-square and Fisher exact tests were used to determine overrepresentation of marker allele with an alpha of 0.05.ResultsAn association was unveiled between a marker in MYO1H (rs10850110) and the mandibular prognathism phenotype (P = 0.03). MYO1H is a Class I myosin that is in a different protein group than the myosin isoforms of muscle sarcomeres, which are the basis of skeletal muscle fiber typing. Class I myosins are necessary for cell motility, phagocytosis, and vesicle transport.ConclusionsMore strict clinical definitions might increase homogeneity and aid the studies of genetic susceptibility to malocclusions. We provide evidence that MYO1H can contribute to mandibular prognathism.
| S-EPMC3600843 | biostudies-literature
Project description:Mandibular prognathism (MP) is a severe maxillofacial disorder with undetermined genetic background. We collected a Chinese pedigree with MP which involved in 23 living members of 4 generations. Genome-wide linkage analysis were carried out to obtain the information in this family and a new MP-susceptibility locus, 12pter-p12.3 was identified. Whole-exome sequencing identified a novel heterozygous mutation in fibroblast growth factor (FGF) 23 (; p.A12D) which well segregated with MP in this pedigree within the locus. The mutation was also detected in 3 cases out of 65 sporadic MP patients, but not in any of the 342 control subjects. The p.A12D mutation may disrupt signal peptide function and inhibit secretory in FGF23. Furthermore, mutant FGF23 was overexpressed in 293T cells, increased cytoplasmic accumulation was observed compared with the wild type. We have discovered that c.35C>A mutation in FGF23 strongly associated with MP, which expand our understanding of the genetic contribution to MP pathogenesis.
| S-EPMC4462018 | biostudies-literature
Project description:The isolated type of orofacial cleft, termed non-syndromic cleft lip with or without cleft palate (NSCL/P), is the second most common birth defect in China, with Asians having the highest incidence in the world. NSCL/P involves multiple genes and complex interactions between genetic and environmental factors, imposing difficulty for the genetic assessment of the unborn fetus carrying multiple NSCL/P-susceptible variants. Although genome-wide association studies (GWAS) have uncovered dozens of single nucleotide polymorphism (SNP) loci in different ethnic populations, the genetic diagnostic effectiveness of these SNPs requires further experimental validation in Chinese populations before a diagnostic panel or a predictive model covering multiple SNPs can be built. In this study, we collected blood samples from control and NSCL/P infants in Han and Uyghur Chinese populations to validate the diagnostic effectiveness of 43 candidate SNPs previously detected using GWAS. We then built predictive models with the validated SNPs using different machine learning algorithms and evaluated their prediction performance. Our results showed that logistic regression had the best performance for risk assessment according to the area under curve. Notably, defective variants in MTHFR and RBP4, two genes involved in folic acid and vitamin A biosynthesis, were found to have high contributions to NSCL/P incidence based on feature importance evaluation with logistic regression. This is consistent with the notion that folic acid and vitamin A are both essential nutritional supplements for pregnant women to reduce the risk of conceiving an NSCL/P baby. Moreover, we observed a lower predictive power in Uyghur than in Han cases, likely due to differences in genetic background between these two ethnic populations. Thus, our study highlights the urgency to generate the HapMap for Uyghur population and perform resequencing-based screening of Uyghur-specific NSCL/P markers.
| S-EPMC6364041 | biostudies-literature
Project description:BackgroundIt is well known that genetic components play an important role in the etiology of mandibular prognathism, but few susceptibility loci have been mapped.MethodologyIn order to identify linkage regions for mandibular prognathism, we analyzed two Chinese pedigrees with 6,090 genome-wide single-nucleotide polymorphism (SNP) markers from Illumina Linkage-12 DNA Analysis Kit (average spacing 0.58 cM). Multipoint parametric and non-parametric (model-free) linkage analyses were used for the pedigrees.Principal findingThe most statistically significant linkage results were with markers on chromosome 4 (LOD=3.166 and NPL=3.65 with rs 875864, 4p16.1, 8.38 cM). Candidate genes within the 4p16.1 include EVC, EVC2.ConclusionWe detected a novel suggestive linkage locus for mandibular prognathism in two Chinese pedigrees, and this linkage region provides target for susceptibility gene identification, a process that will provide important insights into the molecular and cellular basis of mandibular prognathism.
| S-EPMC2937026 | biostudies-literature
Project description:Genome-wide association studies (GWASs) are the most widely used method to identify genetic risk loci associated with orofacial clefts (OFC). However, despite the increasing size of cohort, GWASs are still insufficient to detect all the heritability, suggesting there are more associations under the current stringent statistical threshold. In this study, we obtained an integrated epigenomic dataset based on the chromatin conformation of a human oral epithelial cell line (HIOEC) using RNA-seq, ATAC-seq, H3K27ac ChIP-seq, and DLO Hi-C. Presumably, this epigenomic dataset could reveal the missing functional variants located in the oral epithelial cell active enhancers/promoters along with their risk target genes, despite relatively less-stringent statistical association with OFC. Taken a non-syndromic cleft palate only (NSCPO) GWAS data of the Chinese Han population as an example, 3664 SNPs that cannot reach the strict significance threshold were subjected to this functional identification pipeline. In total, 254 potential risk SNPs residing in active cis-regulatory elements interacting with 1 718 promoters of oral epithelium-expressed genes were screened. Gapped k-mer machine learning based on enhancers interacting with epithelium-expressed genes along with in vivo and in vitro reporter assays were employed as functional validation. Among all the potential SNPs, we chose and confirmed that the risk alleles of rs560789 and rs174570 reduced the epithelial-specific enhancer activity by preventing the binding of transcription factors related to epithelial development. In summary, we established chromatin conformation datasets of human oral epithelial cells and provided a framework for testing and understanding how regulatory variants impart risk for clefts.
| S-EPMC9411193 | biostudies-literature
Project description:With an average worldwide prevalence of approximately 1.2/1000 live births, orofacial clefts are the most common craniofacial birth defects in humans. Like other complex disorders, these birth defects are thought to result from the complex interplay of multiple genes and environmental factors. Significant progress in the identification of underlying genes and pathways has benefited from large populations available for study, increased international collaboration, rapid advances in genotyping technology, and major improvements in analytic approaches. Here we review recent advances in genetic epidemiological approaches to complex traits and their applications to studies of nonsyndromic orofacial clefts. Our main aim is to bring together a discussion of new and previously identified candidate genes to create a more cohesive picture of interacting pathways that shape the human craniofacial region. In future directions, we highlight the need to search for copy number variants that affect gene dosage and rare variants that are possibly associated with a higher disease penetrance. In addition, sequencing of protein-coding regions in candidate genes and screening for genetic variation in noncoding regulatory elements will help advance this important area of research.
| S-EPMC3437188 | biostudies-literature