Cellular and developmental basis of orofacial clefts.
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ABSTRACT:
SUBMITTER: Ji Y
PROVIDER: S-EPMC7901717 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Zebrafish is a model organism that affords experimental advantages toward investigating the normal function of genes associated with congenital birth defects. Here we summarize zebrafish studies of genes implicated in orofacial cleft (OFC). The most common use of zebrafish in this context has been to explore the normal function an OFC-associated gene product in craniofacial morphogenesis by inhibiting expression of its zebrafish ortholog. The most frequently deployed method has been to inject embryos with antisense morpholino oligonucleotides targeting the desired transcript. However, improvements in targeted mutagenesis strategies have led to widespread adoption of CRISPR/Cas9 technology. A second application of zebrafish has been for functional assays of gene variants found in OFC patients; such in vivo assays are valuable because the success of in silico methods for testing allele severity has been mixed. Finally, zebrafish have been used to test the tissue specificity of enhancers that harbor single nucleotide polymorphisms associated with risk for OFC. We review examples of each of these approaches in the context of genes that are implicated in syndromic and non-syndromic OFC. Developmental Dynamics 246:897-914, 2017. © 2017 Wiley Periodicals, Inc.
| S-EPMC5777297 | 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
Project description:Orofacial clefts (OFCs) are the most common congenital birth defects in humans and immediately recognized at birth. The etiology remains complex and poorly understood and seems to result from multiple genetic and environmental factors along with gene-environment interactions. It can be classified into syndromic (30%) and nonsyndromic (70%) clefts. Nonsyndromic OFCs include clefts without any additional physical or cognitive deficits. Recently, various genetic approaches, such as genome-wide association studies (GWAS), candidate gene association studies, and linkage analysis, have identified multiple genes involved in the etiology of OFCs. This article provides an insight into the multiple genes involved in the etiology of OFCs. Identification of specific genetic causes of clefts helps in a better understanding of the molecular pathogenesis of OFC. In the near future, it helps to provide a more accurate diagnosis, genetic counseling, personalized medicine for better clinical care, and prevention of OFCs.
| S-EPMC7938794 | biostudies-literature
Project description:Orofacial clefts (OFC) are complex birth defects. Studies using contemporary genomic techniques, bioinformatics, and statistical analyses have led to appreciable advances in identifying the causes of syndromic forms of clefts. This commentary gives an overview of the important cleft gene discoveries found using various genomic methods and tools.
| S-EPMC5241211 | biostudies-literature
Project description:Cleft lip (CL), cleft palate (CP) and cleft lip and palate (CLP) are the most common types of orofacial clefts in dogs. Orofacial clefts in dogs are clinically relevant because of the associated morbidity and high newborn mortality rate and are of interest as comparative models of disease. However, the incidence of CL, CP and CLP has not been investigated in purebred dogs, and the financial impact on breeders is unknown. The aims of this study were to document the incidence patterns of CL, CP and CLP in different breeds of dogs, determine whether defect phenotype is associated with skull type, genetic cluster and geographic location, and estimate the financial impact in breeding programs in the United States by means of an anonymous online survey. A total of 228 orofacial clefts were reported among 7,429 puppies whelped in the 12 preceding months. Breeds in the mastiff/terrier genetic cluster and brachycephalic breeds were predisposed to orofacial clefts. Certain breeds in the ancient genetic cluster were at increased odds of orofacial clefts. Male purebred dogs were at increased odds of CPs. Results confirm that brachycephalic breeds are overrepresented among cases of orofacial clefts. Furthermore, geographic region appeared to be a relevant risk factor and orofacial clefts represented a considerable financial loss to breeders. Improved understanding of the epidemiology of orofacial clefts (frequency, causes, predictors and risk factors) may help in identifying ways to minimize their occurrence. Information gained may potentially help veterinarians and researchers to diagnose, treat and prevent orofacial clefts.
| S-EPMC6827884 | 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:ObjectivesTo perform a case-control study of maternal occupational physical activity and risk for orofacial clefts in Texas during 1999-2009.MethodsWe used logistic regression to assess 14 measures of physical activity estimated from a job exposure matrix, using the maternal occupation reported on the birth certificate, among 887 children with cleft lip with or without cleft palate (CLP), 436 children with cleft palate only (CP), and 1932 controls.ResultsAfter adjusting for several potential confounders, seven measures of physical activity (as a categorical and/or continuous variable) were significantly associated with CLP, CP, or both. Positive associations were seen for keeping balance, kneeling, standing, and walking/running (odds ratio 95% confidence interval range 1.0-1.9 for fourth versus first quartile). A significant positive trend was also seen for bending/twisting. Negative associations were seen for repetitive motion and sitting.ConclusionsMaternal occupational physical activity may be related to the etiology of orofacial clefts.
| S-EPMC8924980 | biostudies-literature
Project description:Objective: This retrospective study aims to evaluate the utility of exome sequencing (ES) in identifying genetic causes of congenital orofacial clefts (OFCs) in fetuses with or without other structural abnormalities, and to further explore congenital OFCs genetic causes. Methods: The study enrolled 107 singleton pregnancies diagnosed with fetal OFCs between January 2016 and May 2022, and categorized them into two groups: isolated cleft lip and/or palate (CL/CP) and syndromic CL/CP. Cases with positive karyotyping and chromosomal microarray analysis results were excluded. Whole-exome sequencing was performed on eligible fetuses and their parents. Monogenic variants identified by ES and perinatal outcomes were recorded and evaluated during postnatal follow-up. Results: Clinically significant variants were identified in 11.2% (12/107) of fetuses, with no significant difference in detection rate between the isolated CL/CP group and the syndromic CL/CP group (8/83, 9.6% vs. 4/24, 16.7%, p = 0.553). Additionally, sixteen (16/107, 15.0%) fetuses had variants of uncertain significance. We identified 12 clinically significant variations that correlated with clinical phenotypes in 11 genes from 12 fetuses, with CHD7 being the most frequently implicated gene (n = 2). Furthermore, we observed a significant difference in termination rates and survival rates between the isolated CL/CP and syndromic CL/CP groups (41.0% vs. 70.8% and 56.6% vs. 20.8%, p < 0.05 for both). Conclusion: Based on our findings, it is clear that ES provides a significant increase in diagnostic yield for the molecular diagnosis of congenital OFCs, thereby substantially improving the existing prenatal diagnostic capabilities. This study also sheds light on seven novel pathogenic variants, broadening our understanding of the genetic underpinnings of OFCs and expanding the disease spectrums of relevant genes.
| S-EPMC10512413 | biostudies-literature
Project description:BACKGROUND: The association between the risk of orofacial clefts in infants and the use of corticosteroids during pregnancy is unclear from the available evidence. We conducted a nationwide cohort study of all live births in Denmark over a 12-year period. METHODS: We collected data on all live births in Denmark from Jan. 1, 1996, to Sept. 30, 2008. We included live births for which information was available from nationwide health registries on the use of corticosteroids during pregnancy, the diagnosis of an orofacial cleft and possible confounders. RESULTS: There were 832,636 live births during the study period. Exposure to corticosteroids during the first trimester occurred in 51,973 of the pregnancies. A total of 1232 isolated orofacial clefts (i.e., cleft lip, cleft palate, or cleft lip and cleft palate) were diagnosed within the first year of life, including 84 instances in which the infant had been exposed to corticosteroids during the first trimester of pregnancy. We did not identify any statistically significant increased risk of orofacial clefts associated with the use of corticosteroids: cleft lip with or without cleft palate, prevalence odds ratio (OR) 1.05 (95% confidence interval [CI] 0.80-1.38]; cleft palate alone, prevalence OR 1.23 (95% CI 0.83-1.82). Odds ratios for risk of orofacial clefts by method of delivery (i.e., oral, inhalant, nasal spray, or dermatologic and other topicals) were consistent with the overall results of the study and did not display significant heterogeneity, although the OR for cleft lip with or without cleft palate associated with the use of dermatologic corticosteroids was 1.45 (95% CI 1.03-2.05). INTERPRETATION: Our results add to the safety information on a class of drugs commonly used during pregnancy. Our study did not show an increased risk of orofacial clefts with the use of corticosteroids during pregnancy. Indepth investigation of the pattern of association between orofacial clefts and the use of dermatologic corticosteroids during pregnancy indicated that this result did not signify a causal connection and likely arose from multiple statistical comparisons.
| S-EPMC3080529 | biostudies-other
Project description:ObjectivesTo conduct a systematic review and meta-analysis to assess whether individuals with nonsyndromic orofacial clefts (OCs) display a higher frequency of dental anomalies (DAs) when compared with individuals without OCs.MethodsA literature search of indexed databases (PubMed, Cochrane, Web of Science, Embase, Scopus, and LILACS) was conducted without language restriction up to and including February 1, 2020. Cross-referencing was used to further identify articles. Several cleft teams across the United States and Europe were contacted to obtain unpublished data. The eligibility criteria were observational studies with original data that statistically compared individuals with OC without syndromes and those without OC on any type of DA in primary and/or permanent dentition. Random effects meta-analysis through the Mantel-Haenszel estimator was used to evaluate the association between OC and DA based on odds ratios (ORs) with 95% confidence intervals (CIs).ResultsThe literature search generated 933 records, and 75 full-text articles were reviewed. Twenty-six studies encompassing 15,213 individuals met the inclusion criteria. The meta-analysis revealed statistically significant associations between OC and agenesis (OR, 14.2; 95% CI, 9.4 to 21.3), supernumerary teeth (OR, 5.7; 95% CI, 3.3 to 9.7), developmental enamel defects (OR, 5.6; 95% CI, 3.5 to 9.0), microdontia (OR, 14.8; 95% CI, 4.0 to 54.6), peg-shaped anterior teeth (OR, 12.2; 95% CI, 3.6 to 41.2), taurodontism (OR, 1.7; 95% CI, 1.0 to 2.7), tooth malposition and/or transposition (OR, 5.6; 95% CI, 2.8 to 11.5), tooth rotation (OR, 3.2; 95% CI, 1.3 to 8.2), and tooth impaction (OR, 3.6; 95% CI, 1.1 to 12.2). The OR estimates of the reviewed studies exhibited significant heterogeneity (P < 0.0001). No association was observed between OC and fusion and/or gemination.ConclusionWithin the limitations of this study, the available evidence suggests that individuals with OCs are more likely to present with a range of DAs than their unaffected peers.Knowledge transfer statementThe findings of the current review suggest that individuals with orofacial clefts (OCs) are more likely to present with a range of dental anomalies than their unaffected peers. Understanding the association between OCs and dental anomalies is essential in guiding clinicians during treatment-planning procedures and is important in raising our awareness of the possible need for future dental treatment for patients with OCs.
| S-EPMC8447105 | biostudies-literature