Search

Background: The epidemiology of cleft lip (CL) and cleft palate (CLP) has not previously been described in the context of the Bhutan and Bhutanese populations. Using National Birth Defects Surveillance Data and other vital statistics, we present the comprehensive epidemiology of the cleft lip and palate in Bhutan. Methodology: The National Birth Defects Surveillance Data Registry from 2015 to 2022 is reviewed retrospectively, covering 8 years of birth defect surveillance in the country from records maintained with three referral hospitals in the country. The baseline prevalence and incidence of cleft lip and palate have been presented over the years. The incidence of cleft lip and palate was defined as the number of cases per 1000 live births. We used Poisson's regression to compute the incidence of cleft lip and palate. Pearson chi-square tests (χ2) were used to examine the associations of maternal and child characteristics with cleft lip and palate. Results: A total of 1401 newborns with various birth defects were born among the 89,078 live births from 2015 to 2022 in Bhutan. Of these, 122 (8.7%) constituted orofacial clefts. The prevalence of orofacial clefts tended to increase, with a period prevalence of 1.37 per 1000 live births. There were more cases in males (72) than in females (50). The incidence rate ratio ranged from 1.2 to 2.0 compared with the 2015 baseline year, indicating increased rates over time. Conclusion: Orofacial clefts constituted 8.7% of total birth defects and 1.37 per 1000 live births over the years. The increasing prevalence trends and incidence rate ratios over the years underscore the importance of ongoing surveillance and interventions to address the burden of orofacial clefts in Bhutan. Clinical trial number: Not applicable. [ABSTRACT FROM AUTHOR]

Background: Little is known about factors associated with the severity of cleft lip with or without cleft palate (CL/P) especially during the COVID-19 pandemic with its dramatic changes. Objectives: The aim of this multi-national study is to measure the association between CL/P severity, COVID-19 infection, and fear of COVID-19 in five Arab countries. Methods: This cross-sectional study took place in major governmental hospitals in five Arab countries from November 2020 to April 2023. Participants were infants born with CL/P and their mothers who were in their 1st trimester during the COVID-19 pandemic. Clinical examination was carried out, and CL/P cases were grouped according to phenotype: cleft lip and palate (CLP) versus cleft lip (CL), cleft extension (incomplete versus complete), and site (unilateral versus bilateral) to assess severity. Information on maternal COVID-19 infection and fear of COVID-19 were gathered. Results: The study recruited 273 CL/P infants. Maternal COVID-19 infection during one-month pre-gestation and 1st trimester was significantly associated with higher odds of CL/P severity (AOR = 2.707; P = 0.002) than mothers without the COVID-19 infection. Using supplements during pregnancy showed a protective effect (AOR = 0.573; P = 0.065). Conclusion: Mothers infected with COVID-19 before and during pregnancy had more than twofold higher odds of having an infant with a more severe CL/P phenotype. [ABSTRACT FROM AUTHOR]

Background: Uninterrupted folate metabolism plays a vital role in embryonic development, ensuring a supply of one‐carbon‐activated folate cofactors for essential processes. Folate deficiency has been implicated in the development of orofacial clefts (OFC) and congenital heart disease (CHD). Although both malformations have been extensively studied in lieu of folate deficiency, the results of corresponding studies are ambiguous due to the interplay of maternal and fetal genomes controlling folate metabolism in the developing fetus. Methods: We used the innovative study design to compare affected and unaffected siblings from the same mother, thus minimizing the effect of the maternal genome. Thus, it might be possible to identify genetic markers of congenital malformations that pertain exclusively to the child. This study compared demographic and environmental factors between OFC or CHD‐affected and unaffected pregnancies as well as the presence of polymorphisms in genes of folate metabolism between OFC or CHD‐affected and unaffected siblings. Results: Only the maternal fever in the first trimester was a risk factor for OFC, whereas the maternal advanced age, medication administration, and common polymorphism in the FPGS gene increased the risk of CHD formation. Both OFC and CHD formation were associated with a higher number of variant loci in genes of folate–methionine cycles. Conclusions: Both OFC and CHD formation were associated with a higher number of mutated loci in genes of folate–methionine cycles, indicating polygenic and possibly multifactorial inheritance. [ABSTRACT FROM AUTHOR]

ABSTRACT: Objectives: Metabolic syndrome (MetS) has been suggested to play a role in congenital defects. This study investigated the association of MetS and its components with orofacial clefts (OFCs). Methods: We conducted a case-control study in Northeast Thailand. Ninety-four cases with cleft lip, with or without cleft palate, were frequency matched with 94 controls on the infant's age and mother's education. We administered a mother's health questionnaire and collected anthropometric measurements and blood samples. Multiple logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Subgroup analyses were performed among infants without a family history of OFCs, mothers who were not currently breastfeeding, and mothers who were >6 months postpartum. Results: When compared to mothers of normal weight, the OR associated with OFCs were 2.44 (95% CI, 1.04-5.76, P = .04) in overweight mothers, and 3.30 (95% CI, 1.14-9.57, P = .03) in obese mothers. Low HDL-C raised the risk of OFCs 2.95 times (95% CI, 1.41-6.14, P = .004) compared to normal HDL-C levels. Mothers with 4 or 5 features of MetS were 2.77 times as likely to have the affected child than those who did not (95% CI, 0.43-17.76), but this difference was not statistically significant (P = .28). Subgroup analyses showed similar results, uncovering an additional significant association between underweight mothers and OFCs. Conclusions: The results indicate a robust association between underweight and overweight/obese maternal body mass index and increased OFC risk. Additionally, low HDL-C in mothers is linked to an elevated risk of OFCs. Further research is needed to evaluate if promoting strategies to maintain optimal body weight and enhance HDL-C levels in reproductive-age and pregnant women icould contribute to a reduction of the risk of OFCs in their progeny.

Abstract Background The epidemiology of cleft lip (CL) and cleft palate (CLP) has not previously been described in the context of the Bhutan and Bhutanese populations. Using National Birth Defects Surveillance Data and other vital statistics, we present the comprehensive epidemiology of the cleft lip and palate in Bhutan. Methodology The National Birth Defects Surveillance Data Registry from 2015 to 2022 is reviewed retrospectively, covering 8 years of birth defect surveillance in the country from records maintained with three referral hospitals in the country. The baseline prevalence and incidence of cleft lip and palate have been presented over the years. The incidence of cleft lip and palate was defined as the number of cases per 1000 live births. We used Poisson’s regression to compute the incidence of cleft lip and palate. Pearson chi-square tests (χ2) were used to examine the associations of maternal and child characteristics with cleft lip and palate. Results A total of 1401 newborns with various birth defects were born among the 89,078 live births from 2015 to 2022 in Bhutan. Of these, 122 (8.7%) constituted orofacial clefts. The prevalence of orofacial clefts tended to increase, with a period prevalence of 1.37 per 1000 live births. There were more cases in males (72) than in females (50). The incidence rate ratio ranged from 1.2 to 2.0 compared with the 2015 baseline year, indicating increased rates over time. Conclusion Orofacial clefts constituted 8.7% of total birth defects and 1.37 per 1000 live births over the years. The increasing prevalence trends and incidence rate ratios over the years underscore the importance of ongoing surveillance and interventions to address the burden of orofacial clefts in Bhutan. Clinical trial number Not applicable.

Orofacial clefts are one of the most common congenital defects that have a worldwide prevalence of 1 in 700 live births. Paul Tessier a French surgeon in 1976 classified this wide range of abnormalities into a simplified classification known as Tessier’s classification based on anatomical position of the cleft. It is numbered from 0-14 and is further grouped into 4 groups midline clefts, paramedian clefts, orbital clefts, and lateral clefts. Tessier cleft no.7 is an uncommon lateral facial cleft consisting of macrostomia, muscular diastasis of face, abnormalities of the zygoma, retrognathism of the mandible, alveolar clefts, and presence of accessory maxillae. This article aims to provide insights into clinical and radiographic findings as well as early surgical intervention and treatment protocol for this specific group of patients.

Orofacial clefts (OFCs) have been linked to various toxic and essential trace elements (TETEs) worldwide. However, review estimation is absent. Therefore, addressing the hypothesis that TETEs are associated with OFCs is the main area of this review. A systematic literature search was conducted using electronic databases through PubMed, Web of Science, Scopus, Science Direct, and Google Scholar between 2004 and August 2022. The "AND" and "OR" operators were used to make our search results inclusive and restrictive as follows: ("Toxic element*" OR "Heavy metal*") AND ("Toxic element*" OR "Lead OR Arsenic OR Mercury*")) AND ("Essential trace element*" OR "Zinc OR Selenium OR Copper*")) AND ("Orofacial cleft*" OR "Cleft lip*" OR "Cleft palate*") AND ("Infant*" OR "Newborn*" OR "Neonate*")). The presence of toxic elements was linked to the development of OFCs. The results showed that higher levels of toxic elements in various biological sample types were related to increased risks for OFCs. Increased concentrations of essential trace elements (ETEs) lowered the risk of OFCs. Maternal consumption of diets rich in ETEs, including zinc (Zn), selenium (Se), copper (Cu), cobalt (Co), and molybdenum (Mo), was linked to a more pronounced reduction in the risk of OFCs. Based on the findings, it is acceptable to infer that maternal exposure to toxic elements, whether through environmental contaminants or dietary sources, was associated with an elevated risk of OFCs. Furthermore, the study revealed that ETEs exhibited a potential protective role in reducing the incidence of OFCs. This observation highlights the importance of reducing exposure to toxic elements during pregnancy and suggests that optimizing maternal intake of ETEs could be an effective preventive strategy. [ABSTRACT FROM AUTHOR]

Featured Application: Systematic assessment of diagnostic imaging records should be applied to eliminate the risk of overlooking clinically significant incidental findings and facilitate successful interdisciplinary treatment planning (especially in cleft lip and/or palate cases). Incidental findings (IFs) depicted in imaging tests during the diagnostic evaluation of patients with cleft lip and/or palate (CL/P) can guide clinicians during treatment planning procedures for effective, comprehensive cleft care. Evidence regarding IFs in different anatomical regions distant from the dentition is scarce. The aim of this study was to compare the prevalence of IFs in various anatomical areas between patients with non-syndromic CL/P and unaffected subjects. Orthopantomographs (OPTs), lateral cephalometric (LC) radiographs, and cone beam computed tomography (CBCT) scans of 120 subjects (case group: n = 40, 18 females, age 14.5 ± 5.0 years; control group: n = 80, 36 females, age 14.6 ± 4.9 years) were examined, and IFs were assessed by four observers. A significantly higher prevalence of IFs (p < 0.001) was reported in the case group (97.5%) compared with the control group (62.5%). The most prevalent location of IFs in the case group was the maxilla (92.5%), followed by the nasal cavity (75.8%) and the mandible (63.2%), while in the control group, the highest rates of IFs occurred in the maxilla (43.8%), mandible (41.3%), and temporomandibular joint (TMJ) (14.7%). No gender-dependent pattern for IF occurrence was detected overall. Orofacial clefts may affect the mandible. However, the reported IFs were limited compared to those in the maxilla. In conclusion, individuals with CL/P are more likely to present with a range of IFs than their unaffected peers. Understanding the association between CL/P and IFs is critical for successful interdisciplinary treatment, raising awareness of the potential need for future dental care for cleft patients, and managing extra-dental aberrations. A systematic assessment of diagnostic records is required to eliminate the risk of overlooking clinically significant IFs. [ABSTRACT FROM AUTHOR]

Background: Orofacial clefts (OFCs) are among the most common birth defects (BD). In 2008, a series of improvements began in the Costa Rican Birth Defect Register Center (CREC). We aim to explore trends between 1996 and 2021. Methods: A trend analysis of OFCs from 1996 to 2021 and a descriptive analysis of OFCs from 2010 to 2021 were performed based on data from the CREC, the national BD surveillance system. Prevalence at birth was calculated according to the type: cleft palate (CP), cleft lip with or without CP (CL ± P), and presentation (isolated, multiple non‐syndromic, or syndromes). We used joinpoint regression to identify if a significant change in trend occurred; the average annual percent change (AAPC) was determined. Marginal means and prevalence ratios by subperiod (1996–2009 as referent and 2010–2021) were estimated using Poisson regression and compared using Wald's chi‐square tests (α ≤.05). Results: We found a significant AAPC for OFCs prevalence of +1.4: +0.6 for isolated, +2.9 for multiple non‐syndromic, and +7.7 for syndromes (p <.05). When comparing the OFC's prevalence of the subperiod 2010–2021 (11.86 per 10,000) with 1996–2009 (9.36 per 10,000) the prevalence ratio was 1.3 (p <.01): 1.1 (p <.05) for isolated, 1.6 (p <.01) for multiple non‐syndromic, and 3.3 (p <.01) for syndromes. The prevalence of OFCs from 2010 to 2021 was 9.1 for CL ± P and 2.8 for CP. Seventy‐one percent of the OFCs were isolated, 22% multiple non‐syndromic, and 7% syndromes. Conclusion: The trend in OFCs' prevalence is toward increasing, mainly due to improvements in the surveillance system. [ABSTRACT FROM AUTHOR]

Objective Subjects and Methods Results Conclusion This case–control study investigated the associations between maternal plasma vitamin B12, homocysteine, and red blood cell (RBC) folate levels and the risk of cleft lip with or without cleft palate (CL/P) in offspring.The study compared 94 mothers and children with non‐syndromic CL/P from a teaching hospital in Thailand to 94 mother‐infant controls from local well‐baby clinics, frequency‐matched by birth date and mother's education. Data included anthropometric measurements, blood sample analyses, and a questionnaire. Odds ratios (ORs) and 95% confidence intervals (CIs) estimated the associations through multiple logistic regression, adjusting for confounders.Mothers with higher plasma vitamin B12 levels had a lower risk of having a child with CL/P compared to those in the lowest quartile. This association was more pronounced among mothers without a family history of orofacial clefts and those who were not underweight. Conversely, elevated homocysteine levels, a marker of impaired B vitamin metabolism, increased the risk of CL/P. No association was found between RBC folate and CL/P.Higher maternal vitamin B12 levels are associated with a reduced risk of CL/P, while elevated homocysteine levels may increase the risk. [ABSTRACT FROM AUTHOR]

The work presents the connection between the infection of COVID-19 during pregnancy and non-syndromic orofacial clefts (NSOFC). Aim of the study was to compare the incidence of COVID-19 disease during mother´s pregnancy between a group of the children with NSOFC and a control group of the children without NSOFC. COVID-19 was confirmed by polymerase chain reaction (PCR) test. The study showed significantly higher incidence of COVID-19 disease in the group of mothers who gave birth to a child with NSOFC in comparison to the group of mothers who gave birth to a child without NSOFC. Our results indicate the possible participation of the infection of COVID-19 in the formation of NSOFC. [ABSTRACT FROM AUTHOR]

Background/Objectives: Orofacial clefts (OFCs) are some of the most common congenital anomalies worldwide. The aim of this case–control study was to evaluate the association of OFCs with selected maternal characteristics. Methods: Data on isolated non-syndromic cases of OFCs were extracted from the population-based registry of congenital anomalies of Tuscany. A sample of live-born infants without any congenital anomaly was used as the control group. We investigated the association with sex and some maternal characteristics: age, body mass index, smoking, and education. Adjusted odds ratios (OR) were calculated using a logistic regression model. Analyses were performed for the total OFCs and separately for cleft lip (CL) and cleft palate (CP). Results: Data on 219 cases and 37,988 controls were analyzed. A higher proportion of males (57.9%) was observed, particularly for CL. A decreasing trend among the maternal age classes was observed (OR:0.81 (95%CI 0.70–0.94)). Underweight mothers had a higher prevalence of OFCs, in particular for CL (OR:1.88 (95%CI 1.08–3.26)). Conclusions: We found an association of OFCs with lower maternal age. The association with maternal age remains controversial and further epidemiological evidence is needed through multicenter studies. We observed that CL was more common in underweight mothers, suggesting actions of primary prevention. [ABSTRACT FROM AUTHOR]

Abstract Non-syndromic orofacial clefts (NSOFCs) are common birth defects with a complex etiology. While over 60 common risk loci have been identified, they explain only a small proportion of the heritability for NSOFCs. Rare variants have been implicated in the missing heritability. Thus, our study aimed to identify genes enriched with nonsynonymous rare coding variants associated with NSOFCs. Our sample included 814 non-syndromic cleft lip with or without palate (NSCL/P), 205 non-syndromic cleft palate only (NSCPO), and 2150 unrelated control children from Nigeria, Ghana, and Ethiopia. We conducted a gene-based analysis separately for each phenotype using three rare-variants collapsing models: (1) protein-altering (PA), (2) missense variants only (MO); and (3) loss of function variants only (LOFO). Subsequently, we utilized relevant transcriptomics data to evaluate associated gene expression and examined their mutation constraint using the gnomeAD database. In total, 13 genes showed suggestive associations (p = E−04). Among them, eight genes (ABCB1, ALKBH8, CENPF, CSAD, EXPH5, PDZD8, SLC16A9, and TTC28) were consistently expressed in relevant mouse and human craniofacial tissues during the formation of the face, and three genes (ABCB1, TTC28, and PDZD8) showed statistically significant mutation constraint. These findings underscore the role of rare variants in identifying candidate genes for NSOFCs.

Several mutations in the IRF6 gene have been identified as a causative link to VWS. In this investigation, whole-exome sequencing (WES) and Sanger sequencing of a three-generation pedigree with an autosomal-dominant inheritance pattern affected by VWS identified a unique stop-gain mutation-c.748C>T:p.R250X-in the IRF6 gene that co-segregated exclusively with the disease phenotype. Immunofluorescence analysis revealed that the IRF6-p.R250X mutation predominantly shifted its localization from the nucleus to the cytoplasm. WES and protein interaction analyses were conducted to understand this mutation's role in the pathogenesis of VWS. Using LC-MS/MS, we found that this mutation led to a reduction in the binding of IRF6 to histone modification-associated proteins (NAA10, SNRPN, NAP1L1). Furthermore, RNA-seq results show that the mutation resulted in a downregulation of TGFβ2-AS1 expression. The findings highlight the mutation's influence on TGFβ2-AS1 and its subsequent effects on the phosphorylation of SMAD2/3, which are critical in maxillofacial development, particularly the palate. These insights contribute to a deeper understanding of VWS's molecular underpinnings and might inform future therapeutic strategies. [ABSTRACT FROM AUTHOR]

Combining subtypes of orofacial clefts has been fruitful for genetic studies and has identified many risk loci that are shared between phenotypes, but may miss genetic variants that are distinct between subtypes. Cleft palate has long been understood to have different genetic risk loci compared with cleft lip or cleft lip and palate, reflecting differences in palatal development. However, current evidence suggests that there are shared genetic effects and subtype-specific effects, including opposite effects between cleft lip and cleft palate, that are poorly understood and may be underrecognized. Further subdivision of the cleft phenotype by laterality or inclusion of subclinical phenotypes has led to the identification of novel risk loci. Current sample sizes are still small and emphasize the need for deeper phenotyping and considering multiple models of genetic architecture underlying disease risk. Orofacial clefts (OFCs) are common, affecting 1:1000 live births. OFCs occur across a phenotypic spectrum – including cleft lip (CL), cleft lip and palate (CLP), or cleft palate (CP) – and can be further subdivided based on laterality, severity, or specific structures affected. Herein we review what is known about the genetic architecture underlying each of these subtypes, considering both shared and subtype-specific risks. While there are more known genetic similarities between CL and CLP than CP, recent research supports both shared and subtype-specific genetic risk factors within and between phenotypic classifications of OFCs. Larger sample sizes and deeper phenotyping data will be of increasing importance for the discovery of novel genetic risk factors for OFCs and various subtypes going forward. [ABSTRACT FROM AUTHOR]

Summary: Orofacial clefts (OFCs) are among the most common human congenital birth defects. Previous multiethnic studies have identified dozens of associated loci for both cleft lip with or without cleft palate (CL/P) and cleft palate alone (CP). Although several nearby genes have been highlighted, the “casual” variants are largely unknown. Here, we developed DeepFace, a convolutional neural network model, to assess the functional impact of variants by SNP activity difference (SAD) scores. The DeepFace model is trained with 204 epigenomic assays from crucial human embryonic craniofacial developmental stages of post-conception week (pcw) 4 to pcw 10. The Pearson correlation coefficient between the predicted and actual values for 12 epigenetic features achieved a median range of 0.50–0.83. Specifically, our model revealed that SNPs significantly associated with OFCs tended to exhibit higher SAD scores across various variant categories compared to less related groups, indicating a context-specific impact of OFC-related SNPs. Notably, we identified six SNPs with a significant linear relationship to SAD scores throughout developmental progression, suggesting that these SNPs could play a temporal regulatory role. Furthermore, our cell-type specificity analysis pinpointed the trophoblast cell as having the highest enrichment of risk signals associated with OFCs. Overall, DeepFace can harness distal regulatory signals from extensive epigenomic assays, offering new perspectives for prioritizing OFC variants using contextualized functional genomic features. We expect DeepFace to be instrumental in accessing and predicting the regulatory roles of variants associated with OFCs, and the model can be extended to study other complex diseases or traits.

Abstract Background A fundamental ethical issue in African genomics research is how socio-cultural factors impact perspectives, acceptance, and utility of genomic information, especially in stigmatizing conditions like orofacial clefts (OFCs). Previous research has shown that gatekeepers (e.g., religious, political, family or community leaders) wield considerable influence on the decision-making capabilities of their members, including health issues. Thus, their perspectives can inform the design of engagement strategies and increase exposure to the benefits of genomics testing/research. This is especially important for Africans underrepresented in genomic research. Our study aims to investigate the perspectives of gatekeepers concerning genomic risk information (GRI) in the presence of OFCs in a sub-Saharan African cohort. Methods Twenty-five focus group discussions (FGDs) consisting of 214 gatekeepers (religious, community, ethnic leaders, and traditional birth attendants) in Lagos, Nigeria, explored the opinions of participants on genomic risk information (GRI), OFC experience, and the possibility of involvement in collaborative decision-making in Lagos, Nigeria. Transcripts generated from audio recordings were coded and analyzed in NVivo using thematic analysis. Results Three main themes—knowledge, beliefs, and willingness to act—emerged from exploring the perspective of gatekeepers about GRI in this group. We observed mixed opinions regarding the acceptance of GRI. Many participants believed their role is to guide and support members when they receive results; this is based on the level of trust their members have in them. However, participants felt they would need to be trained by medical experts to do this. Also, religious and cultural beliefs were crucial to determining participants’ understanding of OFCs and the acceptance and utilization of GRI. Conclusions Incorporating cultural sensitivity into public engagement could help develop appropriate strategies to manage conflicting ideologies surrounding genomic information in African communities. This will allow for more widespread access to the advances in genomics research in underrepresented populations. We also recommend a synergistic relationship between community health specialists/scientists, and community leaders, including spiritual providers to better understand and utilize GRI.

Abstract Background Gender inequality may be associated with the burden of orofacial clefts (OFCs), particularly in low-and middle-income countries (LMICs). To investigate the OFCs’ burden and its association with gender inequality in the Eastern Mediterranean region (EMR). Methods Country-specific data on the OFCs’ prevalence and Disability-Adjusted Life Years (DALYs) from 1990 to 2019 were gathered from the Global Burden of Disease database by age and gender. Estimated annual percentage change (EAPCs) was used to investigate the OFCs’ trends. The association of the Gender Inequality Index (GII) with prevalence and DALY rates was determined using multiple linear regression. Human Development Index (HDI), Socio-Demographic Index (SDI), and Gross Domestic Product (GDP) were also considered as potential confounders. Results In 2019, the overall regional OFCs’ prevalence and DALYs (per 100,000 person-years) were 93.84 and 9.68, respectively. During the 1990–2019 period, there was a decrease in prevalence (EAPC = -0.05%), demonstrating a consistent trend across genders. Moreover, within the same timeframe, DALYs also declined (EAPC = -2.10%), with a more pronounced reduction observed among females. Gender differences were observed in age-specific prevalence rates (p-value = 0.015). GII was associated with DALYs (βmale= -0.42, p-value = 0.1; βfemale = 0.48, p-value = 0.036) and prevalence (βmale= -1.86, p-value

Objectives: Although children with orofacial clefts have an increased risk for sleep-disordered breathing, no studies have examined the association of sleep duration. Thus, this study aimed to examine associations between orofacial clefts and sleep duration at 1 month, 6 months, 1 year, and 3 years of age in Japan. Design: A cohort study from the Japan Environment and Children's Study. Setting and Patients: This study consisted of 91 497 children, including ones with isolated cleft lip and palate (n = 69), isolated cleft lip only (n = 48), and isolated cleft palate only (n = 37), for which recruitment was undertaken during 2011 to 2014. Main Outcome Measures: Seep durations (hours per day) at 1 month, 6 months, 1 year, and 3 years of age, as reported by their mothers. Results: In the control group, mean sleep durations and standard deviations at 1 month, 6 months, 1 year, and 3 years of age were 15.2 (2.5), 13.6 (1.9), 12.9 (1.6), and 11.6 (1.2) h, respectively. Compared to the control group, linear regression models reported effect sizes and 95% confidence intervals shorter than 1 h for sleep duration of each type of isolated orofacial cleft at each time point. Conclusions: This study suggested null associations between isolated orofacial clefts and sleep duration at 1 month, 6 months, 1 year, and 3 years of age. Children with isolated orofacial clefts had sufficient mean sleep duration. [ABSTRACT FROM AUTHOR]

Incidental findings (IFs) depicted in imaging tests during the diagnostic evaluation of patients with cleft lip and/or palate (CL/P) can guide clinicians during treatment planning procedures for effective, comprehensive cleft care. Evidence regarding IFs in different anatomical regions distant from the dentition is scarce. The aim of this study was to compare the prevalence of IFs in various anatomical areas between patients with non-syndromic CL/P and unaffected subjects. Orthopantomographs (OPTs), lateral cephalometric (LC) radiographs, and cone beam computed tomography (CBCT) scans of 120 subjects (case group: n = 40, 18 females, age 14.5 ± 5.0 years; control group: n = 80, 36 females, age 14.6 ± 4.9 years) were examined, and IFs were assessed by four observers. A significantly higher prevalence of IFs (p < 0.001) was reported in the case group (97.5%) compared with the control group (62.5%). The most prevalent location of IFs in the case group was the maxilla (92.5%), followed by the nasal cavity (75.8%) and the mandible (63.2%), while in the control group, the highest rates of IFs occurred in the maxilla (43.8%), mandible (41.3%), and temporomandibular joint (TMJ) (14.7%). No gender-dependent pattern for IF occurrence was detected overall. Orofacial clefts may affect the mandible. However, the reported IFs were limited compared to those in the maxilla. In conclusion, individuals with CL/P are more likely to present with a range of IFs than their unaffected peers. Understanding the association between CL/P and IFs is critical for successful interdisciplinary treatment, raising awareness of the potential need for future dental care for cleft patients, and managing extra-dental aberrations. A systematic assessment of diagnostic records is required to eliminate the risk of overlooking clinically significant IFs.

Background/Objectives: Orofacial clefts (OFCs) are some of the most common congenital anomalies worldwide. The aim of this case–control study was to evaluate the association of OFCs with selected maternal characteristics. Methods: Data on isolated non-syndromic cases of OFCs were extracted from the population-based registry of congenital anomalies of Tuscany. A sample of live-born infants without any congenital anomaly was used as the control group. We investigated the association with sex and some maternal characteristics: age, body mass index, smoking, and education. Adjusted odds ratios (OR) were calculated using a logistic regression model. Analyses were performed for the total OFCs and separately for cleft lip (CL) and cleft palate (CP). Results: Data on 219 cases and 37,988 controls were analyzed. A higher proportion of males (57.9%) was observed, particularly for CL. A decreasing trend among the maternal age classes was observed (OR:0.81 (95%CI 0.70–0.94)). Underweight mothers had a higher prevalence of OFCs, in particular for CL (OR:1.88 (95%CI 1.08–3.26)). Conclusions: We found an association of OFCs with lower maternal age. The association with maternal age remains controversial and further epidemiological evidence is needed through multicenter studies. We observed that CL was more common in underweight mothers, suggesting actions of primary prevention.

Orofacial clefts are the most common congenital malformation, but the global burden and trends of orofacial clefts have not been comprehensively analysed. The aim of this study was to assess the global incidence, deaths and disability-adjusted life years (DALYs) of orofacial clefts by countries, regions, sex and sociodemographic index (SDI) from 1990 to 2019. The data on orofacial clefts were obtained from the Global Burden of Disease Study 2019. The incidence, deaths and DALYs were analysed by countries, regions, sex and SDI. Age-standardized rates and estimated annual percentage change (EAPC) were calculated to evaluate the burden and temporal trend of orofacial clefts. The association between EAPC and the human development index was assessed. Globally, the incidence, deaths and DALYs of orofacial clefts decreased from 1990 to 2019. The high SDI region showed the biggest downward trend in incidence rate from 1990 to 2019, along with the lowest age-standardized death rate and DALY rate. Some countries, such as Suriname and Zimbabwe, experienced increased death rate and DALY rate over time. The age-standardized death rate and DALY rate were negatively associated with the level of socioeconomic development. Global achievement is evident in the control of the burden of orofacial clefts. The future focus of prevention should be on low-income countries, such as South Asia and Africa, by increasing healthcare resources and improving quality. This is the most recent estimate of the global epidemiology of orofacial clefts, with some countries not previously assessed. The global burden of orofacial clefts showed downward trends from 1990 to 2019; however, some low-income countries are still suffering from increasing burdens. Effective measures should be taken to reduce the burden of orofacial clefts in the uncontrolled regions. [ABSTRACT FROM AUTHOR]

Orofacial clefts (OFCs) are one of the most common types of structural birth defects. The etiologies are complicated, involving with genetic, epigenetic, and environmental factors. Studies have found that maternal diabetes and metabolic syndrome are associated with a higher risk of OFCs in offspring. Metabolic syndrome is a clustering of several disease risk factors, including hyperglycemia, dyslipidemia, obesity, and hypertension. Metabolic disease during pregnancy can increase risk of adverse outcomes and significantly influence fetal development, including orofacial formation and fusion. An altered metabolic state may contribute to developmental disorders or congenital defects including OFCs, potentially through epigenetic modulations, such as histone modification, DNA methylation, and noncoding RNA expression to alter activities of critical morphogenetic signaling or related developmental genes. This review summarizes the currently available evidence and underlying mechanisms of how the maternal metabolic syndrome is associated with OFCs in mostly human and some animal studies. It may provide a better understanding of the interactions between intrauterine metabolic status and fetal orofacial development which might be applied toward prevention and treatments of OFCs. [ABSTRACT FROM AUTHOR]

Orofacial clefts (OFCs) are birth anomalies that occur frequently, affecting the lip and roof of the mouth. The complex etiology includes both genetic and environmental factors that influence their occurrence. OFCs are congenital malformations that are prevalent in the general population and affect the lip, palate, or both. A complex interplay between genetic and environmental factors leads to their development. This review intends to discuss the various molecular pathways involved in OFCs. Advances in genomic technologies have made significant strides in understanding the molecular basis of OFCs. Syndromic OFCs are associated with specific genetic mutations, such as TP63, IRF6, MSX1, and TBX22. Non-syndromic OFCs involve multiple genes and pathways, including PVRL1, FOXE1, MTHFR, and FGFR1. The WNT, TGF-beta, and FGF signaling pathways have also been implicated in OFC pathogenesis. Children with these defects are posed with significant speech, feeding, and hearing challenges, as well as an array of psychosocial problems which warrant multidisciplinary management. Unraveling the etiopathogenesis of the disease has paved the way for personalized medicine and opportunities to improve treatment modalities. An interdisciplinary approach between clinicians, geneticists, and researchers is pivotal in understanding the various aspects of OFCs and in developing effective prevention and treatment protocols. [ABSTRACT FROM AUTHOR]

Introduction: The frequency and implications of secondary findings (SFs) from genomic testing data have been extensively researched. However, little is known about the frequency or reporting of SFs in Africans, who are underrepresented in large‐scale population genomic studies. The availability of data from the first whole‐genome sequencing for orofacial clefts in an African population motivated this investigation. Methods: In total, 130 case‐parent trios were analyzed for SFs within the ACMG SFv.3.0 list genes. Additionally, we filtered for four more genes (HBB, HSD32B, G6PD and ACADM). Results: We identified 246 unique variants in 55 genes; five variants in four genes were classified as pathogenic or likely pathogenic (P/LP). The P/LP variants were seen in 2.3% (9/390) of the subjects, a frequency higher than ~1% reported for diverse ethnicities. On the ACMG list, pathogenic variants were observed in PRKAG (p. Glu183Lys). Variants in the PALB2 (p. Glu159Ter), RYR1 (p. Arg2163Leu) and LDLR (p. Asn564Ser) genes were predicted to be LP. Conclusion: This study provides information on the frequency and pathogenicity of SFs in an African cohort. Early risk detection will help reduce disease burden and contribute to efforts to increase knowledge of the distribution and impact of actionable genomic variants in diverse populations. [ABSTRACT FROM AUTHOR]

Background: Nonsyndromic orofacial clefts (NSOFCs) are the most common craniofacial birth malformations in humans and are generally classified as nonsyndromic cleft lip with or without cleft palate (NSCL/P) and nonsyndromic cleft palate only (NSCPO). Genome‐wide association studies (GWASs) of NSOFCs have demonstrated multiple risk loci and candidate genes; however, published risk factors are able to explain only a small fraction of the observed NSOFCs heritability. Methods: Here, we performed GWASs of 1615 NSCPO cases and 2340 controls, and then conducted genome‐wide meta‐analyses of NSOFCs, totaling 6812 NSCL/P cases, 2614 NSCPO cases, and 19,165 controls from the Chinese Han population. Results: We identify 47 risk loci with genome‐wide pmeta‐value <5.0 × 10−8, 5 risk loci (1p32.1, 3p14.1, 3p14.3, 3p21.31, and 13q22.1) of which are new. All of the 47 susceptibility loci conjointly account for 44.12% of the NSOFCs' heritability in the Chinese Han population. Conclusion: Our results improve the comprehending of genetic susceptibility to NSOFCs and provide new views into the genetic etiology of craniofacial anomalies. [ABSTRACT FROM AUTHOR]

Exome sequencing (ES) is now a relatively straightforward process to identify causal variants in Mendelian disorders. However, the same is not true for ES in families where the inheritance patterns are less clear, and a complex etiology is suspected. Orofacial clefts (OFCs) are highly heritable birth defects with both Mendelian and complex etiologies. The phenotypic spectrum of OFCs may include overt clefts and several subclinical phenotypes, such as discontinuities in the orbicularis oris muscle (OOM) in the upper lip, velopharyngeal insufficiency (VPI), microform clefts or bifid uvulas. We hypothesize that expanding the OFC phenotype to include these phenotypes can clarify inheritance patterns in multiplex families, making them appear more Mendelian. We performed exome sequencing to find rare, likely causal genetic variants in 31 multiplex OFC families, which included families with multiple individuals with OFCs and individuals with subclinical phenotypes. We identified likely causal variants in COL11A2, IRF6, SHROOM3, SMC3, TBX3, and TP63 in six families. Although we did not find clear evidence supporting the subclinical phenotype hypothesis, our findings support a role for rare variants in the etiology of OFCs. [ABSTRACT FROM AUTHOR]

Birth defects have always been one of the most important diseases in medical research as they affect the quality of the birth population. Orofacial clefts (OFCs) are common birth defects that place a huge burden on families and society. Early screening and prevention of OFCs can promote better natal and prenatal care and help to solve the problem of birth defects. OFCs are the result of genetic and environmental interactions; many genes are involved, but the current research has not clarified the specific pathogenesis. The mouse animal model is commonly used for research into OFCs; common methods of constructing OFC mouse models include transgenic, chemical induction, gene knockout, gene knock-in and conditional gene knockout models. Several main signal pathways are involved in the pathogenesis of OFCs, including the Sonic hedgehog (SHH) and transforming growth factor (TGF)-β pathways. The genes and proteins in each molecular pathway form a complex network to jointly regulate the formation and development of the lip and palate. When one or more genes, proteins or interactions is abnormal, OFCs will form. This paper summarises the mouse models of OFCs formed by different modelling methods, as well as the key pathogenic genes from the SHH and TGF-β pathways, to help to clarify the pathogenesis of OFCs and develop targets for early screening and prevention. [ABSTRACT FROM AUTHOR]

AbstractBackground Orofacial clefts are the most common congenital malformation, but the global burden and trends of orofacial clefts have not been comprehensively analysed. The aim of this study was to assess the global incidence, deaths and disability-adjusted life years (DALYs) of orofacial clefts by countries, regions, sex and sociodemographic index (SDI) from 1990 to 2019.Methods The data on orofacial clefts were obtained from the Global Burden of Disease Study 2019. The incidence, deaths and DALYs were analysed by countries, regions, sex and SDI. Age-standardized rates and estimated annual percentage change (EAPC) were calculated to evaluate the burden and temporal trend of orofacial clefts. The association between EAPC and the human development index was assessed.Results Globally, the incidence, deaths and DALYs of orofacial clefts decreased from 1990 to 2019. The high SDI region showed the biggest downward trend in incidence rate from 1990 to 2019, along with the lowest age-standardized death rate and DALY rate. Some countries, such as Suriname and Zimbabwe, experienced increased death rate and DALY rate over time. The age-standardized death rate and DALY rate were negatively associated with the level of socioeconomic development.Conclusion Global achievement is evident in the control of the burden of orofacial clefts. The future focus of prevention should be on low-income countries, such as South Asia and Africa, by increasing healthcare resources and improving quality.KEY MESSAGESThis is the most recent estimate of the global epidemiology of orofacial clefts, with some countries not previously assessed.The global burden of orofacial clefts showed downward trends from 1990 to 2019; however, some low-income countries are still suffering from increasing burdens.Effective measures should be taken to reduce the burden of orofacial clefts in the uncontrolled regions.

ABSTRACTOrofacial clefts (OFC) present different phenotypes with a postnatal challenge for oral microbiota development. In order to investigate the impact of OFC on oral microbiota, smear samples from 15 neonates with OFC and 17 neonates without OFC were collected from two oral niches (tongue, cheek) at two time points, i.e. after birth (T0: Ø3d OFC group; Ø2d control group) and 4–5 weeks later (T1: Ø32d OFC group; Ø31d control group). Subsequently, the samples were analyzed using next-generation sequencing. We detected a significant increase of alpha diversity and anaerobic and Gram-negative species from T0 to T1 in both groups. Further, we found that at T1 OFC neonates presented a significantly lower alpha diversity (lowest values for high cleft severity) and significantly higher levels of Enterobacteriaceae (Citrobacter, Enterobacter, Escherichia-Shigella, Klebsiella), Enterococcus, Bifidobacterium, Corynebacterium, Lactocaseibacillus, Staphylococcus, Acinetobacter and Lawsonella compared to controls. Notably, neonates with unilateral and bilateral cleft lip and palate (UCLP/BCLP) presented similarities in beta diversity and a mixture with skin microbiota. However, significant differences were seen in neonates with cleft palate only compared to UCLP/BCLP with higher levels of anaerobic species. Our findings revealed an influence of OFC as well as cleft phenotype and severity on postnatal oral microbiota maturation.

Abstract Background Nonsyndromic orofacial clefts (NSOFCs) are the most common craniofacial birth malformations in humans and are generally classified as nonsyndromic cleft lip with or without cleft palate (NSCL/P) and nonsyndromic cleft palate only (NSCPO). Genome‐wide association studies (GWASs) of NSOFCs have demonstrated multiple risk loci and candidate genes; however, published risk factors are able to explain only a small fraction of the observed NSOFCs heritability. Methods Here, we performed GWASs of 1615 NSCPO cases and 2340 controls, and then conducted genome‐wide meta‐analyses of NSOFCs, totaling 6812 NSCL/P cases, 2614 NSCPO cases, and 19,165 controls from the Chinese Han population. Results We identify 47 risk loci with genome‐wide pmeta‐value

Abstract Introduction The frequency and implications of secondary findings (SFs) from genomic testing data have been extensively researched. However, little is known about the frequency or reporting of SFs in Africans, who are underrepresented in large‐scale population genomic studies. The availability of data from the first whole‐genome sequencing for orofacial clefts in an African population motivated this investigation. Methods In total, 130 case‐parent trios were analyzed for SFs within the ACMG SFv.3.0 list genes. Additionally, we filtered for four more genes (HBB, HSD32B, G6PD and ACADM). Results We identified 246 unique variants in 55 genes; five variants in four genes were classified as pathogenic or likely pathogenic (P/LP). The P/LP variants were seen in 2.3% (9/390) of the subjects, a frequency higher than ~1% reported for diverse ethnicities. On the ACMG list, pathogenic variants were observed in PRKAG (p. Glu183Lys). Variants in the PALB2 (p. Glu159Ter), RYR1 (p. Arg2163Leu) and LDLR (p. Asn564Ser) genes were predicted to be LP. Conclusion This study provides information on the frequency and pathogenicity of SFs in an African cohort. Early risk detection will help reduce disease burden and contribute to efforts to increase knowledge of the distribution and impact of actionable genomic variants in diverse populations.

Objectives: Mammalian palatogenesis is a highly regulated morphogenetic process to form the intact roof of the oral cavity. Long noncoding RNAs (lncRNAs) and mRNAs participate in numerous biological and pathological processes, but their roles in palatal development and causing orofacial clefts (OFC) remain to be clarified. Methods: Palatal tissues were separated from ICR mouse embryos at four stages (E10.5, E13.5, E15, and E17). Then, RNA sequencing (RNA‐seq) was used. Various analyses were performed to explore the results. Finally, hub genes were validated via qPCR and in situ hybridization. Results: Starting from E10.5, the expression of cell adhesion genes escalated in the following stages. Cilium assembly and ossification genes were both upregulated at E15 compared with E13.5. Besides, the expression of cilium assembly genes was also increased at E17 compared with E15. Expression patterns of three lncRNAs (H19, Malat1, and Miat) and four mRNAs (Cdh1, Irf6, Grhl3, Efnb1) detected in RNA‐seq were validated. Conclusions: This study provides a time‐series expression landscape of mRNAs and lncRNAs during palatogenesis, which highlights the importance of processes such as cell adhesion and ossification. Our results will facilitate a deeper understanding of the complexity of gene expression and regulation during palatogenesis. [ABSTRACT FROM AUTHOR]

Vitamins, exogenous organic compounds that play a vital role in metabolic reactions, and fundamental powerful antioxidants with a crucial role in the genetic transcription process, are considered essential nutritional factors. Folic acid (FA), also known as folate, or Vitamin B9, plays an indispensable role in various intracellular reactions, being the main pawn, with a strong impact on medical and dental science. The aim of this paper mainly focuses on presenting the latest and most advanced aspects related to the following topics: (1) the resonance that FA, and more specifically FA deficiency, has at the level of the oral cavity; (2) the elements involved in the molecular landscape, which reflect the interaction and the possible mechanisms of action, through which FA influences oral health; and (3) the particular processes by which FA deficiency causes certain clinical conditions. Moreover, we aim to draw the attention and trigger the curiosity of health professionals on the need to know the specific host–environment interactions, particularly the linkage between individual genotype and phenotypic variability, which in the future could represent the basis of novel and effective treatment methods. From this perspective, we begin by providing an overview of the general radar echo of the human body induced by FA deficiency, before focusing on the genetic strategic substrate and biochemical processes involved in the molecular mechanisms through which FA acts at the cellular level. Finally, we reflect on the resulting conclusions: (1) the complex interrelationships between different types of cytokines (CKs) and abnormal folate metabolism are involved in the occurrence of neural tube defects (NTDs) and orofacial clefts (OFCs); (2) increased oxidative stress, endothelial dysfunction, and genomic instability, induced by folate deficiency, have a major impact on periodontal health; and (3) glutamate carboxypeptidase II, GCP2 1561C>T allelic variant, constitutes the main pawn, which specifically influences the bioavailability of natural folates and FA, as the main actors, with essential roles in oral health. [ABSTRACT FROM AUTHOR]

Objective: Children and adolescents with orofacial clefts may experience ongoing psychosocial impacts due to the continuous nature of cleft treatments, facial and dental differences, and speech and hearing difficulties. The aim of this qualitative systematic review was to better understand the experiences of children and adolescents with orofacial clefts. Design: A systematic search strategy using PubMed, Embase, Emcare, Scopus, and Web of Science databases was performed to identify relevant qualitative studies evaluating the lived experience of children and adolescents with orofacial clefts from inception through to June 2021. Eligible studies were critically appraised using the Joanna Briggs methodology and a meta-aggregative approach. Results: The search identified 2466 studies, with 13 found to meet the inclusion criteria. Extraction of 155 findings resulted in 27 categories, which were meta-aggregated into 7 overarching synthesized findings. These 7 core findings included aspects of child experience and findings that enhanced or impeded child experience at the individual, family, and community levels. Conclusions: Factors that impeded child experience at the individual, family, and community levels were more pronounced than factors that enhanced their experience among children and adolescents with orofacial clefts. Further initiatives are needed to provide support to individuals, families, and school communities to enhance children's experience of orofacial cleft during the formative childhood and adolescent years. [ABSTRACT FROM AUTHOR]

Objective : To describe the current epidemiology of nonsyndromic cleft palate alone (CP) and cleft lip with or without cleft palate (CL ± P) in Texas and examine differences in the characteristics of infants with CP and CL ± P based on the presence/absence of additional defects. Design : We used data from the Texas Birth Defects Registry, a statewide active birth defect surveillance system, from 1815 cases with CP and 5066 with CL ± P, without a syndrome diagnosis (1999-2014 deliveries). All live births in Texas were used for comparison. Poisson regression was used to calculate crude and adjusted prevalence ratios (aPR) for each characteristic, separately for each cleft subphenotype. Results : The prevalence of CL ± P and CP in our study was estimated as 8.3 and 3.0 per 10 000 live births, respectively. After adjusting for several characteristics, several factors were associated with CL ± P, CP, or both, including infant sex and maternal race/ethnicity, age, smoking, and diabetes. There were several differences between infants with isolated versus nonisolated clefts. For example, maternal prepregnancy diabetes was associated with an increased prevalence of CL ± P (aPR 7.91, 95% confidence interval [CI]: 5.53, 11.30) and CP (aPR 3.24, 95% CI: 1.43, 7.36), but only when additional defects were present. Conclusions : Findings from this study provide a contemporary description of the distribution of orofacial clefts in Texas accounting for differences between isolated and nonisolated clefts. They may contribute to increasing our understanding of the etiology of CP and CL ± P. [ABSTRACT FROM AUTHOR]

Neural crest cells (NCCs) comprise a transient progenitor cell population of neuroepithelial origin that contributes to a variety of cell types throughout vertebrate embryos including most mesenchymal cells of the cranial and facial structures. Consequently, abnormal NCC development underlies a variety of craniofacial defects including orofacial clefts, which constitute some of the most common birth defects. We previously reported the generation of manta ray (mray) mice that carry a loss-of-function allele of the gene encoding the preribosomal factor Pak1ip1. Here we describe cranioskeletal abnormalities in homozygous mray mutants that arise from a loss of NCCs after their specification. Our results show that the localized loss of cranial NCCs in the developing frontonasal prominences is caused by cell cycle arrest and cell death. In addition, and consistent with deficits in ribosome biosynthesis, homozygous mray mutants display decreased protein biosynthesis, further linking Pak1ip1 to a role in ribosome biogenesis.

Background: Non-syndromic orofacial clefts (NSOFC) are among the most common congenital malformations. Several studies have investigated the association between stress and NSOFC; however, they have reported different and heterogeneous results. Therefore, this systematic review was conducted to investigate the association between maternal periconceptional stress and non-syndromic orofacial clefts in infants.The research question was “Is maternal periconceptional stress an etiological factor for non-syndromic orofacial clefts in infants”? Methods: Search strategy, inclusion/exclusion criteria, and data extraction from studies reporting periconceptional maternal exposure to stress and NSOFC were implemented without language restrictions. The risks of bias in the identified studies was assessed, and this information was used in the sensitivity analyses to explain heterogeneity. A meta-analysis of the extracted data was performed. Results: Twelve eligible studies were included. Forest plot for meta-analysis of the association between maternal periconceptional exposure to stress and NSOFC among studies with adjustment for potential confounders showed a statistically significant association with an increased risk of NSOFC (odds ratio [OR]:1.17; P = 0.03), which was apparent for both cleft lip with and without palate (OR:2.07; P = 0.007) and cleft palate (OR:1.72; P = 0.003). There was a substantial heterogeneity between studies, which improved when analyzing only studies that were adjusted for potential confounders. Conclusion: Based on the currently available evidence, maternal exposure to periconceptional stress could be considered a risk factor for NSOFCs. Therefore, we strongly recommend research investigating the effect of stress caused by the coronavirus disease-2019 pandemic on the incidence of clefts.

Abstract Background Children with orofacial clefts are highly susceptible to malnutrition, with severe malnutrition restricting their eligibility to receive safe surgery. Ready-to-use therapeutic foods (RUTF) are an effective treatment for malnutrition; however, the effectiveness has not been demonstrated in this patient population prior to surgery. We studied the effectiveness of short-term RUTF use in transitioning children with malnutrition, who were initially ineligible for surgery, into surgical candidates. Methods A cohort of patients from Ghana, Honduras, Malawi, Madagascar, Nicaragua, and Venezuela enrolled in a nutrition program were followed by Operation Smile from June 2017 to January 2020. Age, weight, and length/height were tracked at each visit. Patients were included until they were sufficiently nourished (Z > = -1) with a secondary outcome of receiving surgery. The study was part of a collaborative program between Operation Smile (NGO), Birdsong Peanuts (peanut shellers and distributors), and MANA Nutrition (RUTF producer). Results A total of 556 patients were recruited between June 2017 and January 2020. At baseline 28.2% (n = 157) of patients were diagnosed with severe, 21.0% (n = 117) moderate, and 50.7% (n = 282) mild malnutrition. 324 (58.3%) presented for at least one return visit. Of those, 207 (63.7%) reached optimal nutrition status. By visit two, the mean z-score increased from -2.5 (moderate) to -1.7 (mild) (p

Background: To date, there are over 320 variants identified in the IRF6 gene that cause Van der Woude syndrome or popliteal pterygium syndrome. We sequenced this gene in a South African orofacial cleft cohort to identify the causal IRF6 variants in our population. Method: Saliva samples from 100 patients with syndromic and non‐syndromic CL ± P were collected. Patients were recruited from the cleft clinics at two public, tertiary hospitals in Durban, South Africa (SA), namely Inkosi Albert Luthuli Central Hospital (IALCH) and KwaZulu‐Natal Children's Hospital (KZNCH). We prospectively sequenced the exons of IRF6 in 100 orofacial cleft cases, and where possible, we also sequenced the parents of the individuals to determine the segregation pattern. Results: Two variants were identified; one novel (p.Cys114Tyr) and one known (p.Arg84His) missense variant in IRF6 gene were identified. The patient with the p.Cys114Tyr variant was non‐syndromic with no clinical VWS phenotype expected of individuals with IRF6 coding variants, and the patient with the p.Arg84His had phenotypic features of popliteal pterygium syndrome. The p.Arg84His variant segregated in the family, with the father also being affected. Conclusions: This study provides evidence that IRF6 variants are found in the South African population. Genetic counselling is essential for affected families, particularly in the absence of a known clinical phenotype since it helps with the plans for future pregnancies. [ABSTRACT FROM AUTHOR]

Objectives: Non‐syndromic cleft palate only (NSCPO) is one of the most common craniofacial birth defects with largely undetermined genetic etiology. It has been established that Grainyhead‐like 3 (GRHL3) plays an essential role in the pathogenesis of NSCPO. This study aimed to identify and verify the first‐reported GRHL3 variant underlying NSCPO among the Chinese cohort. Methods: We performed whole‐exome sequencing (WES) on a Chinese NSCPO patient and identified a rare variant of GRHL3 (p.Arg391His). A validated deleterious variant p.Arg391Cys was introduced as a positive control. Zebrafish embryos injection, reporter assays, live‐cell imaging, and RNA sequencing were conducted to test the pathogenicity of the variants. Results: Zebrafish embryos microinjection demonstrated that overexpression of the variants could disrupt the normal development of zebrafish embryos. Reporter assays showed that Arg391His disturbed transcriptional activity of GRHL3 and exerted a dominant‐negative effect. Interestingly, Arg391His and Arg391Cys displayed distinct nuclear localization patterns from that of wild‐type GRHL3 in live‐cell imaging. Bulk RNA sequencing suggested that the two variants changed the pattern of gene expression. Conclusions: In aggregate, this study identified and characterized a rare GRHL3 variant in NSCPO, revealing the critical role of Arginine 391 in GRHL3. Our findings will help facilitate understanding and genetic counseling of NSCPO. [ABSTRACT FROM AUTHOR]

Orofacial clefts represent a heterogeneous group of congenital malformations affecting different structures of the oral cavity and face. Overall, infants with these disorders have a higher lifetime morbidity and mortality compared to unaffected individuals. Therefore, advances in biomedical research are unavoidable. Thus, the overall objective of this work was to conduct a literature review to narratively analyse the 10 main primary studies on orofacial clefts carried out in Spain, published from 2018 to date. According to this review, at an institutional level, the Complutense University of Madrid (UCM) is notable with 4 articles published by the UCM 920202 research group. The Rey Juan Carlos University of Madrid also stands out, with three papers related to different aspects of the personality and quality of life of cleft patients, as well as many other cognitive-emotional variables. In relation to the University of Valencia, we found two studies carried out on large samples of cleft patients. Finally, in Barcelona, an observational study on otorhinolaryngological problems in cleft palate patients is noteworthy. In conclusion, although several studies have been published in recent years on different aspects related to clefts, there is still much work to be done. Spain should craniofacial development. Large, multicenter and collaborative studies are needed to delve deeper into the aetiological mechanisms and, ultimately, into the possible tools for their prevention. Similarly, support is needed to better elucidate questions related to treatments in all dimensions of health, preferably randomised controlled clinical trials, which facilitate the transfer of knowledge and its universal accessibility within the Spanish public health system. [ABSTRACT FROM AUTHOR]