The heterogeneous genetic architectures of orofacial clefts.

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.

Shared genetic risk between major orofacial cleft phenotypes in an African population.

Nonsyndromic orofacial clefts (NSOFCs) represent a large proportion (70%-80%) of all OFCs. They can be broadly categorized into nonsyndromic cleft lip with or without cleft palate (NSCL/P) and nonsyndromic cleft palate only (NSCPO). Although NSCL/P and NSCPO are considered etiologically distinct, recent evidence suggests the presence of shared genetic risks. Thus, we investigated the genetic overlap between NSCL/P and NSCPO using African genome-wide association study (GWAS) data on NSOFCs. These data consist of 814 NSCL/P, 205 NSCPO cases, and 2159 unrelated controls. We generated common single-nucleotide variants (SNVs) association summary statistics separately for each phenotype (NSCL/P and NSCPO) under an additive genetic model. Subsequently, we employed the pleiotropic analysis under the composite null (PLACO) method to test for genetic overlap. Our analysis identified two loci with genome-wide significance (rs181737795 [p = 2.58E-08] and rs2221169 [p = 4.5E-08]) and one locus with marginal significance (rs187523265 [p = 5.22E-08]). Using mouse transcriptomics data and information from genetic phenotype databases, we identified MDN1, MAP3k7, KMT2A, ARCN1, and VADC2 as top candidate genes for the associated SNVs. These findings enhance our understanding of genetic variants associated with NSOFCs and identify potential candidate genes for further exploration.

Maternal micronutrient biomarkers and risk of non-syndromic cleft lip/palate: A case-control study.

OBJECTIVE: 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. SUBJECTS AND METHODS: 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. RESULTS: 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. CONCLUSION: Higher maternal vitamin B12 levels are associated with a reduced risk of CL/P, while elevated homocysteine levels may increase the risk.

Perceptions and beliefs of community gatekeepers about genomic risk information in African cleft research.

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.

Gender inequality and burden of orofacial clefts in the Eastern Mediterranean region: findings from global burden of disease study 1990-2019.

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 (ßmale= -0.42, p-value = 0.1; ßfemale = 0.48, p-value = 0.036) and prevalence (ßmale= -1.86, p-value < 0.001, ßfemale= -2.07, p-value < 0.001). CONCLUSIONS: Despite a declining prevalence, the burden of OFCs remained notably significant in the EMR. Gender inequality is associated with the burden of OFCs in the Eastern Mediterranean region. Countries in the region should establish comprehensive public policies to mitigate gender inequalities in healthcare services available for OFCs.

Role of MTHFR, IRF6, PAX7 and TP63 SNPs in susceptibility to non-syndromic orofacial cleft, a candidate gene study in a Portuguese population.

BACKGROUND: Non-syndromic orofacial cleft (NSOC) is a complex phenotype, involving multiple genetic and environmental factors. Association studies exploring the genetic susceptibility to this prevalent oral malformation show variability of results in different populations. Using a candidate gene approach, we aimed to verify the role of four single-nucleotide polymorphisms (SNPs) in the susceptibility to NSOC in Portuguese patients. METHODS: A total of 254 non-consanguineous individuals of Portuguese were recruited, including 120 patients with NSOC and 134 controls. About 92% of these patients had non-syndromic cleft lip with or without cleft palate (NSCL/P) and 8% had only non-syndromic cleft palate (NSCP). SNPs in the MTHFR (rs1801133), IRF6 (rs642961), PAX7 (rs742071) and TP63 (rs9332461) genes were studied, using a real-time approach with TaqMan probes. Allelic, genotypic, dominant, recessive and over-dominant models were explored using a chi-squared test. Adjusted p-value was calculated for multiple comparisons using the Benjamini-Hochberg false discovery rate (FDR). RESULTS: All SNPs were in Hardy-Weinberg equilibrium. For MTHFR, IRF6, and PAX7 SNPs, no statistically significant difference was highlighted for any of the evaluated models. For TP63 SNP, data fitted an over-dominant model, with a protective effect for heterozygotes (OR 1.897; CI 95% [1.144-3.147]; p < .016, when comparing controls vs. cases), but significance was lost when applying adjusted p-value for multiple comparisons (4 × 5 tests). CONCLUSION: In this Portuguese population, there was no evidence of an association between the evaluated SNPs and NSOC. For TP63 SNP, the possibility of a protective effect of heterozygotes should be further investigated.

COVID-19 vaccine and non-syndromic orofacial clefts in five arab countries. A case-control study.

OBJECTIVES: Risk factors for non-syndromic orofacial cleft (NSOFCs) include genetic profile and environmental exposure to medication and illnesses during pregnancy. We assessed the association between the COVID-19 vaccination and the incidence of NSOFC across five Middle Eastern countries. MATERIALS AND METHODS: This multi-country, hospital-based, case-control study included infants with NSOFCs whose first 3 intrauterine months coincided with the time when pregnant women were allowed to receive COVID-19 vaccination in the countries participating in the study. Newborns with NSOFCs were examined for cleft type and their parents were interviewed for maternal exposures and COVID-19 vaccination. Controls were newborns matched to cases in gender and setting. RESULTS: The study recruited 977 (348 children with NSOFCs and 629 controls). Maternal use of nicotine (Adjusted Odds Ratio (AOR): 2.437; P = 0.044) and family history of NSOFC (AOR: 11.059; P < 0.001) increased significantly the AOR of having a child with NSOFC. On the other hand, COVID-19 vaccine administration to pregnant mothers have significantly decreased the AOR of having a child with NSOFC (AOR: 0.337; P = 0.006). CONCLUSION: This study suggests that COVID-19 vaccination is not related to NSOFC and might protect against having a child affected with such a congenital anomaly. CLINICAL RELEVANCE: The finding of this study is important for healthcare providers for considering COVID-19 vaccination for pregnant woman. Clear communication and education about the potential risks and benefits would be crucial for informed decision-making. The study's results would directly impact pregnant individuals, as they would need accurate information to make informed decisions about their health and the health of their infants.

Maternal Exposure to Stress During Covid-19 and Non-Syndromic Orofacial Clefts: A Cohort Retrospective Study.

OBJECTIVE: The coronavirus (COVID-19) pandemic presents an opportunity to study stress's effect on the development of non-syndromic orofacial clefts (NSOFCs). This study was aimed at assessing maternal stress exposure during the pregestational to first trimester pregnancy periods and the development of NSOFCs during a year of the COVID-19 pandemic. DESIGN: Cohort study of infants with NSOFCs and controls matched based on recruitment site and age. SETTING: Government hospitals in Saudi Arabia between November 2020 and November 2021. MAIN OUTCOME MEASURES: Data collection included NSOFC clinical examination and maternal stress exposure assessment using the Modified Life Events Questionnaire, the Fear of COVID-19 Scale, and a focus on the lack of pregnancy planning and a threatened miscarriage. RESULTS: Of the 557 infants recruited, 191 had NSOFCs. Logistic regression analysis with adjusted odds ratios (AORs) that removed the effects of confounders showed that any of the seven stressful life events (AOR:3.78, P < .001) and the family histories of relatives with NSOFCs (AOR:9.73, P < .001) increased the AOR for NSOFC development. In contrast, maternal folic acid (AOR:0.56, P.010), threatened miscarriage (AOR:0.17, P = .001), fear of COVID-19 (AOR:0.83, P = .038), and suspected COVID-19 infection (AOR:0.43, P = .008) decreased the AOR for NSOFC development. CONCLUSION: Along with an established risk associated with family history of birth defects, stressful life events may be a risk factor for NSOFC development. Beyond folic acid's known benefit, it may be that higher maternal health concerns contribute to increased protective health behaviors during pregnancy. Ongoing research is needed to specify the maternal risk factors for NSOFC.

Genome-wide association study of multiethnic nonsyndromic orofacial cleft families identifies novel loci specific to family and phenotypic subtypes.

Nonsyndromic orofacial clefts (OFCs) are among the most common craniofacial birth defects worldwide, and known to exhibit phenotypic and genetic heterogeneity. Cleft lip plus cleft palate (CLP) and cleft lip only (CL) are commonly combined together as one phenotype (CL/P), separately from cleft palate alone. In comparison, our study analyzes CL and CLP separately. A sample of 2218 CL and CLP cases, 4537 unaffected relatives of cases, and 2673 pure controls with no family history of OFC were selected from the Pittsburgh Orofacial Cleft (Pitt-OFC) multiethnic study.genome-wide association studies were run for seven specific phenotypes created based on the cleft type(s) observed within these families, as well as the combined CL/P phenotype. Five novel genome-wide significant associations, 3q29 (rs62284390), 5p13.2 (rs609659), 7q22.1 (rs6465810), 19p13.3 (rs628271), and 20q13.33 (rs2427238), and nine associations (p ≤ 1.0E-05) within previously confirmed OFC loci-PAX7, IRF6, FAM49A, DCAF4L2, 8q24.21, ARID3B, NTN1, TANC2 and the WNT9B:WNT3 gene cluster-were observed. We also found that single nucleotide polymorphisms within a subset of the associated loci, both previously known and novel, differ substantially in terms of their effects across cleft- or family-specific phenotypes, indicating not only etiologic differences between CL and CLP, but also genetic heterogeneity within each of the two OFC subtypes.

Genome-wide Enrichment of De Novo Coding Mutations in Orofacial Cleft Trios.

Although de novo mutations (DNMs) are known to increase an individual's risk of congenital defects, DNMs have not been fully explored regarding orofacial clefts (OFCs), one of the most common human birth defects. Therefore, whole-genome sequencing of 756 child-parent trios of European, Colombian, and Taiwanese ancestry was performed to determine the contributions of coding DNMs to an individual's OFC risk. Overall, we identified a significant excess of loss-of-function DNMs in genes highly expressed in craniofacial tissues, as well as genes associated with known autosomal dominant OFC syndromes. This analysis also revealed roles for zinc-finger homeobox domain and SOX2-interacting genes in OFC etiology.

Gene-environment interactions: aligning birth defects research with complex etiology.

Developmental biologists rely on genetics-based approaches to understand the origins of congenital abnormalities. Recent advancements in genomics have made it easier than ever to investigate the relationship between genes and disease. However, nonsyndromic birth defects often exhibit non-Mendelian inheritance, incomplete penetrance or variable expressivity. The discordance between genotype and phenotype indicates that extrinsic factors frequently impact the severity of genetic disorders and vice versa. Overlooking gene-environment interactions in birth defect etiology limits our ability to identify and eliminate avoidable risks. We present mouse models of sonic hedgehog signaling and craniofacial malformations to illustrate both the importance of and current challenges in resolving gene-environment interactions in birth defects. We then prescribe approaches for overcoming these challenges, including use of genetically tractable and environmentally responsive in vitro systems. Combining emerging technologies with molecular genetics and traditional animal models promises to advance our understanding of birth defect etiology and improve the identification and protection of vulnerable populations.

Rare variants found in multiplex families with orofacial clefts: Does expanding the phenotype make a difference?

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.

Identification of a new familial case of 3q29 deletion syndrome associated with cleft lip and palate via whole-exome sequencing.

Many unbalanced large copy number variants reviewed in the paper are associated with syndromic orofacial clefts, including a 1.6 Mb deletion on chromosome 3q29. The current report presents a new family with this recurrent deletion identified via whole-exome sequencing and confirmed by array comparative genomic hybridization. The proband exhibited a more severe clinical phenotype than his affected mother, comprising right-sided cleft lip/alveolus and cleft palate, advanced dental caries, heart defect, hypospadias, psychomotor, and speech delay, and an intellectual disability. Data analysis from the 3q29 registry revealed that the 3q29 deletion increases the risk of clefting by nearly 30-fold. No additional rare and pathogenic nucleotide variants were identified that could explain the clefting phenotype and observed intrafamilial phenotypic heterogeneity. These data suggest that the 3q29 deletion may be the primary risk factor for clefting, with additional genomic variants located outside the coding sequences, methylation changes, or environmental exposure serving as modifiers of this risk. Additional studies, including whole-genome sequencing or methylation analyses, should be performed to identify genetic factors underlying the phenotypic variation associated with the recurrent 3q29 deletion.

Time-series expression profiles of mRNAs and lncRNAs during mammalian palatogenesis.

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.

Two rare variants reveal the significance of Grainyhead-like 3 Arginine 391 underlying non-syndromic cleft palate only.

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.

Imaging Factors Affecting Prenatal Counseling in Orofacial Clefts.

INTRODUCTION: We aim to correlate pre- and postnatal data regarding the cleft type and surgical prognostic factors associated to orofacial clefts. METHODS: Retrospective study concerning all cases of orofacial cleft evaluated prenatally (US+/-MRI) between 2015 and 2020 with available postnatal outcomes. We compared prenatal imaging (cleft type and surgical prognostic factors) with postnatal findings. RESULTS: 48 fetuses were included. Median gestational age at first US/MRI examination: 29+2 WG and 31+6 WG, respectively. The prenatal diagnosis was in accordance with postnatal findings with regard to the cleft type in 88% of the cases (n = 42/48) for US and/or MRI, 84% (n = 38/45) for US only, and 90% (n = 37/41) for MRI only. The nasal septum deviation and nostril collapse were underestimated by prenatal US in 48% (n = 12/25) and 44% (n = 11/25) of cases, respectively (Cohen's kappa of 0.22 and 0.32, respectively). Pre- and postnatal examinations were in accordance with 75% of cases (n = 8) regarding evaluation of anteroposterior maxillary shift in case of unilateral alveolar cleft and in 90% and 80% of cases (n = 10) regarding the degree of protrusion/deviation of the premaxillary protrusion in case of bilateral cleft, respectively. CONCLUSION: Prenatal imaging can accurately assess the type of orofacial cleft and evaluate maxillary shift and deviation of the premaxilla. It underestimates the nose deformity.

Morphological Presentation of Orofacial Clefts: An Epidemiological Study of 5004 Patients in a Tertiary Care Hospital of Central India.

To analyse the morphological presentation of orofacial clefts, gender, syndromes and systemic anomalies associated with them.This was an epidemiological study performed in the patients who were registered for cleft lip and palate surgeries in our centre. The data was evaluated both retrospectively as well as prospectively.The patients registered from November 2006 to April 2021 were studied. Out of 5276 patients, data of 5004 cases were analysed, rest 272 patients were excluded due to lack of information. Statistical analysis and Chi square test were applied.Cleft deformities were more common in males than females. Cleft lip with palate was the commonest phenotype (52.2%). It was followed by isolated cleft lip (22.9%), isolated cleft palate (22.1%), rare clefts (1.62%) and syndromic clefts (1.18%). Unilateral variants were more frequent than bilateral. In unilateral, left side was more common than the right side. Among bilateral, most of the cases had premaxillary protrusion. In the present study, 3.46% of all the patients had associated anomalies affecting their other organs. Less common cleft phenotypes like microform cleft lip and submucous cleft palate ± bifid uvula showed frequency of 0.62% and 0.64% respectively.Thorough examination of cleft deformity should be done as it may appear as an isolated deformity or part of a syndrome and have associated systemic anomalies. This may help us to deliver comprehensive care to the patients and can prevent potential operative complications.

Epidemiology of Nonsyndromic, Orofacial Clefts in Texas: Differences by Cleft Type and Presence of Additional Defects.

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.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.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.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.

Childhood Experiences and Perspectives of Individuals With Orofacial Clefts: A Qualitative Systematic Review.

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.

Ethnic Differences in the Brazilian Population Influence the Impact of BMP4 Genetic Variants on Susceptibility of Nonsyndromic Orofacial Clefts.

OBJECTIVE: The study evaluated the association of BMP4 tag-SNPs and SNP-SNP interactions involving genes active by BMP4 pathway during craniofacial development in the susceptibility of nonsyndromic orofacial clefts (NSOC) in the Brazilian population. DESIGN: Case-control study. SETTING: Brazilian Oral Cleft Group. PARTICIPANTS: The study included 881 healthy controls and 800 patients with different types of NSOC: 232 with cleft lip only (NSCLO), 568 with cleft lip and palate (NSCLP), and 274 with cleft palate only (NSCPO). INTERVENTIONS: The genomic DNA was genotyped with allelic discrimination assays for five BMP4 tag-SNPs (rs11623717, rs17563, rs2071047, rs2761887 and rs4898820), and analyzed their allelic and genotypic associations using multiple logistic regression. The interactions of these variants with genes involved in the BMP4 signaling pathway, including FGFR1, GREM1, NOG, VAX1 and the 4p16.2 locus, were explored. MAIN OUTCOME MEASURES: BMP4 variants in the NSOC risk. RESULTS: Although only nominal p values were identified when the whole sample was considered, subgroup analysis including the patients with high African genomic ancestry showed significant associations of rs2761887 with risk for nonsyndromic cleft lip with or without cleft palate (NSCL ± P)[(ORhom: 2.16; 95% CI: 1.21-3.85; p = 0.01) and (ORrec: 2.05; 95% CI: 1.21-3.47; p = 0.006)]. Thirteen significant SNP-SNP interactions involving BMP4 and the SNPs at FGFR1, GREM1, NOG and VAX1 and at locus 4p16.2 for increased risk of NSCL ± P were identified. CONCLUSIONS: Our results demonstrate an increased risk of NSCL ± P in Brazilian individuals with enrichment of African ancestry in the presence of the BMP4 rs2762887 polymorphism, and reveal relevant genetic contribution of SNP-SNP epistatic interactions involving BMP4 variants to NSCL ± P risk.