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.

Genome-wide study of gene-by-sex interactions identifies risks for cleft palate.

Structural birth defects affect 3-4% of all live births and, depending on the type, tend to manifest in a sex-biased manner. Orofacial clefts (OFCs) are the most common craniofacial structural birth defects and are often divided into cleft lip with or without cleft palate (CL/P) and cleft palate only (CP). Previous studies have found sex-specific risks for CL/P, but these risks have yet to be evaluated in CP. CL/P is more common in males and CP is more frequently observed in females, so we hypothesized there would also be sex-specific differences for CP. Using a trio-based cohort, we performed sex-stratified genome-wide association studies (GWAS) based on proband sex followed by a genome-wide gene-by-sex (G × S) interaction testing. There were 13 loci significant for G × S interactions, with the top finding in LTBP1 (RR = 3.37 [2.04-5.56], p = 1.93 × 10-6). LTBP1 plays a role in regulating TGF-ß bioavailability, and knockdown in both mice and zebrafish lead to craniofacial anomalies. Further, there is evidence for differential expression of LTBP1 between males and females in both mice and humans. Therefore, we tested the association between the imputed genetically regulated gene expression of genes with significant G × S interactions and the CP phenotype. We found significant association for LTBP1 in cell cultured fibroblasts in female probands (p = 0.0013) but not in males. Taken altogether, we show there are sex-specific risks for CP that are otherwise undetectable in a combined sex cohort, and LTBP1 is a candidate risk gene, particularly in females.

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.

Genome scan reveals several loci associated with torus palatinus.

OBJECTIVE: Torus Palatinus (TP) is a common trait with an unclear aetiology. Although prior studies suggest a hereditary component, the genetic factors that influence TP risk remain unknown. The purpose of this study is to identify genetic variants associated with TP. MATERIALS AND METHODS: We assessed the TP status of 829 individuals from various ancestral backgrounds using 3D palate scans. We then carried out a genome-wide association study (GWAS) to identify common variants associated with TP. We also performed gene-based tests across the exome to investigate the role of low-frequency coding variants. RESULTS: Our GWAS did not identify any genome-wide significant signals but identified suggestive associations including hits on chromosomes 2, 5 and 17 with p-values less than 5 × 10-6. Candidate genes at these suggestive loci have been implicated in normal-range craniofacial features, syndromes with facial and oral malformations, and bone density. We did not find evidence that low-frequency coding variants influence TP risk. In addition, we failed to replicate associations identified in prior genetic studies of TP. CONCLUSION: These findings suggest that multiple genes likely influence the development of TP. Independent replication will be required to confirm our suggestive associations.

Evaluation of Weight, Height, Body Mass Index, and Nutritional Status of Children With and Without Orofacial Cleft in Nigeria.

OBJECTIVE: To compare the weight, height, BMI and nutritional status of patients with and without cleft lip and/or cleft palate (CLP). DESIGN: Cross-sectional study. SETTING: Lagos University Teaching Hospital. PATIENTS, PARTICIPANTS: Patients with CLP and a control group of participants without CLP aged between 1 month and 6 years. All patients in the CLP group had not received surgical or nutritional intervention. OUTCOME MEASURES: Weight, height, BMI, their respective percentiles, and nutritional status according to the WHO 2006 growth curves of participants. RESULTS: Patients with CLP (n = 60, 21 males, 39 females, mean age: 19.1 months) had significantly lower percentile weight and height compared to those of controls (n = 60, 26 females, mean age, 23.6 months) in univariate analyses (all p < 0.01). Multivariate linear regression revealed significant interactions with age group for weight. In addition, proportions of underweight and short stature were significantly higher in the CLP group compared to the control group (all p < 0.05), and these significant differences were dependent on the age group with between-group significant differences only in age groups less than 25 months. CONCLUSIONS: Overall, patients with CLP had significantly lower weight, height, BMI and nutritional status than their unaffected peers, and these differences were dependent on age group. Significantly lower nutritional status was seen in patients with CLP up to 24 months of age, which highlights the need for early nutritional intervention in the management of CLP.

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.

Pediatric Surgical Waitlist in Low Middle Income Countries During the COVID-19 Pandemic.

INTRODUCTION: Coronavirus disease-19 led to a significant reduction in surgery worldwide. Studies, however, of the effect on surgical volume for pediatric patients in low-income and middle-income countries (LMICs) are limited. METHODS: A survey was developed to estimate waitlists in LMICs for priority surgical conditions in children. The survey was piloted and revised before it was deployed over email to 19 surgeons. Pediatric surgeons at 15 different sites in eight countries in sub-Saharan Africa and Ecuador completed the survey from February 2021 to June 2021. The survey included the total number of children awaiting surgery and estimates for specific conditions. Respondents were also able to add additional procedures. RESULTS: Public hospitals had longer wait times than private facilities. The median waitlist was 90 patients, and the median wait time was 2 mo for elective surgeries. CONCLUSIONS: Lengthy surgical wait times affect surgical access in LMICs. Coronavirus disease-19 had been associated with surgical delays around the world, exacerbating existing surgical backlogs. Our results revealed significant delays for elective, urgent, and emergent cases across sub-Saharan Africa. Stakeholders should consider approaches to scale the limited surgical and perioperative resources in LMICs, create mitigation strategies for future pandemics, and establish ways to monitor waitlists on an ongoing basis.

Achieving a robust mentoring and research capacity program in a LMIC - the BRAINS faculty development model.

BACKGROUND: A research and training program (RTP) was carried out to build the capacity of faculty and improve the culture of research in the College of Medicine, University of Lagos (CMUL), Nigeria. METHODS: Realist-guided mixed methods evaluation of the BRAINS project was carried out using secondary data generated during the 5-years (2015 - 2020) of project implementation. Capacity building workshops and mentored research activities targeted at faculty in the CMUL were conducted. Overall, 1,418 participants attended the workshops in batches. Among the participants, forty-five faculty received grants and were mentored by senior professionals (local & international) to conduct research. Data were extracted from all project-related documents including coursework biodata, workshop evaluation forms, quarterly project reports, and end- of-project reports, submitted by the mentees, minutes of meetings, and the proposal submitted for funding. It was in the form of continuous variables and prose (sentences & stories). Quantitative data were analysed with IBM SPSS statistics version 20. Mean knowledge score and mean difference was calculated, paired t-test was carried out using p < 0.05 to determine statistical significance. The prose was thematically analysed to generate themes and narratives. Both were subsequently combined for interpretation and used to refine the initial programme theory into an evidence-informed theory. RESULTS: Twelve courses were deployed, and 1,418 participants (47.8% males and 52.2% females) from medical, nursing, and allied medical departments were trained. Eighty participants were trained in Responsible Conduct of Research and eighty-one on Manuscript Writing over three years. A comparison of the pre/post-test knowledge scores showed a positive mean difference. Thematic analysis of workshop data produced three thematic domains representing effectiveness and gains namely: cognitive, reward, and behavioural. 45 trainees were awarded grants and mentored, and analysis of mentee's data generated 4 themes: Achieving a robust mentoring program; Benefits of the mentoring program; Resilience in research; Improving the mentoring program. CONCLUSION: By contributing to the body of knowledge available on RTPs, this evaluation identified key components that contributed to the success of the project and developed a model for achieving a robust training and mentoring program which can be replicated in other LMICs.

Wound Healing Following Palatoplasty Using Either Honey or Warm Saline Mouth Bath for Postoperative Wound Care: A Randomized-Controlled Study.

OBJECTIVE: To evaluate and compare the effect of honey or saline mouth bath for wound care on the rate of re-epithelisation of the lateral palatal defects and occurrence of early postoperative complications following palatoplasty. METHODOLOGY: This was a prospective randomized study on participants with non-syndromic cleft palate conducted at a tertiary health institution in Lagos, Nigeria. The test group received oral honey drops for post-operative care for an initial period of two weeks post-surgery, while the control group had regular oral toileting using a warm saline solution. The primary outcome was epithelisation of lateral palatal defect at 2- and 4-weeks post repair. Descriptive and comparative statistics were computed, and the p-value was set at <0.05. RESULTS: Fifty participants were recruited into the study, 24 in the Test group and 26 in the Control group. The frequency of occurrence of oronasal fistula in the Test group was 4.0% while in the Control group was 10.0%, however, this was not statistically significant. Complete epithelisation of the lateral palatal defect was clinically observed in 66.7% of the participants in the Test group at 2 weeks post-operation, while only 38.5% of participants in the Control group had clinically observed complete epithelisation at the same time point (ß = 1.70, p = .035, 95% CI 1.122-26.533). At four weeks, all wounds had epithelised irrespective of the study group. CONCLUSION: The application of honey appears to aid earlier epithelization of palatal surgical wounds following cleft palate repair and reduced the incidence of palatal fistula.

A Review of the Use of Buccal Fat Pad in Cleft Palate Repair.

OBJECTIVE: To review the available evidence on the use of the Buccal Fat Pad in primary and secondary Cleft Palate repair. METHODS: This is a narrative review. A computerized literature search was conducted for articles published till February 2022 using the Mesh phrases buccal fat pad AND cleft palate, Bichat's Fat pad AND cleft palate, buccal fat pad OR Bichats Fat pad AND cleft palate. RESULTS: A total of 35 articles were included in this review based on the set eligibility criteria. Most of the studies were retrospective case reviews (n = 16, 45.7%), and the aggregate number of patients from all included studies was 666. Reported uses of the buccal fat pad (BFP) in association with cleft palate repair include the closure of central cleft palate defect and nasal floor in primary cleft palate repair, oronasal fistula repair following primary repair of cleft palate, and closure of relieving incision defect in primary repair of cleft palate. Complications reported were 24 cases of Oronasal Fistula (ONF), 2 dehiscences, and 4 transient mucosal defects. CONCLUSION: The high success rate, vascularity, ease of tissue harvest, and low donor site morbidity all support its use as an adjunct flap in cleft palate repair, especially in the closure of wide palatal clefts, to prevent post-palatal repair fistula, wound contracture, and subsequently velopharyngeal insufficiency and possibly midface hypoplasia.