Azeez Butali

Van der Woude syndrome (VWS) is the most common syndromic form of orofacial clefts (OFCs). The heritability of VWS is largely (~70%) explained by variants in the IRF6 gene. Experimental studies to confirm genetic variant effects are essential but are time intensive and expensive. Advancing next-generation sequencing techniques has made it possible to identify genetic variation quicker than their causal effects in disease processes can be ascertained. Therefore, employing computational tools to reliably predict their causal effects is crucial for advancing translational research. We conducted Sanger sequencing of the IRF6 gene in 46 VWS cases across 34 families to identify likely causal missense variants. We then assessed structure-informed stability changes to the IRF6 protein when these variants were incorporated into the protein, using DDGun3D. We compared DDGun3D predictions to results from previous experimental studies. Among four variants previously shown to prevent functional rescue in zebrafish, only the variant IRF6(NM_006147.4):c.881T>C, shown to cause rupture of zebrafish embryo, exhibited a high free energy change (∆∆G_fold = 3.5 kcal/mol), indicating that substantial predicted thermodynamic destabilization does not capture all disruptive function of IRF6. Our study demonstrates the utility of a protein structure-based computational approach for functional variant interpretation, providing a complementary method for studying genetic variation. Integrating computational predictions with experimental data can enhance our understanding of genetic conditions. However, success depends on fully elucidating protein structures, which is an active area of research.

Objective: To investigate the likelihood of families with a child with orofacial cleft falling into catastrophic healthcare expenditure (CHE) due to financial burden of caring for the child. Design: Cross-sectional descriptive study using a 35-item interviewer administered proforma. Setting: A tertiary health institution in Lagos, Nigeria. Participants: All consenting caregivers attending the orofacial cleft clinic within the study period. Main outcome measure: The primary outcome was the capacity of families to make out-of-pocket payment (CTP) for treatment. Results: This study enrolled 84 respondents, with CHE analysis based on 83 participants with complete income data. The approximate combined family monthly income of 77.4% was below ₦300,000(∼$222), supporting a median of five family members. A single government-subsidized surgical intervention can cost as much as ₦600,000(∼$444) out-of-pocket. Applying the WHO threshold of out-of-pocket expenditure exceeding 40% of household's capacity to pay(CTP), and using phenotype-specific cost pathways, an estimated 53.0% to 59.0% of families would face CHE from direct treatment costs, with no statistically significant difference across cleft phenotypes. For unilateral and bilateral cleft lip and palate, the 10-year direct cost of comprehensive cleft care at our center ranges from ₦2,975,000 to ₦3,980,000 (∼$2204-$2948), which exceeds the total annual income of many participating families. Conclusion: The result of this study reveals the frailty of the current healthcare financing model for orofacial cleft management in Nigeria and the urgent need for policy intervention to extend insurance coverage to the full multidisciplinary care pathway.

Objective: Sense of coherence (SOC) refers to an individual's psychological orientation that allows for successful stress management. This study aimed to determine the relationship between experience of stigmatization and SOC of caregivers of children with cleft lip and/or palate (CL/P). Design: Cross-sectional. Setting: A tertiary hospital in Nigeria. Patients/Participants: Caregivers of children with CL/P managed from January 2023 to December 2024. Outcome Measures: Caregivers’ stigmatization against their child with CL/P, their experience of societal stigmatization, and their SOC. Results: A total of 158 caregivers, all mothers, participated in this study. Their age ranged from 17 to 44 years, with a median age of 30 years. The age range of participants' children was 1 to 23 weeks, and their median age was 5 weeks. Twenty-two (13.9%) mothers felt shame when their child was born, and 18 (11.4%) wished their child was never born. The majority (81.0%) of participants had low experience of societal stigmatization. For SOC, the minimum score recorded was 26, the maximum was 65, and the mean was 44.9 ± 8.94. Caregiver stigmatization against children with CL/P was more commonly seen among those with low SOC, while most mothers with high SOC exhibited positive reactions toward their child ( P < .05). Similarly, the majority of caregivers with low experience of societal stigmatization had high SOC, while caregivers with high experience of societal stigmatization had low SOC ( P < .05). Conclusion: Low experience of stigmatization was significantly associated with high SOC and vice versa. This study suggests that SOC may be dampened by stigmatization, which can have harmful consequences in cleft management.

Objective: To determine the changes in felt needs of caregivers of children with cleft lip and/or palate (iCL/P) from first clinic presentation to first surgical intervention. Design: Longitudinal observational study. Setting: A tertiary hospital in Nigeria. Patients, Participants: Caregivers of children with nonsyndromic CL/P (iCL/P) managed at a tertiary hospital in Nigeria from January 2023 to December 2024. Intervention: Multiple semistructured counseling sessions. Main Outcome Measures: Caregivers felt needs at time of first clinic presentation (T ₁ ) and at time of first surgical intervention (T ₂ ). Results: Eighty caregivers, all mothers of children with iCL/P were included. Their mean age was 31.1 ± 6.24 years. At T ₁ , information on etiology of iCL/P, surgical intervention, feeding and potential speech challenges were considered very significant needs. Feeding was also considered a primary concern for most participants. At T ₂ , after counseling sessions, there was a statistically significant reduction in the proportion of caregivers who considered information on surgical intervention, improvement in family and community acceptance and improvement in clinical psychology as very significant needs, while potential speech challenge became the primary concern of most caregivers. Caregivers of children below 1 month of age were also found to have significantly higher felt needs compared to those with older children. Conclusions: The waiting period between birth and first corrective surgery can be stressful for caregivers of children with iCL/P. Repeated counseling from first clinic visit to first surgical intervention may be beneficial to caregivers and should focus on the domains of needs highlighted in this study.

Malocclusion is a common oral health problem with a strong hereditary component. Previous genetic studies were limited by small sample sizes and low genomic coverage. To address these limitations, we conducted a genome-wide association study (GWAS) using array-based genotype data in 5 large, multiancestral cohorts. The study included 3,405 participants from the United States and its territories, the Philippines, Colombia, and Nigeria. Class II malocclusion was defined as an Angle’s class II molar relationship with an overjet >3.5 mm, class III malocclusion as an Angle’s class III molar relationship with a negative overjet, and class I malocclusion (controls) as an Angle’s class I molar relationship with an overjet of 0 to 3.5 mm. In the vertical plane, an anterior open bite of any magnitude was classified as “open bite,” while an overbite >3.5 mm was classified as “deep bite,” with controls having an overbite of 0 to 3.5 mm. Multiplanar malocclusion included cases with both sagittal and vertical discrepancies, with controls having an Angle’s class I molar relationship, an overjet of 0 to 3.5 mm, and an overbite of 0 to 3.5 mm. GWAS for each phenotype was conducted within individual cohorts before meta-analysis. We identified genome-wide significant associations ( P ≤ 5E-08) at 11q22.3 (rs372564249, odds ratio [OR] = 3.12) and 3p24.3 (rs13060317, OR = 2.4) for class II and multiplanar malocclusion, respectively. Additionally, we observed a near-significant signal at 12q15 (rs1261646, OR = 1.9, P = 6.2 × 10 ^-8 ) for class II malocclusion and a suggestive association at 1p21.3 (rs7541224, OR = 2.0, P = 1.7 × 10 ^-7 ) for class III malocclusion. The 11q22.3 and 3p24.3 loci were QTLs for the PDGFD and SGO1-AS1 genes, and transcriptomic data showed consistent expression of these genes during facial development. These findings provide valuable insights into malocclusion etiology and lay the groundwork for genetic risk score development.

Introduction: Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a common congenital malformation with complex etiology involving both genetic and environmental factors. Epigenetic mechanisms may mediate environmental contributions, but separating genetic from environmental effects remains challenging. Methods: We present an epigenome-wide association study with 32 monozygotic and 22 dizygotic twin pairs discordant for NSCL/P on blood and saliva samples. Differential methylation analysis was conducted using linear models to identify CpG sites showing significant methylation differences between affected and unaffected twins followed by functional annotation and pathway enrichment analysis. Results: The top-ranked finding is a differentially methylated region comprising two CpG sites at the CYP26A1 locus, cg12110262 (P = 3.21x10 ^-7 ) and cg15055355 (P = 1.39x10 ^-3 ). CYP26A1 is essential for retinoic acid catabolism and craniofacial patterning. The chromatin regulator ANKRD11 , which causes KBG syndrome featuring cleft palate was the second best hit. Differentially methylated CpG sites showed significant enrichment in craniofacial enhancers and overlap with multiple GWAS-validated cleft genes including VAX1, PVRL1, SMAD3 , and PRDM16 . Conclusions: Our findings implicate retinoic acid signaling and chromatin regulation in NSCL/P etiology and demonstrate the value of discordant twin designs for distinguishing environmental from genetic epigenetic contributions to complex malformations.

Oral health disparities in Africa are stark, characterized by limited access, fragmented data systems, low political will, and persistent underfunding. With the WHO Global Oral Health Action Plan 2022–2030 calling for integration, prevention, and equity, African researchers and institutions are stepping into leadership roles to drive contextualized, data-informed, and sustainable solutions. This perspective synthesizes insights from African-led initiatives, including collaborative research networks, institution-based innovations, and field trial systems, which are designed to generate locally relevant evidence for clinical interventions and future research. This article draws on experiences across subregions and institutions, informed by the "Oral Health in Africa" symposium at the 2025 International Association for Dental Research (IADR) General Session. The article covers community field trials in Egypt, the initiative of the Intercountry Centre for Oral Health in Nigeria, and continent-wide research networks. It highlights opportunities for transformative change in African oral health and outlines priorities for data generation, policy alignment, institutional coordination, and funding strategies necessary to deliver on the global oral health agenda. Key words: Oral Health Policy, Research Capacity-Building, Health Systems Strengthening, Africa, Universal Health Coverage (UHC), Community-Based Interventions, WHO Global Strategy.