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.

Rare Variants Analyses Suggest Novel Cleft Genes in the African Population.

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 NSOFC. 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.

Whole Exome Sequencing Identifies Damaging Variants in Indonesians with Clefts.

OBJECTIVES: The interaction between genomics, genetic and environmental factors have been implicated in non-syndromic orofacial cleft development. In the current study, we investigated the contributions of rare and novel genetic variants in known cleft genes using whole exome sequencing (WES) data of Indonesians with non-syndromic orofacial clefts. DESIGN: WES was conducted on 6 individuals. Variants in their exons were called and annotated. These variants were filtered for novelty and rarity using MAF of 0 and 1%. SETTING: Hospital in Indonesia. PATIENTS/PARTICIPANTS: Indonesians with non-syndromic orofacial clefts. INTERVENTIONS: Deleterious variants were prioritized. Pathogenic amino acid changes effect on protein structure and function were identified using HOPE. MAIN OUTCOME MEASURE(S): Rare and novel variants in known cleft genes were filtered and their deleteriousness were predicted using polyphen, SIFT and CADD. RESULTS: We identified rare (MAF <1%) deleterious variants in 4 craniofacial genes namely MMACHC (rs371937044, MAF = 0.00011). SOS1 (rs190222208, MAF = 0.00045), TULP4 (rs199583035, MAF = 0.067), and MTHFD1L (rs143492706, MAF = 0.0044). MMACHC has a mouse knockout model with facial cleft and failure of palatal fusion. The individual with variant in MMACHC presented with nsCPO. CONCLUSIONS: Our study provides additional evidence for the role of TULP4, SOS1, MTHFD1L and MMACHC genes in nsOFC development. This is the first time MMACHC is implicated in nsOFC development in humans.

Damaging Mutations in AFDN Contribute to Risk of Nonsyndromic Cleft Lip With or Without Cleft Palate.

Novel or rare damaging mutations have been implicated in the developmental pathogenesis of nonsyndromic cleft lip with or without cleft palate (nsCL ± P). Thus, we investigated the human genome for high-impact mutations that could explain the risk of nsCL ± P in our cohorts.We conducted next-generation sequencing (NGS) analysis of 130 nsCL ± P case-parent African trios to identify pathogenic variants that contribute to the risk of clefting. We replicated this analysis using whole-exome sequence data from a Brazilian nsCL ± P cohort. Computational analyses were then used to predict the mechanism by which these variants could result in increased risks for nsCL ± P.We discovered damaging mutations within the AFDN gene, a cell adhesion molecule (CAMs) that was previously shown to contribute to cleft palate in mice. These mutations include p.Met1164Ile, p.Thr453Asn, p.Pro1638Ala, p.Arg669Gln, p.Ala1717Val, and p.Arg1596His. We also discovered a novel splicing p.Leu1588Leu mutation in this protein. Computational analysis suggests that these amino acid changes affect the interactions with other cleft-associated genes including nectins (PVRL1, PVRL2, PVRL3, and PVRL4) CDH1, CTNNA1, and CTNND1.This is the first report on the contribution of AFDN to the risk for nsCL ± P in humans. AFDN encodes AFADIN, an important CAM that forms calcium-independent complexes with nectins 1 and 4 (encoded by the genes PVRL1 and PVRL4). This discovery shows the power of NGS analysis of multiethnic cleft samples in combination with a computational approach in the understanding of the pathogenesis of nsCL ± P.

Pattern and prevalence of dental anomalies among a paediatric population in Lagos, Nigeria.

Background: Dental anomalies are craniofacial abnormalities in the size, structure or number of the teeth. This study was conducted to assess the prevalence of dental anomalies among children aged 0-16 years attending the Paediatric Dental Clinic at the Lagos University Teaching Hospital, Lagos, Nigeria. Methods: A cross-sectional design was used and data were obtained from the dental records of the Dental Clinic from January 2014 to August 2019 by two calibrated examiners, who are co-authors of the manuscript. To test for statistical differences, Chi-squared test was utilised for the categorical variables. The prevalence of the different dental anomalies was estimated and presented with frequencies. P < 0.05 was considered statistically significant. Results: Among the 6175 patients' dental records reviewed, 50.85% (n = 3150) were male and the highest proportion of 45.4% (n = 2807) were aged between 6 and 10 years, with a mean age of 8.62 ± 3.85 years. A total of 1090 (17.52%) had dental anomalies; 465 (7.53) anomalies were in the maxilla, 263 (4.6) were in the mandible while 360 (5.83) were in both. The most common anomaly was hypoplasia 550 (9.06%), followed by retained primary tooth 546 (8.84%) and hypodontia 84 (1.36%). Dentinogenesis imperfecta 1 (0.02) and transposition 1 (0.02) were the least prevalent anomalies. Retained primary teeth (5.8%) and the cusp of Carabelli (0.4%) were slightly more prevalent among males. However, females had a higher prevalence of natal/neonatal teeth (0.4%), fusion/germination (0.4%), hypodontia (1.5%) and peg-shaped lateral incisors (0.9%). Conclusion: Dental anomalies' prevalence in this study was 17.52%, with a higher occurrence of anomalies in the maxilla. Hypoplasia was the most prevalent anomaly, after which was retained primary tooth, then hypodontia. Prompt diagnosis and preventive interventions are crucial for the appropriate management of these dental anomalies.

Impact of the coronavirus disease 2019 pandemic on orthodontic patients and their attitude to orthodontic treatment.

INTRODUCTION: This study aimed to assess the impact of the coronavirus disease 2019 (COVID-19) pandemic on the orthodontic patient. It also assessed the knowledge and attitude of patients to the COVID-19 infection and the willingness to carry out specific precautionary measures in the orthodontic clinics to mitigate the spread of the virus. METHODS: It was a cross-sectional descriptive study. Questionnaires were distributed to orthodontic patients via Google forms. The questionnaire assessed participants' knowledge, attitude, the impact of the COVID-19 pandemic on orthodontic treatment, and willingness to carry out infection control precautionary measures in the orthodontic clinic. RESULTS: A total of 304 responses were obtained; 83 males (27.3%), 221 females (72.7%) with a mean age of 35.6 years. Subjects demonstrated good knowledge of COVID-19 infection (94.7%). Most respondents (95%) considered the infection as dangerous and believed the orthodontic patient was at risk of contracting the disease but were willing regardless to carry on with their orthodontic treatment during the pandemic. Fear of contracting the COVID-19 virus during orthodontic appointments and missed orthodontic appointments (74%), and increased treatment time (50%) were the immediate and long-term concerns, respectively. A high acceptance rate of compliance to precautionary measures to mitigate virus spread in the clinic was observed. CONCLUSIONS: The COVID-19 pandemic has had a negative impact on the orthodontic treatment and the financial and emotional wellbeing of orthodontic patients. Patients were willing to continue with orthodontic management during the pandemic while complying with precautionary measures to prevent disease spread in the orthodontic practice setting.

Nigerian undergraduate dental students' knowledge, perception, and attitude to COVID-19 and infection control practices.

PURPOSE/OBJECTIVES: The current coronavirus disease 19 (COVID-19) pandemic has affected most countries. Infection, Prevention, and Control training is important in mitigating the spread of COVID-19. The closure of universities by the Nigerian government has hampered academic activities of dental students. Our objectives were to assess the knowledge, perception, and attitude of undergraduate dental students in Nigeria to the COVID-19 pandemic and infection control practices. METHODS: This was a cross-sectional study of undergraduate clinical dental students from the dental schools in Nigeria. Self-administered questionnaires were distributed to participants using an online data collection platform. Correct responses to the 45-item questionnaire on COVID-19 knowledge were scored to determine their knowledge level. A Likert scale of 1-5 was used to assess the 13-item perception and attitude questions. The level of significance was set at P values ≤ 0.05. RESULTS: A total of 102 undergraduate clinical dental students participated in the study. Males represented 54.9%, and mean age was 25.3 ± 2.4 years. Fifty percent of the students had adequate knowledge of COVID-19. Final-year students (58.1%) demonstrated more adequate knowledge of COVID-19 than penultimate-year students (28.6%, P = 0.008). Most (95.1%) respondents had positive attitudes towards infection control practices against COVID-19. CONCLUSION: Although the clinical dental students had a positive attitude to infection control practices against COVID-19, the overall knowledge of COVID-19 was barely adequate. Guidelines on COVID-19 from reputable health authorities should be reviewed by dental school authorities and disseminated to the students to suit their clinical practice.