Nonsyndromic Cleft Research Articles

Association of selected gene variants with nonsyndromic orofacial clefts in Kuwait

Introduction and objectivesNon-syndromic orofacial clefts (NSOFCs) are complex congenital abnormalities involving both environmental and genetic factors involved in orofacial development. This study aimed to investigate the genetic association of specific genetic variants at different CYRIA gene loci with the development of NSOFCs in Kuwait. MethodsFour genetic variants (rs7552, rs3758249, rs3821949, and rs3917201) at four selected gene loci (CYRIA, FOXE1, MSX1, and TGFB3) were genotyped in a total of 240 DNA samples (patients (n = 114) and random controls (n = 126)) employing TaqMan® allele discrimination assay. For each variant and its genotype, the frequencies were determined and tested for Hardy-Weinberg Equilibrium. Genotype frequencies was compared between patients and controls using Pearson’s test. Logistic regression analyses were employed to test for the associations of the four selected variants with the occurrence of NSOFCSs. ResultsSignificant differences in the distribution of genotypes between cases and controls, rs7552, rs3821949, and rs3917201 were found to have a positive association with NSOFCs. After adjusting for gender, the GG genotype of the rs7552 variant, the AG genotype of the rs3821949 variant, and the CC genotype of the rs3917201 variant showed nearly a two-fold increased risk of NSOFC (p < 0.05). ConclusionThis study reports significant findings on the contribution and modest effect of CYRIA rs7552, MSX1 rs3821949, and TGFB3 rs3917201 in the development of NSOFCs. Our findings provide further evidence on the molecular mechanism and the role of the selected genes in NSOFCs.

Parental Age and Severity of Non-Syndromic Orofacial Clefts: Relationship with De Novo Mutations

Background: This study investigates the relationship between paternal and maternal age, and the severity of orofacial clefts and the presence of de novo mutations in children. Methods: This was a retrospective study of individuals who were diagnosed with non-syndromic cleft lip and/or palate (CL/P) and their unaffected parents, from 2012 to 2019. We obtained data from the AfriCRAN project database for Nigerians with non-syndromic orofacial clefts. These individuals were recruited at the Oral and Maxillofacial Surgery Clinic, Lagos University Teaching Hospital, Lagos. Results: There was no statistically significant association between type of CL ± P and parental age in young fathers (p = 0.93). When older fathers were considered, the percentage of complete (more severe) CL ± P cases increased, especially when they were married to older mothers, and this was statistically significant (p = 0.036). In older fathers, the risk of CL ± P in their offspring was increased (OR: 2.66, CI: 1.04-6.80), and there was also an increased risk of developing right-sided CL ± P (OR: 1.61, CI: 1.0-2.59). There was a reduced risk of isolated clefts of the soft palate in younger fathers (OR: 0.36, CI: 0.07–1.71), but the risk increased when considering complete types (more severe) of isolated clefts of the hard and soft palates (OR: 1.63, CI: 0.7–1.7). There was an increase in de novo mutation in children as the difference between paternal and maternal age increased. Conclusion: The study showed that a higher risk of CL ± P and de novo mutations in children is associated with increased parental age.

Central Auditory Processing Abilities in Children with Non-Syndromic Cleft Lip and Palate: An Electrophysiological Study.

The present study compared the central auditory processing abilities using electrophysiological tests in children with non-syndromic cleft lip and palate (NSCLP) and their age-matched control group. Thirty children aged 7 to 15 years were recruited for the study. Participants were divided into 2 groups. The clinical group (children with NSCLP) comprised 15 children, while the control group (craniofacially typical peers) comprised 15 children with normal hearing sensitivity and auditory processing skills. Electrophysiological tests, including auditory brainstem responses (ABR), binaural interaction component (BIC) of ABR, auditory late latency responses (ALLR), and P300 were assessed. The results showed deviant responses in ABR, BIC, and ALLR in children with NSCLP compared to craniofacially typical counterparts. However, no significant difference was observed in P300 between the two groups. Children with NSCLP may be at a higher risk of central auditory processing disorder due to their abnormal neural transmission in the auditory nervous system. Also, assessing auditory processing abilities in children with NSCLP should include electrophysiological tests in the test battery for additional information regarding neural transmission.

Genetic Variants in METTL16 Affect the Risk of Non-Syndromic Orofacial Clefts.

N6-methyladenosine (m6A) is the most prevalent modification of RNA in eukaryotes which is associated with many cellular processes and diseases. Here, our objective is to explore whether genetic variants in m6A modification genes are associated with the risk of non-syndrome orofacial clefts (NSOCs). The transmission disequilibrium test (TDT) was performed to calculate the association between single nucleotide polymorphisms (SNPs) in m6A modification genes and NSOCs risk in 944 case-parent trios. The function of SNP was predicted by HaploReg, RegulomeDB and histone enrichment data. The expression quantitative trait locus (eQTL) analysis was examined using Genotype-Tissue Expression (GTEx) and eQTLGen. The role of gene in the development of NSOCs was assessed with correlation and enrichment analysis based on gene expression data in mice craniofacial tissue and zebrafish embryo. We identified that rs8078195 (A > C) in METTL16 was suggestively associated with the increased risk of NSOCs (OR = 1.32, p = 1.80E - 03). The region surrounding rs8078195 was subjected to deoxyribonuclease hypersensitivity and enriched with multiple histone modifications. In addition, it had a significant eQTL effect with METTL16 in skin tissue and human peripheral blood, which played an important role in NSOCs development. Bioinformatic analysis indicated that METTL16 contributed to the development of NSOCs probably by regulating cell cycle process. Rs8078195 in METTL16 was associated with the occurrence of NSOCs.

Alterations of senescence-associated markers in patients with non-syndromic cleft lip and palate

Non-syndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common craniofacial anomalies. Abnormal Alu methylation in DNA of the pregnant mother may influence the abnormal development of the child. This study aimed to examine Alu methylation and cellular senescence in NSCL/P patients and their mothers as well as the correlation with the severity of NSCL/P. A total of 39 patients with NSCL/P and 33 mothers were enrolled. Of these patients, 6 were cleft lip only (CLO), 9 were cleft palate only (CPO), and 24 were cleft lip and palate (CLP). Alu methylation and senescence markers were determined in the white blood cells of NSCL/P patients, their mothers, and in the lip and palatal tissues of patients at the time of cheiloplasty and palatoplasty. Total Alu methylation was not significantly different between groups. However, a decrease in Alu hypermethylation, increased partial Alu methylation, RAGE, and p16 expression were shown in CLP, the most severe cleft type. Alu methylation in tissues did not differ between groups. In mothers, an increase in Alu methylation was observed only in the CLP. Therefore, the pathogenesis of NSCL/P may be related to Alu methylation of the mother promoting loss of Alu methylation and subsequently senescence in the children.

Long-Term Three-Dimensional Morphometric Outcome Study of Nasal Bone in Cleft Patients.

Cleft lip nose deformities are characterized by underlying features in the bony skeleton as well as the soft tissues; however, no previous study has focused on the evaluation of the nasal bone. The aim of this study was to compare nasal bone features among adult patients with unilateral cleft lip with or without cleft palate, those with bilateral cleft lip and palate, and controls. Included in this retrospective study were patients aged ≥16 years with nonsyndromic cleft who underwent long-term orthodontic treatment and controls aged 18-45 years who underwent surgery for jaw deformities at Keio University Hospital. Piriform width, nasal width, and nasomaxillary angle values measured on CT were compared among the groups using the Wilcoxon rank sum test. Nine patients had unilateral cleft lip and alveolar cleft, 19 had unilateral cleft lip and cleft palate, and 14 had bilateral cleft lip and palate (BCLCP). There were 18 controls. Mean piriform width and mean nasomaxillary angle were significantly greater in the BCLCP group than the control group (20.1±2.54mm versus 18.8±1.35mm, P<0.05; and 105.8±8.13 degrees versus 100.4±7.95 degrees, P<0.05, respectively). There was no significant difference in mean nasal width among the groups. Nasal bone morphology was not affected by initial cleft lip alone or by the presence or absence of cleft palate. Patients with bilateral cleft lip and palate have a wider and lower nose than those without cleft deformity and might benefit more from reduction of the bony nasal width than from treatment of the soft tissues.

The mediating role of abnormal ZEB1 methylation in the association between nickel exposure and non-syndromic orofacial cleft

Our previous study found a positive relationship between fetal nickel exposure and the risk of OFCs. The teratogenic mechanism of nickel is not clear. In this study, we aim to examine the mediating effect of DNA methylation on the association of nickel(Ni) exposure with NSOFC in fetuses. 10 cases and 10 controls was used for screening target gene by Illumina Infinium Methylation EPIC(850k) BeadChip. 36 cases and 78 controls was conducted to determine DNA methylation level of selected gene in umbilical cord blood by Mass spectrometry assay. Mediation analysis was used to evaluate the potential mediating effect of selected gene methylation on the relation between concentrations of Ni and the risk for NSOFC. In the discovery stage, ZEB1 gene was identified to be hypermethylated in both nickel exposure and NSOFC group for validation. In the verification stage, the overall average methylation level of ZEB1 was significant higher in NSOFC cases(median = 8.70, interquartile range(IQR): 5.75–11.53) as compared to controls (median = 5.35, IQR: 4.30–7.78). The risk for NSOFC was increased by 1.43-fold with hypermethylation of ZEB1. Significant correlation was observed between concentrations of Ni in umbilical cord and methylation level of ZEB1. The hypermethylation of ZEB1 had a mediating effect by 20.47 % of total effect of Ni on NSOFC risk. Hypermethylation of ZEB1 is associated with the risk for NSOFC and may partially explain the association between Ni exposure and NSOFC risk. Our findings provide new insights into the epigenetic mechanisms underlying NSOFC and suggesting potential targets for future therapeutic interventions.

Prenatal co-exposure to phthalate metabolites and bisphenols among non-syndromic cleft lip and/or palate in offspring

Phthalate metabolites and bisphenols can cause adverse pregnancy outcomes. However, there is no study to evaluate the associations of prenatal exposure to phthalate metabolites and bisphenols with non-syndromic cleft lip and/or palate (NSCL/P) risk in offspring. A population-based case-control study was conducted in a multicenter setting from 2005 to 2021, enrolling 448 pregnant women. Seven phthalate metabolites and six bisphenols were quantified in placenta using liquid chromatography-tandem mass spectrometry. In the logistic regression analysis, high levels of mono-ethyl phthalate, mono-cyclohexyl phthalate, mono-octyl phthalate, bisphenol A, bisphenol AF, bisphenol AP, and fluorene-9-bisphenol were associated with increased NSCL/P risk with odds ratios (95% confidence intervals) of 1.86(1.07,3.25), 6.56(3.47,12.39), 8.49(4.44,16.24), 8.34(4.32,16.08), 3.19(1.81,5.62), 2.78(1.59,4.86), and 5.16(2.82,9.44). The Bayesian kernel machine regression model revealed that co-exposure to phthalate metabolites and bisphenols was associated with increased NSCL/P risk. Similarly, quantile-based g-computation analysis indicated that each quantile increase in mixture concentration was positively related to higher risk for NSCL/P [odds ratio (95% confidence interval) = 2.98(1.97,4.51)]. This study provides novel evidence that prenatal single and co-exposure to phthalate metabolites and bisphenols were associated with increased NSCL/P risk, suggesting that exposure to phthalate metabolites and bisphenols during pregnancy should be minimized to reduce the incidence of NSCL/P in offspring.

Analysis of Influencing Risk Factors of Nonsyndromic Unilateral Cleft Lip in South Sulawesi

Abstract Objective This study is to determine the most dominant risk factors for the potential occurrence of nonsyndromic unilateral cleft lip in South Sulawesi, Indonesia. Materials and Methods This is a retrospective study of several hospitals in South Sulawesi, Indonesia. An analysis was performed on the medical records of patients with nonsyndromic unilateral clefts. In the period from January 2018 to December 2022, risk factors include gender, parental education, family history of cleft lip and palate, maternal history of smoking or exposure to secondhand smoke, and consumption of drugs and alcohol during gestational age. The size of the sample is determined using the cluster sampling technique. Statistics uses chi-square test analysis and logistic regression for nominal variables. It uses SPSS Statistics version 25, with a value of p &lt; 0.05. Results The highest risk factor was found in patients with parents with a history of alcohol consumption during pregnancy and in patients with family history of cleft lip and palate, history of smoking or exposure to cigarette smoke, history of drug consumption, and gender. In comparison, parents' education level does not have a significant influence. Conclusion History of alcohol consumption during pregnancy, family history of cleft lip and palate, history of smoking or exposure to cigarette smoke, history of drug consumption, and gender are considered risk factors for nonsyndromic unilateral cleft lip in South Sulawesi, Indonesia.

Association of rs8670 Polymorphism in the MSX1 Gene With Non-Syndromic Cleft Lip With or Without Cleft Palate in Malay Population.

This study aimed to investigate the association between variants present in the MSX1 gene and the risk of developing non-syndromic cleft lip with or without cleft palate (NSCL±P) among individuals of Malay ethnicity in Malaysia. This case-control study involved 89 patients with NSCL±P and 100 healthy control subjects. Polymerase chain reaction (PCR) was performed on both exon 1 and exon 2 of the MSX1 gene using four pairs of primers. The amplification products were then subjected to denaturing high-pressure liquid chromatography for initial screening, and the presence of a heteroduplex peak was validated using direct sequencing analysis to detect the single-nucleotide polymorphism. Five previously known variations (c.-36G>A, p.Ala30Ala, p.Ala34Gly, p.Gly110Gly, and rs8670: C>T) were detected within the MSX1 gene in both NSCL±P patients and controls.A significant association was found between the rs8670: C>T variant and NSCL±P (p = 0.017; OR: 0.368; 95% CI: 0.152 - 0.893), with this particular single-nucleotide polymorphism present in 20% (20) among controls and 7.9% (7) of the NSCL±P cases. Our data showed a lower incidence of thers8670: C>Tpolymorphism among NSCL±P cases compared to control in this Malay population. However, since this variant is located in the 3'UTR, it could potentially impact the stability ofMSX1mRNA.

Executive function performance in persons with non-syndromic cleft lip and palate

Background: Executive functions (EFs) are crucial cognitive functions that mature from birth to adolescence. They are vital for daily task execution and overall success and also influence language and communication development. Children with EFs deficits often experience delays in language and speech abilities. These impairments are particularly prevalent among individuals with cleft lip and palate. Consequently, speech and language pathologists must address these impairments through assessments and interventions. Despite this urgent need for action, there is a scarcity of research on executive function performance in this population in Thailand, prompting an investigation to address this issue. This study explores executive function performance in this population to enhance the quality of life for individuals with cleft lip and palate. Materials and methods: Using a survey-based approach, executive function performance was assessed in 5- to 15-year-old volunteer with non-syndromic cleft lip and palate attending the speech therapy camp provided by the Princess Sirindhorn IT Foundation Craniofacial Center at Chiang Mai University in April 2024. Parents completed the Behavior Rating Inventory of Executive Function (Parent form), with scores ≥65 indicating executive function difficulties. Results: The study involved 29 participants, 14 males (48.28%) and 15 females (51.72%), with a mean age of 8 years and 9 months. Average scores for executive function abilities in BRI, MI, and GEC were 52.21, 56.48, and 58.90, respectively. There are several participants with abnormal executive function in each age group, along with their average T-scores across different domains. Children aged 5, 6-8, and 9-11 have T-scores for executive function performances falling into problematic levels for 1, 2, and 5 individuals, respectively. Conclusion: Most of the sample group demonstrated executive function skills within the normal range. However, a certain number of individuals experienced issues with executive function. These findings offer guidance for speech and language pathologists and emphasize the importance of executive function in individuals with cleft palates.

Psychopathology in Infants, Toddlers, and Preschool Children with Nonsyndromic Clefts of the Lip and/or Palate: A Case-Control Study.

The aim of this study is to assess psychopathology and maternal interactions in infants, toddlers, and preschool children with nonsyndromic clefts of the lip and/or palate (NSCLP) and association of psychopathology with cleft-related factors and maternal interactions. Twenty-six children from 4 to 72 months of age with NSCLP, who were attending the Plastic, Reconstructive and Aesthetic Surgery Department were included as the case group. Fifty-two healthy children who were matched on age and sex with the case group were taken as controls. Children were assessed in aspects of psychiatric diagnosis, articulation, and development. Speech and language disorders (SLD) (P<0.001), disorders of affect (DA) (P=0.005), feeding behavior disorder (P=0.002), sleep-behavior disorder (SBD) (P=0.038), and disordered mother-child relationship (P<0.001) were more prevalent in children with NSCLP. Dental alignment (P=0.024), number of operations (P=0.006), and type of operations (P=0.012) were associated with DA. The children in the case group, who had disordered relationship with their mothers had significantly more SLD (P=0.036) and SBD (P=0.039). Children with NSCLP are at risk of developing psychopathology, especially SLD and DA. Maternal interactions and the above cleft-related factors and may be the target of interventions to prevent and treat psychiatric disorders in these children.

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.

Prevalence of tooth agenesis and supernumerary teeth related to different Thai cleft lip and cleft palate populations

BackgroundPattern of dental anomalies encountered in cleft patients shows subtle signs of genetic involvement. This study aimed to evaluate the prevalence and pattern of tooth agenesis and supernumerary teeth in Thai cleft population according to the cleft type.MethodsData collected from patients with cleft lip and palate, who had been treated at Tawanchai Cleft Center, Khon Kaen University, Thailand, available during year 2012–2022, were investigated. Records from 194 patients with non-syndromic clefts met the inclusion criteria. Standard dental records, and at least either orthopantomogram (OPG) or cone beam computed tomography (CBCT), were examined. Statistical analysis was performed using chi-square and binominal test (p ≤ 0.05).ResultsPrevalence of tooth agenesis was higher (77.3%) than that of supernumerary teeth (5.7%) and was more common in bilateral cleft lip and palate (BCLP) (88.1%) than in unilateral cleft lip and palate (UCLP) (72.6%) (p = 0.017). The upper lateral incisor was more frequently affected (46.4%), followed by the upper second premolar. The number of missing teeth observed on the left side was significantly higher. Patients with left UCLP (ULCLP) had the highest prevalence of tooth agenesis. A total of 41 tooth agenesis code (TAC) patterns was found. The prevalence of supernumerary teeth was comparable with 6.6% of ULCLP, 5.1% of BCLP, and 4.5% of URCLP. Tooth-number anomalies were observed more often in the BCLP and were most likely to occur on the left side of the maxilla. Both types of anomalies could be featured in a small proportion of cleft patients.ConclusionsMore than half of the patients with non-syndromic cleft lip and palate in this study, presented with tooth-number anomalies. Tooth agenesis was approximately 10-time more prevalent than supernumerary teeth. Tooth agenesis was likely to appear on the left-side of the maxilla regardless of the laterality of the cleft.

Genetic associations and parent-of-origin effects of PVRL1 in non-syndromic cleft lip with or without cleft palate across multiple ethnic populations.

This study investigated the associations of PVRL1 gene variants with non-syndromic cleft lip with or without cleft palate (NSCL/P) by evaluating transmission distortion and parent-of-origin (POO) effects in multiple ethnic populations. We conducted allelic and genotypic transmission disequilibrium tests (TDT) on 10 single-nucleotide variants (SNVs) in PVRL1 using data from 142 Korean families with an affected child. POO effects were analyzed using the POO likelihood ratio test, comparing transmission rates of maternally and paternally inherited alleles. To assess generalizability and ethnic heterogeneity, we compared results from Korean families with data from the Center for Craniofacial and Dental Genetics, which included 2,226 individuals from 497 European and 245 Asian trios. TDT analysis identified significant over-transmission of the rs7940667 (G361V) C allele in Korean families (p=0.007), a finding replicated in both Asian (p=6.5×10-7) and European families (p=1.6×10-10). Eight SNVs showed strong TDT evidence in larger Asian and European datasets after multiple comparison corrections (p<0.0073). Of these, 4 SNVs (rs7940667, rs7103685, rs7129848, and rs4409845) showed particularly robust association (p<5×10-8). POO analysis revealed significant maternal over-transmission of the rs10790330-A allele in Korean families (p=0.044). This finding was replicated in European families (p=9.0×10-4). Additionally, 3 other SNVs, rs7129848 (p=0.001) and the linked SNVs rs3935406 and rs10892434 (p=0.025), exhibited maternal over-transmission in the validation datasets. Our findings provide robust evidence supporting the associations of PVRL1 variants with NSCL/P susceptibility. Further research is necessary to explore the potential clinical applications of these findings.

Pattern of Cleft Lip and Palate Clefts at a Tertiary Care Hospital in Saudi Arabia.

Clefts of the lip and palate (CL/P) and cleft palate (CP) are the most common craniofacial congenital anomalies. Clefts are classified as syndromic and nonsyndromic. Nonsyndromic clefts have no known genetic causes. This study combines prospective and retrospective studies to review the patterns of CL/P and CP and associated syndromes and conditions in patients registered for CL/P surgery at a tertiary care pediatric center in our tertiary care hospital in Saudi Arabia. It included patient data from May 2015 through April 2023. Patient record forms and SPSS (IBM version 20.0) were used to collect and analyze data. A significance level of 5% was used, with p ≤ 0.05 considered statistically significant. Of the 319 patients who met our inclusion criteria, 175 were male. Of the total, 99 had a left unilateral isolated cleft lip, 61 had a right unilateral isolated cleft lip, 69 had a bilateral cleft lip, and 90 had an isolated CP. Of the total, 140 had CL/P. Around 242 were nonsyndromic. The Chi-square test revealed a significant association between the prevalence of isolated CP and CLP and gender. The prevalence of left unilateral isolated cleft lip and bilateral and isolated CP was significantly associated with syndromic and nonsyndromic cases. Males are more likely to be affected by orofacial clefts, which is consistent with the global trend. Isolated CP was the most common orofacial cleft. Within the sample, syndromes' association with orofacial clefts was significantly weaker than that of isolated and bilateral clefts.

A Comparative Analysis of Sector Classification and the Impacted Canine Grading System by Kumar and Daigavane in Patients With Unilateral Cleft Lip and Palate Utilizing Orthopantomogram (OPG) as a Diagnostic Tool.

Introduction Non-syndromic oral clefts, affecting one in 700 newborns in India, are the most prevalent craniofacial anomalies, with genetic or environmental causes impacting various life aspects. Studies indicate higher dental disturbances, particularly impacted canines, in cleft lip and palate (CLP) patients compared to non-cleft individuals. Impacted canines, trapped by hard tissues, require early diagnosis to prevent orthodontic issues. The widely used Ericson and Kurol method employs orthopantomograms (OPGs) to classify canine impaction in typical children. However, diagnosing canines in CLP patients is challenging due to palate defects and post-grafting complications. This study aims to compare the utility of the Kumar and Daigavane (KD) grading system and the sector classification to determine the best method for diagnosing impacted canine eruption paths. Method This cross-sectional comparative observational study was conducted at Sharad Pawar Dental College's Department of Orthodontics and Dentofacial Orthopaedics. The sample size, calculated using a significance level of 5% and a prevalence of 1%, required a minimum of 16 participants aged 9-11 years with non-syndromic clefts and impacted canines. Patients with systemic diseases or over 12 years of age were excluded. The sectoral and KD classification systems collected and evaluated OPGs from qualifying cleft patients. Sector classification considered the angle between the occlusal plane or canine tip and the adjacent tooth's long axis, while KD's classification considered the Frankfort horizontal plane, occlusal plane, vertical height from the occlusal plane, canine apex root position, and canine exposure to the cleft defect. Results The study found an 81.25% agreement between the KD grading system and the sector classification, with a Cohen's kappa value of 0.586, indicating a moderate agreement. The KD system showed 81.82% sensitivity and 80.00% specificity, with positive and negative predictive values of 90.00% and 66.67%, respectively. The receiver operating characteristic (ROC) curve analysis revealed the KD system's superior performance in identifying impacted and non-impacted canines compared to the sector classification. Conclusion The KD grading system demonstrated higher efficacy than the sector classification for evaluating the impacted canines in children with unilateral cleft lip and palate (UCLP). The KD system's high sensitivity and specificity make it a valuable tool for predicting canine eruption paths and addressing anatomical challenges in cleft conditions. This study highlights the need for accurate diagnostic tools tailored to cleft patients and contributes to advancing orthodontic treatment outcomes through improved classification systems.

Testing Reported Associations of Gene Variants with Non-Syndromic Orofacial Clefts in the Polish Population.

Orofacial clefts (OFCs) are the second most common birth defect worldwide. The etiology of OFCs involves complex interactions between genetics and environment. Advances in genomic technologies have identified gene variants associated with OFCs. This study aimed to investigate whether selected SNPs in the MYH9, MTHFR, MAFB, and SUMO1 genes influence the occurrence of non-syndromic OFCs in the Polish population. The study included 209 individuals with non-syndromic OFCs and 418 healthy controls. Saliva and umbilical cord blood samples were collected for DNA extraction. Four SNPs in the MYH9, MTHFR, MAFB, and SUMO1 genes were genotyped using real-time PCR-based TaqMan assays. Statistical analysis was performed using logistic regression to assess the association between SNPs and OFCs. A significant association was found between the rs7078 CC polymorphism and OFCs (OR = 3.22, CI 1.68-6.17, p < 0.001). No significant associations were identified for the rs1081131, rs13041247, and rs3769817 polymorphisms. The research indicates that the rs7078 polymorphism significantly influences the occurrence of orofacial cleft palate in the Polish population, whereas the rs3769817, rs1801131, and rs13041247 SNPs do not show such a correlation.

Effect of facial and nasolabial asymmetry on perceived facial esthetics in children with non-syndromic cleft lip and palate

ObjectiveThe aim of the present study was to objectively assess the degree of residual facial asymmetry after primary treatment of non-syndromic unilateral cleft lip and palate (UCLP) in children and to correlate it with subjective ratings of facial appearance.Materials and methodsStereophotometry was used to record the faces of 89 children with UCLP for comparison of cleft and non-cleft sides up to 5 years after primary cleft closure. Root mean square values were calculated to measure the difference between the shape of cleft and non-cleft sides of the face and were compared to controls without a cleft lip. The Asher-McDade Aesthetic Index (AMAI) was used for subjective rating of the nasolabial area through 12 laypersons.ResultsChildren with a cleft lip (CL) showed no significant difference in RMS values compared to controls. Significant differences occurred when the evaluation was limited to the nasolabial area, however only in patients with cleft lip alveolus (CLA) and cleft lip palate (CLAP)(p < 0.001). In contrast, subjective ratings showed significantly higher values for all three cleft severity groups (CL, CLA, CLAP) compared to controls (p < 0.001). There was a non-linear correlation between the RMS (root mean square) values and the AMAI score.ConclusionsEven non-significant discrete objective deviations from facial symmetry in children after primary closure of UCLP are vigilantly registered in subjective ratings and implemented in the judgement of facial appearance.Clinical relevance3D stereophotometry is a usefull tool in monitoring asymmetry in patients with a cleft.

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

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. 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). 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). 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.