Cleft Palate Only Research Articles

Isolated oral clefts and school grades: population-based cohort study from Norway

ObjectiveTo compare school grades of adolescents in Norway born with isolated cleft with those of their unaffected peers.DesignPopulation-based cohort study.SettingNorway.PatientsA total of 347 419 individuals born in Norway between 1986...

Progress in genetic epidemiology of non-syndromic cleft palate only

One of the most common birth defects is cleft palate only (CPO) of which non-syndromic cleft palate only (NSCPO) accounts for 50%. NSCPO is a complex disease where multiple genes and environmental factors contribute to its risk. Unlike non-syndromic cleft lip with or without cleft palate (NSCL/P), previous genome-wide association studies only identified a few common genetic variations achieving genome-wide significance. This review summarizes the recent findings on genetic epidemiology of NSCPO. According to the current evidence, the candidate genes are divided into three categories: candidate genes with strong evidence, candidate genes with suggestive evidence, and candidate genes with inadequate evidence. The findings of epigenetic studies, the next generation sequencing studies, interaction analysis on NSCPO are also reviewed.

Variant Analyses of Candidate Genes in Orofacial Clefts in Multi‐Ethnic Populations

Cleft lip with or without cleft palate (CL/P) and cleft palate only (CPO) are congenital birth defects where the upper lip and/or palate fail to fuse properly during embryonic facial development. CL/P and CPO fall under the larger category of orofacial clefts (OFCs), which affect ~1.2/1000 live births world-wide and imposes significant social and financial burdens on affected individuals and their families. The etiology of orofacial clefts is complex and likely results from a combination of genetic mutations with environmental covariates. Recent genome wide association studies (GWAS) and whole exome sequencing (WES) for orofacial clefting identified significant genetic associations and variants in several genes. Of these genes, we investigated the role of common and rare variants in the SHH, RORA, MRPL53, ACVR1, and GDF11 genes. We sequenced these five genes in multi-ethnic CL/P and CPO samples in order to find mutations that may provide potential explanations for OFCs missing heritability. In total, 19 variants of interest were found, seven of which were in SHH, one in RORA, three in MRPL53, six in ACVR1, and two in GDF11. Types of mutations found included stop-gained, missense, synonymous, intronic, and splice site variants. Of these 19 variants, 3 novel missense variants were found, one in SHH, one in RORA, and one in GDF11. Rare and novel variants were further analyzed using in-silico predictive tools such as SIFT, Polyphen-2, Provean score, CADD, and HOPE. This study provides evidence that mutations in SHH, RORA, MRPL53, ACVR1, and GDF11 may contribute to risk of OFCs in various populations.

5,10-Methylenetetrahydrofolate reductase (MTHFR) C677T/A1298C polymorphisms in patients with nonsyndromic cleft lip and palate.

Cleft lip with or without cleft palate (CL/P) is considered a multifactorial genetic disorder. Folic acid metabolism has been suggested to underlie the development of CL/P. The gene for the enzyme 5,10-methylentetrahydrofolate reductase (MTHFR) contributes to folic acid metabolism, and polymorphisms of this gene at C677T (rs1801133) and A1298C (rs1801131) are reported to alter its enzyme activity and are suggested to be involved in CL/P development. We investigated C677T and A1298C polymorphisms of the MTHFR gene in Japanese patients with nonsyndromic CL/P and cleft palate only (CPO). We examined 240 patients with CL/P, 103 fathers and 153 mothers of the patients, and 68 healthy controls. Restriction fragment length polymorphisms (RFLPs) of C677T and A1298C of MTHFR were analyzed. We determined the frequencies of the polymorphisms in the patients and controls and performed a transmission equilibrium test and haplotype analysis of both MTHFR C677T and A1298C. There were no significant differences in the frequencies of MTHFR C677T and A1298C polymorphisms between the patients and controls. We did not observe transmission equilibrium or linkage equilibrium among the cases. In this experimental condition, we did not detect an association of MTHFR C677T and/or A1298C polymorphisms with the development of CL/P in this Japanese cohort.

The Cleft Nurse Specialist: A Key Building Block in the Cleft Multidisciplinary Team.

The cleft nurse specialist (CNS) plays a key role in counselling and supporting parents from the diagnosis onward. The CNS started in 2012 and we aimed to perform a qualitative study to determine the benefits this brought to the cleft community from the parents' perspective. The cleft database was used to locate babies born in 2010/2011 and 2013/2014. Parents were contacted by phone by 2 authors and completed a questionnaire on the care and support they received following the diagnosis, in the early days and around the time of surgery. Parents of 38 babies completed the survey. In 2010/2011, only 21% had an antenatal diagnosis compared to 47% in 2013/2014.2011/2012: 3 unilateral cleft lip and palate (UCLP), 3 bilateral cleft lip and palate (BCLP), 4 CLO, 9 cleft palate only (CPO).2013/2014: 5 UCLP, 7 BCLP, 7 CPO.2011/2012: 68% were counselled by a surgeon, 42% were seen >1 week after birth, with some over a month.2013/2014: 84% were counselled by the CNS, 53% were seen within 48 hours, and 100% within 7 days.Parents in 2013/2014 felt more supported by the cleft team throughout pregnancy and the early days, with home visits being particularly advantageous. The introduction of the CNS to the cleft multidisciplinary team has significantly improved the pathway for parents and is a key link with the wider cleft team. With the improvement in antenatal diagnosis, counselling occurs at an earlier stage and prepares parents for the difficulties commonly experienced in the early days. Key themes included; home visits and direct contact with the CNS.

Maternal preconception and first trimester exposure to PM10 and the risk of oral clefts in offspring: a population-based, case–control study

BackgroundCurrent literature describes limited and controversial evidence on the associations between maternal preconception and first trimester exposure to particulate matter with a diameter ≤10 µm (PM10) and the risk of...

Association between forkhead box E1 polymorphisms and risk of non‐syndromic cleft lip with or without cleft palate: A meta‐analysis

The purpose of the present work was to investigate the association between forkhead box E1 (FOXE1) and the risk of nonsyndromic cleft lip with or without cleft palate (NSCL/P). Relevant studies were searched in several professional databases up to July 31, 2019. The pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using a fixed-effect model or a random-effect model to analyze the relationship between FOXE1 polymorphisms and NSCL/P. A total of four single nucleotide polymorphisms (SNPs), including rs3758249, rs4460498, rs1443434, and rs10217225, were analyzed. The overall findings showed that FOXE1 rs4460498 was statistically associated with NSCL/P (including cleft lip with or without cleft palate (CL/P) and cleft palate only (CPO)). Genotypes CC and CT of rs4460498 were significantly more closely correlated with NSCL/P (including CL/P and CPO) than genotype TT (NSCL/P: TT vs CC, OR = 0.630, P= 0.000; TT vs TC+CC, OR = 0.775, P= 0.020; CL/P: TT vs CC, OR = 0.664, P= 0.000; TT vs TC+CC, OR = 0.738, P= 0.006. CPO: TT vs CC, OR = 0.761, P= 0.027; TT vs TC+CC, OR = 0.792, P= 0.045). For rs10217225, only the TT genotype might have contributed to the elevated risk of CL/P (TT vs CC OR=2.236, P=0.000). The other FOXE1 polymorphisms were not associated with NSCLP, CL/P, or CPO. The meta-analysis provided confirmation that the polymorphism of FOXE1 rs10217225 was correlated with an increased risk of CL/P, and the polymorphism of FOXE1 rs4460498 was a protective factor for NSCL/P, including CLP and CPO.

Genetic factors define CPO and CLO subtypes of nonsyndromicorofacial cleft.

Nonsyndromic orofacial cleft (NSOFC) is a severe birth defect that occurs early in embryonic development and includes the subtypes cleft palate only (CPO), cleft lip only (CLO) and cleft lip with cleft palate (CLP). Given a lack of specific genetic factor analysis for CPO and CLO, the present study aimed to dissect the landscape of genetic factors underlying the pathogenesis of these two subtypes using 6,986 cases and 10,165 controls. By combining a genome-wide association study (GWAS) for specific subtypes of CPO and CLO, as well as functional gene network and ontology pathway analysis, we identified 18 genes/loci that surpassed genome-wide significance (P < 5 × 10−8) responsible for NSOFC, including nine for CPO, seven for CLO, two for both conditions and four that contribute to the CLP subtype. Among these 18 genes/loci, 14 are novel and identified in this study and 12 contain developmental transcription factors (TFs), suggesting that TFs are the key factors for the pathogenesis of NSOFC subtypes. Interestingly, we observed an opposite effect of the genetic variants in the IRF6 gene for CPO and CLO. Moreover, the gene expression dosage effect of IRF6 with two different alleles at the same single-nucleotide polymorphism (SNP) plays important roles in driving CPO or CLO. In addition, PAX9 is a key TF for CPO. Our findings define subtypes of NSOFC using genetic factors and their functional ontologies and provide a clue to improve their diagnosis and treatment in the future.

Dynamic Nasolabial Growth After Primary Surgery for Patients With Bilateral Cleft Lip: A Five-Year Follow-Up Study

Bilateral complete cleft lip (BCCL) causes severe tissue deficit and usually requires multiple revisions after primary repair. In the present study, we aimed to illustrate the nasolabial changes after primary BCCL correction. The present retrospective cohort study compared patients who had undergone BCCL and palate (BCCLP) and cleft palate only (CPO). All included patients had undergone surgery at the same treatment center (West China Hospital of Stomatology) from 2007 to 2012. The patients returned for follow-up surgery at 6months and 5years after their primary repair surgery. We retrieved the facial plaster casts of the enrolled patients and recorded the key nasolabial measurements. The outcome variables included the prolabial length (PL), peak distance, nasal width, and columellar length (CL). The data were analyzed using a general linear model for repeated measures, and the linear association was tested using SPSS. The level of testing efficiency (P value) was set at .05. A total of 160 patients, 80 who had undergone BCCLP and 80 CPO controls, were included. All nasolabial measurements in the BCCLP group had increased during the 5-year follow-up period. The PL of the BCCLP group had increased more quickly than the PL of the CPO group (P=.000<.05), but the CL had increased nearly as much (P=.270). For the primary correction of bilateral cleft lip nose deformity, dissection and repositioning of the cleft lip and nose did not significantly inhibit the growth of the nasolabial region in the first 5years after surgery. Nose deformities should not remain uncorrected after primary surgical repair. In contrast, cleft surgeons should focus on the finer adjustment of columella with less doubt regarding adverse effects.

Comprehensive analysis of differentially expressed profiles of non‑coding RNAs in peripheral blood and ceRNA regulatory networks in non‑syndromic orofacial clefts.

Non-syndromic orofacial clefts (NSOC), which include cleft lip with or without cleft palate (CL/P) and cleft palate only (CPO), are common congenital birth defects in humans. Accumulating evidence indicates that long non-coding RNAs (lncRNAs) and microRNAs (miRNAs or miRs) play important roles in NSOC; however, the potential regulatory associations between them remain largely unknown. In this study, we performed next-generation RNA sequencing (RNA-seq) to identify transcriptome profiles, including mRNAs, lncRNAs and miRNAs, in patients with CL/P and CPO. A total of 36 lncRNAs, 1,341 mRNAs and 60 miRNAs were found to be differentially expressed in the CL/P group compared to the control group, and 57 lncRNAs, 1,255 mRNAs and 162 miRNAs were found to be differentially expressed in the CPO group compared to the control group. Subsequently, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to validate the expression of selected lncRNAs, miRNAs and mRNAs. In addition, bioinformatics methods were employed to explore the potential functions of ncRNAs and to construct lncRNA-miRNA-mRNA regulatory networks. To the best of our knowledge, this is the first study to comprehensively analyze regulated non-coding RNAs (ncRNAs) in CL/P and CPO, providing a novel perspective on the etiology of NSOC and laying the foundation for future research into the potential regulatory mechanisms of ncRNAs and mRNAs in NSOC.

Birth prevalence of orofacial clefts among perinatal infants: A register-based study in Bao'an district, Shenzhen, China.

The birth prevalence of orofacial clefts (OFCs) has been widely studied, but results are considerable varied, and epidemiological studies in southern China are few in numbers. To address this gap, we carried out a register-based study to estimate the birth prevalence of OFCs in Bao'an district, Shenzhen, China. Data of perinatal infants born between 2003 and 2017 were extracted from Shenzhen Maternal and Child Health Management System. The overall OFCs birth prevalence with 95% confidence interval (CI) as well as subgroup analysis based on selected demographic factors was conducted. Cochran-Armitage trend tests were applied to evaluate the time trend by 5-year intervals. The overall birth prevalence of OFCs, cleft lip with or without cleft palate (CL/P) and cleft palate only (CPO) was 1.30 (95% CI 1.21-1.39), 1.00 (95% CI 0.92-1.08), and 0.30 (95% CI 0.25-0.34) per 1,000 births, respectively. An overall declining tendency was observed in the OFCs (from 1.83 to 1.04 per 1,000 births), specifically CL/P (from 1.53 to 0.69 per 1,000 births) birth prevalence over 5-year intervals, with statistical significance (p < 0.01). Subgroup analysis revealed that the CL/P and CPO birth prevalence was differed by infant gender, household registration, maternal age, and parity. Our findings had firstly reported the birth prevalence of OFCs in Bao'an district, and might help other researchers to plan more comprehensive public health strategies to reduce the occurrence of OFCs in further generation.

Non-syndromic cleft palate: Association analysis on three gene polymorphisms of the folate pathway in Asian and Italian populations.

Periconceptional folic acid supplementation can reduce the risk of inborn malformations, including orofacial clefts. Polymorphisms of MTHFR, TCN2, and CBS folate-related genes seem to modulate the risk of cleft lip with or without cleft palate (CL/P) in some populations. CL/P and cleft palate only (CPO) are different malformations that share several features and possibly etiological causes. In the present investigation, we conducted a family-based, candidate gene association study of non-syndromic CPO. Three single nucleotide polymorphisms, namely, rs1801133 of MTHFR, rs1801198 of TCN2, and rs4920037 of CBS, were investigated in a sample that included 129 Italian and 65 Asian families. No evidence of association between the three genotyped polymorphisms and CPO was found in the Italian and Asian cases, indeed the transmission disequilibrium test did not detect any asymmetry of transmission of alleles. This investigation, although with some limitation, further supports that CL/P and CPO diverge in their genetic background.

The effects of IRF6 rs2235373 polymorphism on mRNA expression changes in non-syndromic cleft lip and palate with various phenotypes

Introduction: The IRF6 rs2235373 (C/T) is a polymorphism in the intron region that has been associated with non-syndromic cleft lip and palate (NS CLP) among some populations. Polymorphism in introns can also affect the transcription that should be detected through some changes in IRF6 mRNA expression. This study was aimed to evaluate the effects of IRF6 rs2235373 polymorphism on mRNA expression changes in NS CLP with its phenotypes which include complete unilateral (CU) CLP, complete bilateral (CB) CLP, cleft lip only (CLO), and cleft palate only (CPO). Methods: This study was a laboratory analytical study, using samples from 198 individuals in Indonesia (136 individuals with NS CL/P consisted of CU CLP (n=42), CB CLP (n=34), CLO (n=33), CPO (n=27), and 62 individuals as controls). DNA was extracted from venous blood, and the segment of rs2235373 was evaluated by PCR and Sanger sequencing. mRNA expressions analysis preceded by RNA extraction from oral epithelium, then real-time (RT) PCR was performed. mRNA expression changes were analysed by Livak method and Kruskal Wallis test followed by the Mann Whitney test through CC, GT, and TT genotype. Result: The mRNA expression of TT genotype from NS CU CLP and control was 3.36 higher value than CC genotype (p=0.008), and the mRNA expression of CT genotype from NS CB CLP and control was 0.16 lower value than CC genotype (p=0.000). Conclusion: The IRF6 rs2235373 polymorphism of TT genotype tend to cause mRNA overexpression in NS CU CLP, and CT genotype tend to cause mRNA underexpression in NS CB CLP.Keywords: Non-syndromic cleft lip and palate, NS CLP phenotype, IRF6, rs2235373, mRNA expression.

Genomic analyses in African populations identify novel risk loci for cleft palate.

Orofacial clefts are common developmental disorders that pose significant clinical, economical and psychological problems. We conducted genome-wide association analyses for cleft palate only (CPO) and cleft lip with or without palate (CL/P) with ~17million markers in sub-Saharan Africans. After replication and combined analyses, we identified novel loci for CPO at or near genome-wide significance on chromosomes 2 (near CTNNA2) and 19 (near SULT2A1). In situ hybridization of Sult2a1 in mice showed expression of SULT2A1 in mesenchymal cells in palate, palatal rugae and palatal epithelium in the fused palate. The previously reported 8q24 was the most significant locus for CL/P in our study, and we replicated several previously reported loci including PAX7 and VAX1.

Increased Risk for Neurodevelopmental Disorders in Children With Orofacial Clefts

Children with orofacial clefts (OFC) may have an increased risk of poor mental health. This study aimed to investigate the risk of psychiatric diagnoses in individuals with OFC, stratified by cleft type. A nationwide register-based cohort of all individuals born with nonsyndromic OFC in Sweden between 1973 and 2012 (n= 7,842) was compared to a matched cohort (n= 78,409) as well as to their unaffected siblings (n= 9,637). The risk of psychiatric diagnoses, suicide attempts, and suicides was examined by crude and adjusted Cox regression models. Effect modification by sex was investigated with interaction terms in the models. Children with cleft lip (CL) had a significantly higher risk of any psychiatric disorder, intellectual disability, and language disorders; children with cleft lip and palate (CLP) had, in addition, an increased risk of autism spectrum disorder (ASD). Children with cleft palate only (CPO) had risk increases for the same diagnoses as children with CL and CLP, but with higher hazard ratios, and also for psychotic disorders, attention-deficit/hyperactivity disorder (ADHD), and other behavioral or emotional disorders in childhood. Sex stratification indicated higher risk increases among females in CL and CLP but not in CPO. Siblings without OFC were less likely to be diagnosed with any psychiatric disorder, intellectual disability, language disorder, ASD, or ADHD compared to their siblings with OFC. Children with nonsyndromic clefts had a significantly higher risk of neurodevelopmental disorders. This risk is unlikely to be explained by familial influences such as inherited genetic or shared environmental factors.

Maternal Folic Acid Supplementation and the Risk of Oral Clefts in Offspring.

There is controversial evidence from the literature regarding the protective effect of folic acid supplementation during pregnancy against orofacial clefts. The authors undertook this meta-analysis to assess whether folate supplementation during pregnancy can reduce the risk of nonsyndromic cleft lip with or without cleft palate (CL/P) and cleft palate only (CPO) in infants. Eligible articles were identified by searching databases, including PubMed, Medline, Scopus, ISI (Web of Knowledge) to September 2017. A meta-analysis was performed to evaluate the effects of maternal supplementation on oral clefts. Odds ratios (ORs) and 95% confidence intervals (CIs) were pooled using Stata software. Publication bias was assessed by the Begg and Egger test. (Registration ID: CRD42018083922) RESULTS:: Out of the 1630 articles found in the authors' initial literature searches, 6 cohort studies, and 31 case-control studies were included in the authors' final meta-analysis. The results of the main analysis revealed that maternal folate supplementation was associated with a modest but statically significant decreased risk of all cleft subtypes (OR = 0.69, 95% CI: 0.60, 0.78). Folic acid intake alone was inversely associated with CL/P (OR = 0.73, 95% CI: 0.62-0.85,) but to a lesser extent than CPO (OR = 0.75, 95% CI = 053-1.04). Multivitamin intake had a significant protective effect for CL/P (OR = 0.65 95% CI = 0.55-0.80) as well as CPO (OR = 0.69, 95% CI = 0.53-0.90). Our results indicate that maternal supplementation in early pregnancy reduces the risk of nonsyndromic CL/P and CPO in infants. These data can serve to reassure women planning a pregnancy to consume multivitamins during the periconception period to protect against oral clefts.

Pbx loss in cranial neural crest, unlike in epithelium, results in cleft palate only and a broader midface.

Orofacial clefting represents the most common craniofacial birth defect. Cleft lip with or without cleft palate (CL/P) is genetically distinct from cleft palate only (CPO). Numerous transcription factors (TFs) regulate normal development of the midface, comprising the premaxilla, maxilla and palatine bones, through control of basic cellular behaviors. Within the Pbx family of genes encoding Three Amino‐acid Loop Extension (TALE) homeodomain‐containing TFs, we previously established that in the mouse, Pbx1 plays a preeminent role in midfacial morphogenesis, and Pbx2 and Pbx3 execute collaborative functions in domains of coexpression. We also reported that Pbx1 loss from cephalic epithelial domains, on a Pbx2‐ or Pbx3‐deficient background, results in CL/P via disruption of a regulatory network that controls apoptosis at the seam of frontonasal and maxillary process fusion. Conversely, Pbx1 loss in cranial neural crest cell (CNCC)‐derived mesenchyme on a Pbx2‐deficient background results in CPO, a phenotype not yet characterized. In this study, we provide in‐depth analysis of PBX1 and PBX2 protein localization from early stages of midfacial morphogenesis throughout development of the secondary palate. We further establish CNCC‐specific roles of PBX TFs and describe the developmental abnormalities resulting from their loss in the murine embryonic secondary palate. Additionally, we compare and contrast the phenotypes arising from PBX1 loss in CNCC with those caused by its loss in the epithelium and show that CNCC‐specific Pbx1 deletion affects only later secondary palate morphogenesis. Moreover, CNCC mutants exhibit perturbed rostro‐caudal organization and broadening of the midfacial complex. Proliferation defects are pronounced in CNCC mutants at gestational day (E)12.5, suggesting altered proliferation of mutant palatal progenitor cells, consistent with roles of PBX factors in maintaining progenitor cell state. Although the craniofacial skeletal abnormalities in CNCC mutants do not result from overt patterning defects, osteogenesis is delayed, underscoring a critical role of PBX factors in CNCC morphogenesis and differentiation. Overall, the characterization of tissue‐specific Pbx loss‐of‐function mouse models with orofacial clefting establishes these strains as unique tools to further dissect the complexities of this congenital craniofacial malformation. This study closely links PBX TALE homeodomain proteins to the variation in maxillary shape and size that occurs in pathological settings and during evolution of midfacial morphology.

Association between BMP4 gene polymorphisms and cleft lip with or without cleft palate in a population from South China

ObjectivePrevious studies have suggested an association between several polymorphisms of the BMP4 gene and susceptibility to non-syndromic cleft lip with or without cleft palate (NSCL/P) in various populations. However, this association may vary according to ethnic group and the form of NSCL/P. This study analyzed the association between the BMP4 gene polymorphisms rs762642, rs17563, and rs10130587 with the risk of cleft lip only (CLO), cleft palate only (CPO), and cleft lip with palate (CLP) in a population from South China. MethodsThis case-control study included 165 patients with NSCL/P (53 patients with CPO, 52 with CLO, and 60 with CLP) and 52 healthy volunteers. Peripheral blood samples were collected from all subjects to genotype the rs762642, rs17563, and rs10130587 polymorphisms by direct sequencing. Genotype and allelic frequencies of these polymorphisms were compared between healthy volunteers and patients with various forms of NSCL/P. ResultsThe genotype and allelic frequencies of rs762642 differed significantly between subgroups (CPO and CLP) and normal controls, whereas a significant difference was observed only in the CLO subgroup for the rs17563 polymorphism and in the CLO and CLP groups for the rs10130587 polymorphism. In addition, we identified a novel association of a BMP4 gene polymorphism, which was in linkage disequilibrium with the rs10130587 polymorphism, with CLO and CLP. ConclusionThe BMP4 gene polymorphisms rs762642, rs17563, and rs10130587 exhibit different associations with different forms of NSCL/P, suggesting that different forms of NSCL/P may have different etiologies.

MSH homeobox 1 polymorphisms and the risk of non-syndromic orofacial clefts: a meta-analysis.

MSH homebox 1 (MSX1) is a susceptibility gene for non-syndromic orofacial clefts (NSOCs). Here, a meta-analysis was conducted to assess their associations. A systematic search of PubMed to 1 September 2017, was performed to retrieve all eligible studies. Odds ratios (ORs) were used to calculate the associations. The stability of the results was evaluated by sensitivity analysis. Publication bias was assessed using Begg's funnel plots and the Egger test. In silico Msx1 expression during early mouse craniofacial development was evaluated by the Gene Expression Omnibus. In the overall analysis, MSX1 rs12532 (G>A) contributed to a decreased risk of NSOC. In an analysis stratified according to disease type, rs12532 was associated with the risk of cleft palate only (CPO) but not with the risk of cleft lip with or without cleft palate (CL/P). The association of rs12532 with the occurrence of NSOC in Asian and Caucasian populations but not South American populations was observed in an analysis stratified according to ethnicity. However, no significant associations were detected between any of the other MSX1 SNPs and the risk of NSOC in either the overall or subgroup analysis. The Msx1 gene was widely expressed in mouse craniofacial structures from embryonic day (E)8.5-E10.5. Taken together, the study indicates that MSX1 rs12532 is associated with the risk of NSOC.

Maternal exposure to ambient air pollutant and risk of oral clefts in Wuhan, China

Maternal exposure to ambient air pollution has been related to oral clefts in offspring; however, the epidemiologic evidence is equivocal. Especially, the association between high levels of exposure to ambient air pollution during pregnancy and oral clefts remains unclear. The objective of this study was to evaluate whether high levels of maternal exposure to PM2.5, PM10, O3, CO and SO2 are related to increased risk of oral clefts in Wuhan, China. A population-based study was conducted using cohort of 105,927 live-born infants, fetal deaths, and stillbirths during a two-year period from 2011 to 2013. For each participant, weekly and monthly averages of daily mean concentrations for each pollutant were estimated. Multiple logistic regression analyses were constructed to quantify the adjusted odds ratios (aORs) for the relationship between each air pollutant and oral clefts while controlling for key covariates. Using monthly averages, a cleft lip with or without cleft palate (CLP) was associated with PM2.5 (aORs 2nd month = 1.34, CI:1.19–1.49; aORs 3rd month=1.14, CI:1.02–1.28), PM10 (aORs 2nd month = 1.11, CI:1.00–1.23) and CO (aORs 2nd month = 1.31, CI:1.14–1.51; aORs 3rd month = 1.17, CI:1.03–1.33). A cleft palate only (CPO) was associated with PM2.5 (aORs 2nd month = 1.24, CI: 1.03–1.48), and O3 (aORs 2nd month = 1.21, CI: 1.03–1.42; aORs 3rd month = 1.18, CI: 1.02–1.37). Our findings reveal an association between air pollutants exposure and the risk of oral clefts. Future studies are needed to confirm these associations, and clarify the causality related to specific pollutants during the most relevant vulnerable exposure time windows for oral clefts during pregnancy.