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Background: 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. Methods: 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). Results: 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). Conclusion: 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. [ABSTRACT FROM AUTHOR]

Objectives: Risk factors for non-syndromic orofacial cleft (NSOFCs) include genetic profile and environmental exposure to medication and illnesses during pregnancy. We assessed the association between the COVID-19 vaccination and the incidence of NSOFC across five Middle Eastern countries. Materials and methods: This multi-country, hospital-based, case-control study included infants with NSOFCs whose first 3 intrauterine months coincided with the time when pregnant women were allowed to receive COVID-19 vaccination in the countries participating in the study. Newborns with NSOFCs were examined for cleft type and their parents were interviewed for maternal exposures and COVID-19 vaccination. Controls were newborns matched to cases in gender and setting. Results: The study recruited 977 (348 children with NSOFCs and 629 controls). Maternal use of nicotine (Adjusted Odds Ratio (AOR): 2.437; P = 0.044) and family history of NSOFC (AOR: 11.059; P < 0.001) increased significantly the AOR of having a child with NSOFC. On the other hand, COVID-19 vaccine administration to pregnant mothers have significantly decreased the AOR of having a child with NSOFC (AOR: 0.337; P = 0.006). Conclusion: This study suggests that COVID-19 vaccination is not related to NSOFC and might protect against having a child affected with such a congenital anomaly. Clinical relevance: The finding of this study is important for healthcare providers for considering COVID-19 vaccination for pregnant woman. Clear communication and education about the potential risks and benefits would be crucial for informed decision-making. The study's results would directly impact pregnant individuals, as they would need accurate information to make informed decisions about their health and the health of their infants. [ABSTRACT FROM AUTHOR]

• This study reports genetic and molecular mechanism of NSOFC in Kuwait. • Significant association of CYRIA rs7552, MSX1 rs3821949, and TGFB3 rs3917201 with NSOFC was demonstrated with a small effect contribution. • The findings of this study support a combined gene effect in craniofacial development and the risk of associated variants in NSOFC. • Our findings have provided insight into the genetic background of NSOFCs in an Arab ethnic group sampled from the Kuwaiti population. Non-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. Four 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. Significant 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). This 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. [ABSTRACT FROM AUTHOR]

Objective: To survey the frequency and pattern of family history for non‐syndromic orofacial clefts (NSOFC). Initial hypothesis: more complex forms have a higher frequency of positive family history. Materials and Methods: A retrospective study was carried with 2,668 subjects with three different types of clefts (CL Group (cleft lip), CLP Group (cleft lip and palate), and CP group (cleft palate)); family history information was collected. The Chi‐square (X2) and Z‐test were used. Results: A positive family history was found in 31% of the sample. The CLP Group had highest percentage and highest proportion of affected relatives, being these factors statistically significant when compared to the CP Group. Comparisons between the CLP Male and CL Male with CP Male were statistically significant. First‐degree kinship was the most frequently found. Conclusions: The initial hypothesis was confirmed, subjects with CLP had the highest percentage of positive family history, the highest proportion of affected relatives and had more affected relatives in comparison with CP. It is more common to find affected relatives in the CLP Male and CL Male groups when compared with CP Male. CLP and CP groups present a pattern of occurrence of the type of cleft in the family. [ABSTRACT FROM AUTHOR]

Background: It was the aim of this study to investigate tooth agenesis patterns, which are expressed to different subphenotypes according to the TAC method in a spectrum of non-syndromic orofacial cleft patients. Methods: A total of 183 orofacial cleft patient records were assessed for tooth agenesis and TAC patterns. The association between TAC and sex, and cleft type was examined, and logistic regression models were additionally applied. Additionally, the distribution of missing teeth by cleft type and the tooth agenesis inter-quadrant association were examined. Results: The most frequent cleft type was CLPL (n = 72; 39.3%), while the maxillary left lateral incisor was the most frequently missing tooth that was strongly dependent on the cleft type (29.5%, p < 0.001). Of the 31 TAC patterns identified, four were the most prevalent and occurred in 80.8% of the sample, while 20 TAC patterns were unique. Cleft type contrary to sex (p = 0.405) was found to play a significant role in TAC distribution (p = 0.001). The logistic regression's results suggested that overall, neither sex nor cleft type were associated with tooth agenesis. Prevalence of tooth agenesis in each quadrant clearly depended on cleft type; and there was a strong association found between tooth agenesis in different quadrants. Conclusions: Thirty-one different subphenotypes were identified in TAC patterns. The first four TAC patterns accounted for the 80.8% of the sample's variability while twenty of the patterns were unique. A strong association was present between TAC pattern and cleft type. No association was found between the sex of the patient, tooth agenesis and TAC patterns. Tooth agenesis depended strongly on the cleft type, and the most frequently missing tooth was the maxillary left lateral incisor. The interquadrant association for tooth agenesis found suggests a genetic link in the etiology of clefts. [ABSTRACT FROM AUTHOR]

Non‐syndromic orofacial clefts (NSOFCs) are prevalent birth defects with a complex etiology where several interacting genetic and environmental factors have been observed. This narrative review describes maternal exposures that have been significantly associated with protective effects or risk factors. The statistically significant information reported here was found in meta‐analysis studies, taking advantage of their precision in defining intervention effects and their management of heterogeneity between studies. In addition, I propose a hypothesis explaining the biological basis for the results of the meta‐analyses. This review aims to improve the evidence available in parent counseling, to prevent the occurrence of orofacial clefts by suggesting lifestyle changes. [ABSTRACT FROM AUTHOR]

Background: It was the aim of this study to investigate tooth agenesis patterns, which are expressed to different subphenotypes according to the TAC method in a spectrum of non-syndromic orofacial cleft patients. Methods: A total of 183 orofacial cleft patient records were assessed for tooth agenesis and TAC patterns. The association between TAC and sex, and cleft type was examined, and logistic regression models were additionally applied. Additionally, the distribution of missing teeth by cleft type and the tooth agenesis inter-quadrant association were examined. Results: The most frequent cleft type was CLPL (n = 72; 39.3%), while the maxillary left lateral incisor was the most frequently missing tooth that was strongly dependent on the cleft type (29.5%, p < 0.001). Of the 31 TAC patterns identified, four were the most prevalent and occurred in 80.8% of the sample, while 20 TAC patterns were unique. Cleft type contrary to sex (p = 0.405) was found to play a significant role in TAC distribution (p = 0.001). The logistic regression’s results suggested that overall, neither sex nor cleft type were associated with tooth agenesis. Prevalence of tooth agenesis in each quadrant clearly depended on cleft type; and there was a strong association found between tooth agenesis in different quadrants. Conclusions: Thirty-one different subphenotypes were identified in TAC patterns. The first four TAC patterns accounted for the 80.8% of the sample’s variability while twenty of the patterns were unique. A strong association was present between TAC pattern and cleft type. No association was found between the sex of the patient, tooth agenesis and TAC patterns. Tooth agenesis depended strongly on the cleft type, and the most frequently missing tooth was the maxillary left lateral incisor. The interquadrant association for tooth agenesis found suggests a genetic link in the etiology of 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. [ABSTRACT FROM AUTHOR]

Objective: The coronavirus (COVID-19) pandemic presents an opportunity to study stress's effect on the development of non-syndromic orofacial clefts (NSOFCs). This study was aimed at assessing maternal stress exposure during the pregestational to first trimester pregnancy periods and the development of NSOFCs during a year of the COVID-19 pandemic., Design: Cohort study of infants with NSOFCs and controls matched based on recruitment site and age., Setting: Government hospitals in Saudi Arabia between November 2020 and November 2021., Main Outcome Measures: Data collection included NSOFC clinical examination and maternal stress exposure assessment using the Modified Life Events Questionnaire, the Fear of COVID-19 Scale, and a focus on the lack of pregnancy planning and a threatened miscarriage., Results: Of the 557 infants recruited, 191 had NSOFCs. Logistic regression analysis with adjusted odds ratios (AORs) that removed the effects of confounders showed that any of the seven stressful life events (AOR:3.78, P < .001) and the family histories of relatives with NSOFCs (AOR:9.73, P < .001) increased the AOR for NSOFC development. In contrast, maternal folic acid (AOR:0.56, P.010), threatened miscarriage (AOR:0.17, P = .001), fear of COVID-19 (AOR:0.83, P = .038), and suspected COVID-19 infection (AOR:0.43, P = .008) decreased the AOR for NSOFC development., Conclusion: Along with an established risk associated with family history of birth defects, stressful life events may be a risk factor for NSOFC development. Beyond folic acid's known benefit, it may be that higher maternal health concerns contribute to increased protective health behaviors during pregnancy. Ongoing research is needed to specify the maternal risk factors for NSOFC., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: MicroRNA (miRNA) processing genes play important roles in the craniofacial development. The aim of this study was to explore the associations between single nucleotide polymorphisms (SNPs) of miRNA processing genes with the risk of non‐syndromic orofacial clefts (NSOC). Methods: We genotyped 12 potentially functional SNPs from seven miRNA processing genes (GEMIN3, DROSHA, DGCR8, GEMIN4, PIWIL1, XPO5, and DICER) in a case–control study of 602 NSOC cases and 605 controls. Results: Two SNPs were associated with the susceptibility of CL/P: rs10719 in DROSHA led to an increased risk of cleft lip with or without palate (CL/P) (GA/AA: p = .024, OR = 1.33, 95% CI = [1.04, 1.70]; GG + GA/AA: p = .037, OR = 1.29, 95% CI = [1.02, 1.63]), while rs493760 in DROSHA (CC/TT: p = .049, OR = 0.58, 95% CI = [0.34, 0.99]) could reduce the risk of CL/P. In addition, rs10719 (A)‐rs493760 (C) haplotype contributed to a decreased risk of CL/P (OR = 0.77, 95% CI = [0.63, 0.94]), whereas the rs10719 (G)‐rs493760 (C) haplotype contributed to the increased risk of cleft palate only (CPO) (OR = 2.70, 95% CI = [1.15, 6.35]). However, there was no difference observed in these SNPs after the Bonferroni correction. Conclusion: Taken together, our results provided the potential evidence that rs10719 and rs493760 might contribute to the risk of CL/P and suggested potential genetic basis and mechanisms of CL/P. The lack of association between these SNPs and CPO might be due to the limited sample size of CPO subgroup. [ABSTRACT FROM AUTHOR]

Objective Previous genomewide association studies ( GWAS) identified a region near MAFB at chr20q12 associated with non-syndromic orofacial clefts ( NSOC) susceptibility. However, whether other SNPs in this area could independently contribute to non-syndromic orofacial clefts in Chinese populations remained obscure. Materials and Methods We selected 24 SNPs based on a haplotype-tagging SNP strategy and evaluated their associations with risk of non-syndromic orofacial clefts in a large-scale two-stage case-control study with 1278 cases and 1295 controls. Genotyping was performed with Sequenom and TaqMan assay. Associations between the SNPs and risk of non-syndromic orofacial clefts were estimated from unconditional logistic regression analyses. Results Overall, six SNPs were found to be the susceptible factors of non-syndromic orofacial clefts. The most significant and independent SNP was rs6129653 (additive model of P value = 1.4E-06). In subgroup analysis, its significant associations with cleft lip only ( CLO) and cleft lip and palate ( CLP) were observed. Furthermore, in silico bioinformatics analysis indicated that rs6129653 was located in the transcriptionally active region and associated with MAFB expression in human brain tissues. Conclusions Rs6129653 was an independent locus of non-syndromic orofacial clefts among Chinese populations possibly due to its potential of distal transcriptional regulation of MAFB expression. [ABSTRACT FROM AUTHOR]

Objective FOXE1 plays an important role in craniofacial development. The aim of this study was to investigate associations between genetic variants of FOXE1 and risk of non-syndromic orofacial clefts in a Chinese population. Materials and Methods Three potentially functional SNPs of FOXE1 (rs3758250 and rs907577 in the 5′ upstream and rs7043516 in the 3′- UTR) were selected and their associations with non-syndromic orofacial cleft susceptibility were investigated in a case-control study from a Chinese population (602 cases and 605 controls). Genotyping was performed with double ligation and multiplex fluorescence PCR. Associations between the SNPs and risk of non-syndromic orofacial clefts and its subgroups were estimated from unconditional logistic regression analysis. Luciferase reporter assay was conducted to assess SNP function. Results Overall, we did not find any of the individual SNP or haplotype was associated with NSOC susceptibility. Nevertheless, in stratified analysis, we found rs7043516, locating in the 3′- UTR of FOXE1, was associated with risk of cleft lip only. Further in vitro luciferase assay indicated that this SNP could contribute to differential binding ability with mi RNA. Conclusions Taken together, this study showed that rs7043516 may be considered as a potentially susceptible marker of cleft lip only among Chinese Han populations. [ABSTRACT FROM AUTHOR]

Objectives Non-syndromic orofacial clefts ( NSOC) are the most common human craniofacial malformation in all worldwide populations. Recently, the jumoji AT-rich interaction domain 2 ( JARID2) had been reported to be a novel candidate gene for non-syndromic cleft lip with or without cleft palate ( CL/P). The SNPs rs2076056, rs2237138 and rs2299043 in JARID2 were highly significant in Italian families. Material and Methods In the current research, a case-control study was conducted to examine the association between these three SNPs and NSOC in a northern Chinese Han population. Genotyping of the three SNPs were performed using SNaPshot minisequencing technique. Results Distribution of rs2237138 genotypes in CL/P group was different from those in the control group ( P = 0.04), but significant results did not persist after Benjamini and Hochberg false discovery rate ( FDR) correction for multiple tests. Further logistic regression analysis showed that rs2237138 GG genotypes were associated with decreased CL/P susceptibility ( OR = 0.34, 95% CI = 0.13-0.84), compared with the AA wild-type homozygote. For the haplotype CGT, a statistically difference was identified between the CL/P group and controls ( P = 0.04). And carriers of GAT haplotype were considered to be less frequent among cleft palate only group as compared to controls ( P = 0.02). However, both of the haplotypes association did not remain statistically significant after Benjamini and Hochberg FDR correction. Conclusion We got a weak association between these polymorphisms and NSOC in both single-marker and haplotype analyses. Our data further strengthen the conclusion that JARID2 polymorphisms are associated with NSOC susceptibility. [ABSTRACT FROM AUTHOR]

Background The axis inhibition protein 2 ( AXIN2) is an important regulator of β-catenin degradation in the Wnt pathway, which plays a key role in craniofacial morphogenesis. The goal of this study was to investigate the potential relationship between AXIN2 polymorphisms and the risks of non-syndromic orofacial clefts ( NSOC) in a Chinese Han population. Methods Four polymorphisms of AXIN2 (rs2240307, rs11867417, rs2240308, and rs7591) were selected to perform a case-control study with 599 NSOC cases and 602 healthy individuals from a Chinese Han population. The single nucleotide polymorphisms ( SNPs) were genotyped on basis of double ligation and multiplex fluorescence PCR. Results Weak associations were found between these four SNPs and the risk of NSOC. Further stratified analysis showed that the overall genotype frequencies of rs2240307 were different between the cleft palate only ( CPO) group and the control group ( P = 0.048), and GG genotype markedly contributed to the susceptibility to CPO ( OR = 3.22, 95% CI = 1.13-9.18). The similar effect was also observed on GA/ AA genotype compared with GG homozygote ( OR = 0.30, 95% CI = 0.11-0.84). The results of LD analysis between each pair of SNPs revealed that two SNPs (rs11867417 and rs7591) were in a LD block ( r2 > 0.8). But no statistically significant was found between cases and controls from haplotype analysis in these two loci. Conclusions The borderline results gave us a hint that rs2240307 contributed to the susceptibility to CPO in a Chinese Han population, which was conductive to improving our awareness of the causes of NSOC. [ABSTRACT FROM AUTHOR]

MSX1 is a favorable candidate gene for susceptibility to non-syndromic orofacial clefts (NSOCs). However, the roles of MSX1 genetic variants in the development of NSOC are controversial and vary among human populations. In the present study, the roles of 4 potentially functional single-nucleotide polymorphisms (SNPs) of MSX1 (rs12532 in 3′-untranslated region [UTR], and rs3821947, rs3821949, and rs4464513 in 5′ upstream) were investigated in a case-control study of 602 NSOC cases and 605 healthy controls. The findings showed that rs12532 located within 3′-UTR of MSX1 could influence the risk of developing NSOC. Individuals who carried the variant genotype (rs12532AA genotype) showed a decreased possibility of developing NSOC (AA vs. GG: OR = 0.69, 95% CI = [0.49, 0.98]). Interestingly, similar effects were also observed on cleft lip with palate (CLP), in a stratified analysis (allelic comparison-12532A allele vs. 12532G allele, OR = 0.80, 95% CI = [0.66, 0.99]; genotypic comparison-AA vs. GG, OR = 0.58 95% CI = [0.37, 0.91]). Sequence analysis indicated that this SNP might alter the binding ability of miR-3649, confirmed by luciferase activity assay showing a lower expression level of rs12532 A allele compared with that of the G allele (p < .001 for 293A and COS7 cell lines). Furthermore, an in vivo study showed that MSX1 expression among individuals carrying the AA genotype of rs12532 was markedly lower than that in those with the GG genotype, while the inverse correlation was observed for miR-3649, thus providing a possible interaction between MSX1 and miR-3649 in the etiology of NSOC. Taken together, these findings indicate that SNPs in the miRNA-binding sites might play an important role in the development of NSOCs. Furthermore, if confirmed in subsequent studies, the polymorphisms may be considered as additional markers for the evaluation of infants’ risk of NSOCs. [ABSTRACT FROM PUBLISHER]

Background Non-syndromic orofacial clefts (NSOC) are the most common craniofacial birth defects and are considered as complex and multifactorial diseases involving the interplay of genetic predisposition and environmental exposures. Recent studies demonstrated that EYA1, a member of eye absent gene family, might contribute to the development of orofacial clefts. This study aimed to evaluate the association between EYA1 gene polymorphism and NSOC in western Chinese population. Method Two single-nucleotide polymorphisms, rs13260349 and rs2380716, were investigated among 199 case-parent trios, and the linkage disequilibrium (LD) test, transmission disequilibrium test, family based association test, and haplotype analysis were performed. Results Weak evidence of LD was found between these markers (D' = 0.573, r2 = 0.218); allel C and genotype C/C at rs13260349 showed an overtransmission in CL/P; haplotype T-T (rs13260349-rs2380716) displayed an association with NSOC and CL/P. Conclusions The results showed evidence of weak association between the two SNPs of EYA1 (rs13260349 and rs2380716) and NSOC. [ABSTRACT FROM AUTHOR]

Oral Diseases (2011) , 304-308 Non-syndromic orofacial clefts (NSOC) are the most common developmental disorders in human beings. Recently, two genome-wide association studies in European Caucasians identified three novel NSOC susceptibility loci: rs987525 on 8q24, rs7078160 on 10q25.3, and rs223371 on 17q22. The aim of this study was to determine the association of these polymorphisms with NSOC susceptibility and its subgroups in a Chinese Han population. In this study, 199 NSOC patients and 210 healthy individuals were recruited. SNP rs987525 was not genotyped because of its low frequency in the study subjects. The other two polymorphisms (rs7078160 and rs223371) were respectively genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and Taqman-MGB assay. Overall genotype distributions of rs7078160 and rs223371 polymorphisms were consistent with Hardy-Weinberg equilibrium test. The allele and genotype frequencies of the two polymorphisms were not significantly different between cases and controls. Further analysis indicated that none of the genotypes was associated with increased risk of NSOC. Similar results were also found when all cleft cases were stratified by cleft types. Our findings are consistent with a lack of involvement of the rs7078160 and rs223371 polymorphisms in the development of NSOC in the Chinese Han population. [ABSTRACT FROM AUTHOR]

Abstract: Objective: CDH1 plays a key role in cell adhesion, which is vital to normal craniofacial morphogenesis and palatal fusion. It is therefore attractive as a candidate gene for non-syndromic orofacial clefts (NSOC). The SNP rs16260 (C>A), locating upstream of the transcriptional start site of CDH1 promoter, has a significant effect on transcriptional activity and CDH1 expression. The aim of this study was to determine the association of rs16260 with risk of NSOC and its subgroups in a Chinese Han population. Materials and methods: 140 NSOC cases and 107 healthy individuals were recruited in the present study. The SNP rs16260 was genotyped by polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP). Results: The genotype distributions of rs16260 in controls were consistent with Hardy–Weinberg equilibrium test. Lack of association was found between rs16260 and risk of NSOC. When all cleft cases were subsequently stratified into four groups (i.e. cleft lip with or without cleft palate, cleft lip only, cleft lip with cleft palate and cleft palate only), interestingly, we found that rs16260 overall genotype frequencies in cleft palate only (CPO) groups were significantly different with those in the controls (P =0.004) and rs16260 AA genotype significantly increased the risk of CPO by 5.90-fold (OR=6.90, 95% CI=1.47–32.40), providing the first evidence of CDH1 genetic variation in the etiology of CPO. Conclusions: CDH1 promoter SNP rs16260 may contribute to risk of CPO in a Chinese Han population. [ABSTRACT FROM AUTHOR]

Non-syndromic orofacial clefts (NSOFC), which include cleft lip and palate (CLP), cleft lip only (CLO), and cleft palate only (CPO), contains a range of disorders affecting the lips and oral cavity. No systematic review and meta-analysis has been carried out to synthesize the prevalence of NSOFC in Chinese perinatal infants. We aimed to quantify and understand the variation of prevalence national and regional levels. Four English databases and four Chinese databases were searched using a comprehensive search strategy from inception to April 2017. The random effect model was used for this meta-analysis. To determine the sources of heterogeneity, subgroup analyses and meta-regression were conducted based on different categories. The protocol has been pre-registered in the PROSPERO, number CRD42017062293. 110 studies, including 15,094,978 Chinese perinatal infants, were eligible for inclusion. The pooled prevalence rate for NSOFC was 1.67‰ (95% CI 1.53-1.82), varying with provinces. The pooled prevalence estimate was 0.56‰ (0.50-0.63) for CLO, 0.82‰ (0.73-0.90) for CLP, and 0.27‰ (0.24-0.30) for CPO. Significant associations were found between overall prevalence estimates and survey year and study region. The prevalence of NSOFC was severe in Chinese perinatal infants, varying with provinces. The results will serve as a baseline for future assessment of the overall effectiveness of NSOFC control, and will also support and inform health policy for planning and helping health debates., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.