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Objective: Paired box 7 ( PAX7 ) has been considered as a candidate gene for non-syndromic cleft lip with or without palate (NSCL/P). However, there is no research for the XXX, and previous studies concentrated on limited variants. This study aimed to conduct sufficiently dense and powerful scans of variants at PAX7 and explored the roles of variants at PAX7 in NSCL/P among the XXX., Design: Targeted region sequencing was performed to thoroughly screen variations, followed by a two-phase association analysis. 159 NSCL/P cases and 542 controls were analyzed in phase 1. Then in phase 2, the validation study was performed using 1626 cases and 2255 controls. We also explored the roles of variants at PAX7 gene in NSCL/P subtypes. Additionally, indirect associations were found by calculating LD and haplotypes., Setting: The study was conducted in XXX., Patients, Participants: 159 NSCL/P cases and 542 controls were analyzed in phase 1. Then in phase 2, the validation study was performed using 1626 cases and 2255 controls., Interventions: Blood samples were collected., Main Outcome Measures: To explore the association analysis between variants at PAX7 and NSCL/P in XXX., Results: The results showed that rs2236810, rs114882979 and rs2236804 were significantly associated with NSCL/P, which were predicted to have regulatory functions. Besides, variants at PAX7 function differently in the NSCL/P subtypes. We also discovered a PAX7 missense variant, NM_001135254 p.A369 V (NM_002584.2:c.1106C > T)., Conclusions: In summary, we confirmed 3 SNPs at PAX7 were significantly associated with NSCL/P in XXX and identified a missense variant, NM_001135254 p.A369 V (NM_002584.2:c.1106C > T)., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The purpose of this study is to analyze the clinical characteristics of patients with Van der Woude syndrome (VWS) and to detect variations in each patient. Finally, the combination of genotype and phenotype can make a clear diagnosis of VWS patients with different phenotype penetrance., Five Chinese VWS pedigree were enrolled. Whole exome sequencing of the proband was performed, and the potential pathogenic variation was further verified by Sanger sequencing in the patient and their parents. The human mutant IRF6 coding sequence was generated from the human full-length IRF6 plasmid by site-directed mutagenesis and cloned into the GV658 vector, RT-qPCR and Western blot were used to detect the expression of IRF6 ., We found one de novo nonsense variation (p. Gln118Ter) and three novel missense variations (p. Gly301Glu, p. Gly267Ala, and p. Glu404Gly) co-segregated with VWS. RT-qPCR analysis revealed that p. Glu404Gly significantly reduced the expression level of IRF6 mRNA. Western blot of cell lysates confirmed that IRF6 p. Glu404Gly abundance levels were lower than those for IRF6 wild type., This discovery of the novel variation ( IRF6 p. Glu404Gly) expands the spectrum of known variations in VWS in Chinese humans. Genetic results combined with clinical phenotypes and differential diagnosis points from other diseases can make a definitive diagnosis and provide genetic counseling for families., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Non-syndromic orofacial clefts (NSOCs) are the most common craniofacial malformation. In the complex aetiology and pathogenesis of NSOCs, genetic factors play a crucial role and IRF6, located at chromosome 1q32.2, is the best documented NSOC susceptibility gene. IRF6 is a key factor in oral maxillofacial development and known to contribute the most in NSOCs. It is essential to conduct a complete review of the existing results on IRF6 to further understand its role in the pathogenesis of NSOCs. Thus, the present authors summarised the research progress on the mechanism of IRF6 in NSOCs from both genetic and functional perspectives in this review.

Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common polygenetic disease. Although genome-wide association studies (GWAS) identified NTN1 gene as a high-priority candidate of NSCL/P, the comprehensive genetic architecture of NTN1 weren't yet known. Thus, this study aimed to determine full-scale genetic variants of NTN1 for NSCL/P in Chinese Han people. Initially, targeted sequencing of NTN1 gene was performed on 159 NSCL/P patients to identify susceptible single nucleotide polymorphisms (SNPs) associated with NSCL/P. Then, association analysis and burden analysis were separately used to validate the common variants and rare variants identified among large size of samples (1608 NSCL/P cases and 2255 controls). Additionally, NSCL/P subtype association analysis was applied to elucidate the etiology discrepancy of non-syndromic cleft lip with palate (NSCLP) and non-syndromic cleft lip only (NSCLO). Lastly, bioinformatics analysis was performed to annotate and prioritize candidate variants. We found 15 NSCL/P-associated SNPs including rs4791774 (P = 1.10E-08, OR = 1.467, 95% CI: 1.286~1.673) and rs9788972 (P = 1.28E-07, OR = 1.398, 95% CI : 1.235~1.584) originally detected by previous GWASs in Chinese Han ancestry. Four NSCLO risk-associated SNPs and eight specific NSCLP associated SNPs were found. Three SNPs (rs4791331, rs4791774 and rs9900753) were predicted to locate at regulatory region of NTN1. Our study validated the association between NTN1 gene and pathogenesis of NSCL/P and reinforced the hypothesis that NSCLP have a different etiology from NSCLO. We also identified three putative regulatory SNPs in NTN1 gene., (© 2023. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Objectives: Non-syndromic cleft lip with or without cleft palate (NSCL ±  P ) is one of the most common birth malformations. Currently, numerous susceptibility SNPs have been reported by GWA studies, however, the replications of them among NSCL ±  P from Han Chinese were very limited., Design: In this study, we selected 16 SNPs around 1q32.2 based on the published GWA studies and replicated them among 302 trios with NSCL ±  P from Han Chinese Population. The genotypic data was analyzed with FBAT, PLINK and R package., Setting: The study was conducted in a tertiary medical center., Patients, Participants: 302 patients with CL ±  P and their parents., Main Outcome Measures: To ascertain the genetic variants in 1q32.2 in patients with CL ±  P in Han Chinese Population., Interventions: Blood samples were collected., Results: We found T allele ( Z  = 4.26, p  = 0.00002) and T/T homozygotes ( Z  = 4.4, p  = 0.000011) at rs12063989 was significantly over-transmitted among non-syndromic cleft lip with or without cleft palate (NSCL ±  P )., Conclusions: We found rs12063989 exhibited significant association with the occurrence of NSCL ±  P , which would provide new evidence for the future study in the etiology of NSCL ±  P .

Objectives: Non-syndromic cleft palate only (NSCPO) is a common congenital deformity with complex etiologies. GRHL3, FAF1, and KCNJ2 have been reported to be involved in the pathogenesis of NSCPO. Up till now, there have been no replication studies based on large Han Chinese. Therefore, this study aimed to investigate associations between GRHL3, FAF1, KCNJ2, and NSCPO sub-phenotypes patients in Han Chinese., Materials and Methods: Firstly, we selected 2 SNPs based on previous literatures: FAF1 (rs3827730) and GRHL3 (rs41268753). Also, we selected 8 tagSNPs in GRHL3 (rs557811, rs609352, rs10903078, rs6659209, rs12401714, rs12568599, rs3887581, rs12024148) and 2 tagSNPs in KCNJ2 (rs75855040 and rs236514). Afterward, we evaluated these SNPs among 1668 NSCPO patients and 1811 normal controls from Han Chinese. Following data were analyzed by PLINK and Haploview program., Results: Association analysis under additive model showed that allele A at rs12568599 in GRHL3 gene is significantly associated with NSCPO (p = 0.0034, OR = 1.38 and 95%CI: 1.11-1.72) and its sub-phenotype incomplete cleft palate (ICP) (p = 0.0039, OR = 1.4 and 95%CI: 1.11-1.75), and it could increase the risk of both NSCPO and ICP., Conclusions: This study firstly found that rs12568599 in GRHL3 is associated with NSCPO and ICP in Han Chinese, indicating that sub-phenotypes of NSCPO have different etiologies., (© 2021 Wiley Periodicals LLC.)

Objectives: This study aimed to reveal the association between single-nucleotide polymorphism of NTN1 and subtypes of non-syndromic cleft lip with or without cleft palate (NSCL/P) in Han Chinese Population., Design: Initially, we selected three single-nucleotide polymorphisms (SNP) (rs4791331, rs4791774 and rs9891446) in NTN1 from previous genetic studies. Then we recruited two Han Chinese cohorts (2004 cases and 1823 controls) and divided cases into subgroups: non-syndromic right-side cleft lip, non-syndromic left-side cleft lip, non-syndromic bilateral cleft lip and non-syndromic cleft lip with palate to further evaluate the associations between the subtypes of NSCL/P and SNPs in NTN1. PLINK and Haploview program were utilized to analyze the data., Results: In the association analysis under additive model, we found that G allele at rs9891446 could specifically increase the risk of right-side cleft lip (P = 0.0073, OR = 1.44, 95%CI: 1.1-1.88), which was consistent with the results of association analysis under genotypic model., Conclusion: This study showed that rs9891446 of NTN1 was specifically associated with right-side cleft lip in Han Chinese, which indicates that different subtypes of non-syndromic cleft lip have distinct genetic background., (Copyright © 2022. Published by Elsevier Ltd.)

Objectives: Non-syndromic cleft lip with or without palate is one of the most common birth malformations. TP63 and GREM1 were recently reported to be associated with NSCL/P. However, there were few studies focused on their associations in non-syndromic cleft lip only (NSCLO)., Design: Initial screening and replication in large cohorts were used to locate the susceptible SNPs of TP63 and GREM1. Firstly, variations were screened among 192 NSCLO cases by the Sanger sequencing. Then, we selected five associated SNPs in initial screening phase and replicated among 1,006 NSCLO cases and 1,823 normal controls., Results: Initial chi-square test showed that rs7653848, rs7624324, rs6790167, and rs1345186 in TP63 and rs2280738 in GREM1 achieved statistical significance (p < .05); the subsequent replication analysis showed that rs1345186 was specifically significant in right-side cleft lip (RCL; p = .017, OR = 1.33, and 95% CI: 1.05-1.69)., Conclusion: This study firstly used the subphenotype of cleft lip samples to verify the association between TP63 and GREM1, which indicated that TP63 is a promising susceptible gene for RCL in Chinese population. And further confirmed the different etiology in the right-sided cleft lip, left-sided cleft lip, and bilateral cleft lip of NSCLO. This will give new reference for the future research and genetic counseling., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. All rights reserved.)

Objectives: This study aimed to initially screen more susceptible variations at PAX9 gene in non-syndromic cleft palate only cases and then test their associations in independent non-syndromic orofacial cleft subtypes from Western Han Chinese population., Design: Initially exons at PAX9 gene were screened for variations among 180 non-syndromic cleft palate only patients by the Sanger sequencing method, and the genotype data from 1000 Genomes Project Database was taken as control to perform Chi-square test. Subsequently, we performed association analysis among 2202 non-syndromic orofacial cleft patients (938 non-syndromic cleft palate only cases, 456 non-syndromic cleft lip only cases and 808 non-syndromic cleft lip and palate cases) and 1823 normal controls to replicate the role of two significant single nucleotide polymorphisms., Results: Two intronic single nucleotide polymorphism rs12885612 (P = 0.047, OR = 0.671 and 95-0.996) and rs12881248 (P = 0.047, OR = 1.006 and 95 %CI: 0.443-0.995) were associated non-syndromic cleft palate only in the initial screen phase. Surprisingly, in replication analysis rs12885612 (P = 0.048, OR = 1.25, 95 %CI: 1.0-1.56) and rs12881248 (P = 0.037, OR = 1.26, 95 %CI: 1.01-1.57) exhibited significant association signal in non-syndromic cleft lip only group, but not in non-syndromic cleft palate only group., Conclusion: In summary, this study firstly revealed that rs12885612 and rs12881248 at PAX9 gene associated with non-syndromic cleft lip only from Western Han Chinese population, which indicated that PAX9 is a promising susceptible gene for non-syndromic cleft lip only in Western Han Chinese population., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: To explore the association between two single nucleotide polymorphisms (SNPs), namely, rs4691383 and rs7667857, in the platelet-derived growth factor-C (PDGF-C) gene, the genotypes, environmental exposure factors, and nonsyndromic cleft lip with or without cleft palate (NSCL/P) in Western Chinese population., Methods: A total of 268 case-parent trios were selected, and two SNPs (rs4691383 andrs7667857) were genotyped by using polymerase chain reaction and restriction enzyme fragment length polymorphic method and direct sequencing method. Hardy-Weinberg equilibrium, linkage disequilibrium test, transmission disequilibrium test, and haplotype analysis were conducted to analyze the data. Meanwhile, the questionnaires on the epidemiology of cleft lip and palate filled by the included samples were collected, and the interaction between the genotypes of the two SNPs and environmental exposure factors was assessed by conditional logistic regression., Results: The A allele at rs4691383 and the G allele at rs7667857 of PDGF-C gene were over-transmitted for NSCL/P (P<0.05). No interaction effect was observed between the three environmental exposure factors (history of smoking/passive smoking, folic acid supplementation, and long-term inhalation of harmful environmental gases) and the PDGF-C genotypes among NSCL/P (P>0.05)., Conclusions: The rs4691383 and rs7667857 at PDGF-C gene are closely related to the occurrence of NSCL/P in Western Chinese population. However, the interaction between environmental exposure factors and PDGF-C genotypes is not obvious in the occurrence of NSCL/P.

Though the mechanism of non-syndromic cleft lip and palate is not completely clear, the disease is affected by the combination of environment and genetics. Special environmental factors have the affect on the incidence of cleft palate. In this paper, the environmental factors related to the occurrence of non-syndromic cleft lip and palate were summarize from three aspects: poor living habits, chemical factors, age and health status of pregnant women during pregnancy. Based on the analysis of this paper, it will help to improve the health and living environment of pregnant women, so as to reduce the incidence of cleft palate.

Objective: Genome-wide association studies (GWAS) found NTN1, NOG and the region between CREBBP and ADCY9 were risks to non-syndromic cleft lip with or without cleft palate (NSCL/P). However, the association of single nucleotide polymorphisms (SNPs) in these genes with NSCL/P in Western China is unknown., Subjects and Methods: We selected seven SNPs in NTN1, NOG and between CREBBP and ADCY9, and then performed transmission disequilibrium test (TDT), parent-of-origin effect and sliding window haplotype analysis to test the associations among 302 NSCL/P case-parent trios from Western Han Chinese., Results: We found allele G at rs4791774 in NTN1 was significantly overtransmitted among non-syndromic cleft lip only (NSCLO) (p = 0.0067, OR = 1.79, 95% CI: 1.17-2.74); rs4791774 and rs9915089 tightly linked with each other among NSCL/P (D' = 0.87, r 2  = 0.67) and haplotypes carrying the risk allele G at rs4791774 were always found to be overtransmitted from parents to cases. Motif analysis indicated that allele G at rs4791774 could greatly alter the affinity of Myc&#95;disc7, so allele G at rs4791774 in NTN1 might modulate C-MYC transcription to participate in the aetiology of NSCLO., Conclusions: Our study suggested allele G at rs4791774 in NTN1 gene is risk of NSCLO, which could greatly increase the risk to have a baby with cleft., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. All rights reserved.)

Objective: Non-syndromic cleft lip with or without palate (NSCL/P) is one of the most common human birth defects, it results from multiple genetic and environmental risk factors. Recently, GWA studies identified associations between NSCL/P and two genetic risk loci, rs7078160 and rs4752028, at VAX1., Design: Currently, we tried to investigate the roles of the two loci among 302 NSCL/P trios (129 non-syndromic cleft lip only (NSCLO) trios and 173 non-syndromic cleft lip and cleft palate (NSCLP) trios) from Western Han Chinese. The two SNPs were genotyped by SNPscan method; Hardy-Weinberg equilibrium test, allelic TDT and parent-of-origin effect were performed by PLINK software, and genotypic TDT and haplotype by FBAT software., Results: Allelic TDT analysis revealed allele A at rs7078160 was over-transmitted among NSCL/P group (P = 0.0086, OR transmission  = 1.36, 95%CI: 1.08-1.72). Parent-of-origin effect analysis revealed a paternal special over-transmission of allele A at rs708260 in NSCL/P group (P = 0.0079). Haplotype AC of rs7078160-rs4752028 was significant over-transmitted in the NSCL/P group., Conclusions: Our study firstly confirmed that allele A at rs7078160 at VAX1 gene was a risk factor for NSCL/P in Western Han Chinese population., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: We aimed to study the association between rs7525173, rs2236518, rs2493264 single nucleotide polymorphism (SNP) in the PRDM16 gene, smoking, alcohol exposures, and nonsyndromic cleft lip with or without cleft palate (NSCL/P)., Methods: A total of 157 case-parent trios were selected, and SNPs were genotyped by using ligase detection reaction (LDR) and direct sequencing methods. Transmission disequilibrium test (TDT) and linkage disequilibrium (LD) tests were con-ducted to analyze the data. A total of 1 710 patients with orofacial clefts and 956 healthy newborns were enrolled in the epidemiological survey. The smoking and drinking exposures of parents during early pregnancy were analyzed., Results: The C allele at rs2236518 was over-transmitted for NSCPO (P<0.05). Statistical differences were observed among three factors, namely, maternal smoking, maternal passive smoking, and maternal drinking (P<0.05)., Conclusions: The rs2236518 at PRDM16 gene, maternal smoking, maternal passive smoking, and maternal drinking were closely related to the occurrence of NSCL/P.

Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a complex disorder, and it results from both of the genetic modifiers and environmental factors, with genetic modifiers contributes to it more than environmental factors. GWASs made great progress in identifying the candidate genes for NSCL/P, but the findings need to be replicated in other populations. In this study, we selected eleven SNPs from recent GWASs and GWAS meta-analysis to investigate their associations among 308 NSCL/P trios (134 non-syndromic cleft lip only (NSCLO) trios and 174 non-syndromic cleft lip with cleft palate (NSCLP) trios) from Han Chinese population. All SNPs were genotyped using SNPscan method and analyzed the data with FBAT, PLINK, and R package. Allelic TDT analysis showed that allele A at rs12543318 was associated with NSCLO trios (P = .0032, OR = 0.57, 95% CI: 0.39-0.83), and parent-of-origin effect analysis indicated that allele A at rs12543318 was significantly maternally undertransmitted among NSCLO (P = .0046), which implied the potential influence of genomic imprinting; global TDT further confirmed this association. Individual genotypic TDT showed homozygote C/C at rs12543318 was overtransmitted among NSCLO (Z = 3.79, P = .00015) and NSCL/P groups (Z = 3.83, P = .00013), which indicated that it could increase the risk to have cleft babies. Our findings indicated that rs12543318 was associated with NSCLO from Western Han Chinese population, which will give new scientific evidence for later researches in the etiology of NSOCs., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Non-syndromic orofacial cleftings (NSOCs) are considered as complex trait, which results from genetic and/or environmental modifiers. Current findings could only explain small portion of the NSOCs. SOX9 gene plays an important role during craniofacial development in animal models and the Pierre Robin sequence (PRS). However, its role in non-syndromic clefts remains unknown., Design: In this study, we selected eight SNPs in and around SOX9 gene to make maximum coverage, and genotyped them by using RFLP-PCR and ligase detection reaction (LDR) methods to test its associations among 151 NSOCs (53 NSCLP, 52 NSCLO and 46 NSCPO) from Western Han Chinese population., Results: Allelic TDT results showed that G allele at rs12941170 of SOX9 was under-transmitted among NSOCs (p=0.00014, OR=0.55 and 95%CI: 0.40-0.75), which could indicate that the G allele is protective against NSOCs; parent-of-origin effect analysis showed that G allele at rs12941170 was maternally under-transmitted (p=0.002), while there was no statistically difference between the maternal and paternal transmission of it. To test if the adjacent SNPs travel together from parents to the affected individual, we carried out the sliding window haplotype analysis, it is interesting to find that the haplotypes carrying the G allele at rs12941170 also was under-transmitted for NSOCs, NSCL/P, NSCLP and NSCPO (lowest p=0.00033)., Conclusions: This study suggested that G allele at rs12941170 was protective, which could decrease the risk for NSOCs from Western Han Chinese population, and it will provide new reference for future research and genetic counseling in NSOCs., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Non-syndromic orofacial clefts (NSOCs) are complex disease involving genetic triggers, environmental factors, and their interplay. Recent studies demonstrated that EYA1, a member of eye absent gene family, might contribute to NSOCs., Methods: We investigated three single nucleotide polymorphisms (SNPs) and eight environmental factors (multivitamin, folic acid and calcium supplementation history, maternal alcohol consumption, common cold history, maternal smoking and environmental tobacco smoke in the first trimester, and paternal smoking in the 3 months before pregnancy) among 294 case-parent trios and 183 individual controls in western Han Chinese to evaluate the relationship between EYA1, environmental factors, and NSOCs. To be better known the gene's role in the etiology of NSOCs, we performed statistical analysis in different aspects including the linkage disequilibrium test, transmission disequilibrium test, haplotype analysis, multiple logistic regression analysis, and conditional logistic regression analysis., Results: Allele C at rs3779748 showed an over-transmission in NSCL/P trios (P = 0.03), and genotype A/A at rs10094908 was under-transmitted among NSCL/P trios (P = 0.03), whereas over-transmitted among NSCPO trios (P = 0.02). The haplotype GC of rs10094908-rs3779748 was over-transmitted among NSCL/P trios (P = 0.05) and NSCPO trios (P = 0.05), respectively. Maternal common cold history, environmental tobacco smoke, and maternal alcohol consumption during the first trimester of pregnancy were risk factors for NSOCs, while calcium supplementation during the first trimester showed a protective effect. No evidence of interactions between EYA1 and environmental factors was found., Conclusions: These results revealed an association between EYA1, some environmental factors, and NSOCs in western Han Chinese., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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, r(2) = 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., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Small ubiquitin-like modifier 1 (SUMO1) and environmental factors have been shown to be associated with nonsyndromic cleft lip with or without cleft palate (NSCL/P) in several populations. This study aimed at confirming the contribution of SUMO1 gene and environmental factors to nonsyndromic orofacial clefts risk in western Han Chinese. Four single-nucleotide polymorphisms were investigated in 212 case trios in western China using conditional logistic regression models and the transmission disequilibrium test under a case-parent trio design. Strong evidence of linkage and linkage disequilibrium was found between these markers and the disease in both single-nucleotide polymorphism analysis (T allele at rs6761234 [p = 0.0005, odds ratio [OR] = 1.82, 95% confidence interval [CI]:1.30-2.57) and C allele at rs12470401 (p < 0.0001, OR = 2.82, 95% CI: 1.90-4.19)] and sliding window haplotype analysis (T-T-T for rs6761234-rs12470401-rs7599810 [p = 0.018], C-C-G for rs12470401-rs7599810-rs6435133 [0.0033], C-T-T-T for rs6761234-rs12470401-rs7599810-rs6435133 [p = 0.018] among others). Interactions between mothers' passive smoking during the first trimester and C/C genotype of rs12470401 showed statistical significance (OR(0) = 2.53 and OR(1) = 8.83). Risk factors identified in this study may provide a better understanding of the etiological role of SUMO1 gene in NSCL/P incidence.

Small ubiquitin-like modifier 1 (SUMO1) has been shown to be associated with cleft lip and palate in animal models. However, rarely studies have linked SUMO1 to nonsyndromic cleft lip with or without cleft palate in humans. The purpose of this study was to confirm the contribution of SUMO1 to nonsyndromic orofacial clefts in western Han Chinese. Four single-nucleotide polymorphisms were investigated in 246 case trios in western China using conditional logistic regression, transmission disequilibrium test, and case-parent trio design. Strong evidence of linkage disequilibrium was found between these markers and the disease in both single-nucleotide polymorphism analysis (G allele at rs6761131 [p=0.0008, odds ratio (OR) = 1.92, 95% confidence interval (CI): 1.31-2.81], C allele at rs7580433 [p<0.0001, OR=2.79, 95% CI: 1.93-4.03], and G allele at rs10185956 [p=0.0069, OR=1.61, 95% CI: 1.14-2.27]) and haplotype analysis (A-C for rs6709162-rs7580433 [p=0.00024], C-G for rs7580433-rs10185956 [p=0.00091], and A-C-A for rs6709162-rs7580433-rs10185956 [p=0.004], among others). The risk factors identified in this study may provide a better understanding of the etiological role of SUMO1 in nonsyndromic cleft lip with or without cleft palate incidence.

Myosin heavy chain 9, nonmuscle (MYH9) and environmental factors have been shown to be associated with nonsyndromic cleft lip with or without cleft palate in several populations. Our study aimed to confirm the contribution of MYH9 and environmental factors to nonsyndromic orofacial cleft risk in western Han Chinese. Four single-nucleotide polymorphisms were investigated in 180 case trios and 224 normal peers in western China using transmission disequilibrium test, family-based association test analysis, and logistic regression models. Strong evidence of linkage disequilibrium was found between these markers and the disease by both single-nucleotide polymorphism analysis (G allele at rs2269529 and T allele at rs16996652) and haplotype analysis (G-T [for rs2269529 and rs16996652] and G-A-T [for rs2269529, rs3752462, and rs16996652] among others). Mothers' illness, medication, and passive smoking during the first trimester may increase the risk of nonsyndromic orofacial clefts, but mothers' vitamin (including folic acid) supplementation during the first trimester is a protective factor. Interactions between mothers' passive smoking during the first trimester and T/T genotype of rs16996652 had statistical significance. Risk factors identified in our study may provide a better understanding of the etiological role of MYH9 and influence of environmental factors in nonsyndromic orofacial cleft incidence.

The interferon regulatory factor 6 (IRF6) gene and environmental factors have been shown to be associated with nonsyndromic cleft lip with or without cleft palate (NSCL/P) in several populations. This study aimed to confirm the contribution of IRF6 and environmental factors to NSCL/P risk in western Han Chinese. Five single nucleotide polymorphisms (SNPs) were investigated in 107 case trios (child and parents) and 100 normal peers in western China using transmission disequilibrium test, case-control analysis, and logistic regression models. Strong evidence of linkage disequilibrium was found between these markers and the disease in both SNP analysis (A allele at rs4844880, G allele at rs2073485, and C allele at rs599021) and haplotype analysis (A-A for rs861019 and rs4844880, A-C for rs4844880 and rs599021, among others). Both mothers' medication and passive smoking during the first trimester of pregnancy may increase the risk of NSCL/P, but mothers' vitamins (including folic acid) supplementation during the first trimester was a protective factor. Interactions between mothers' abortion history and TT genotype of rs2235373 were statistically significant (odds ratio = 6.70, 95% confidence interval =1.69-26.52). Risk factors identified in this study may provide a better understanding of the etiological role IRF6 and environmental factors play in NSCL/P incidence.

Objective: Paired box 7 (PAX7) has been considered as a candidate gene for non-syndromic cleft lip with or without palate (NSCL/P). However, there is no research for the XXX, and previous studies concentrated on limited variants. This study aimed to conduct sufficiently dense and powerful scans of variants at PAX7 and explored the roles of variants at PAX7 in NSCL/P among the XXX. Design: Targeted region sequencing was performed to thoroughly screen variations, followed by a two-phase association analysis. 159 NSCL/P cases and 542 controls were analyzed in phase 1. Then in phase 2, the validation study was performed using 1626 cases and 2255 controls. We also explored the roles of variants at PAX7 gene in NSCL/P subtypes. Additionally, indirect associations were found by calculating LD and haplotypes. Setting: The study was conducted in XXX. Patients, participants: 159 NSCL/P cases and 542 controls were analyzed in phase 1. Then in phase 2, the validation study was performed using 1626 cases and 2255 controls. Interventions: Blood samples were collected. Main outcome measures: To explore the association analysis between variants at PAX7 and NSCL/P in XXX. Results: The results showed that rs2236810, rs114882979 and rs2236804 were significantly associated with NSCL/P, which were predicted to have regulatory functions. Besides, variants at PAX7 function differently in the NSCL/P subtypes. We also discovered a PAX7 missense variant, NM_001135254 p.A369 V (NM_002584.2:c.1106C > T). Conclusions: In summary, we confirmed 3 SNPs at PAX7 were significantly associated with NSCL/P in XXX and identified a missense variant, NM_001135254 p.A369 V (NM_002584.2:c.1106C > T). [ABSTRACT FROM AUTHOR]

rs7590268 present on the 2p21 locus was identified to be associated with non-syndromic cleft lip with or without cleft palate (NSCL/P) in several populations, including the Chinese Han population, indicating that 2p21 was a susceptibility locus for NSCL/P. However, previous studies have only identified common single-nucleotide polymorphism (SNP) within the THADA gene, neglecting the rare variants and other genes in 2p21; thus, this study was designed to investigate additional variants and novel susceptibility genes in 2p21. A total of 159 NSCL/P patients and 542 controls were recruited in the discovery phase, whereas 1830 NSCL/P patients and 2,436 controls were recruited in the replication phase. After targeted region sequencing, we performed association and burden analyses for the common and rare variants, respectively. Furthermore, RNA-seq, proliferation assay and cell cycle analysis were performed to clarify the possible function of the candidate gene ZFP36L2. Association analysis showed that four SNPs were specifically associated with non-syndromic cleft lip only (NSCLO) and two SNPs were associated with both NSCLO and NSCL/P. Burden analysis indicated that ZFP36L2 was associated with NSCLO (p =.0489, OR = 2.41, 95% CI: 0.98–5.90). Moreover, SNPs in the ZFP36L2 targeted gene JUP were also associated with NSCLO. ZFP36L2 also inhibited cell proliferation and induced G2 phase arrest in the GMSM-K cell line. Therefore, we proposed that ZFP36L2 is a novel susceptibility gene of NSCLO in the 2p21 locus, which could lead to NSCLO by modulating cell proliferation and cycle. [ABSTRACT FROM AUTHOR]