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Congenital orofacial cleft, the most common birth defect in the maxillofacial region, exhibits a wide range of prognosis depending on the severity of deformity and underlying etiology. Non-syndromic congenital orofacial clefts typically present with milder deformities and more favorable treatment outcomes, whereas syndromic congenital orofacial clefts often manifest with concomitant organ abnormalities, which pose greater challenges for treatment and result in poorer prognosis. This consensus provides an elaborate classification system for varying degrees of orofacial clefts along with corresponding diagnostic and therapeutic guidelines. Results serve as a crucial resource for families to navigate prenatal screening results or make informed decisions regarding treatment options while also contributing significantly to preventing serious birth defects within the development of population.

Objective: To delve into the intricate relationship between common genetic variations across the entire genome and the risk of non-syndromic cleft lip with or without cleft palate (NSCL/P)., Methods: Utilizing summary statistics data from genome-wide association studies (GWAS), a thorough investigation to evaluate the impact of common variations on the genome were undertook. This involved assessing single nucleotide polymorphism (SNP) heritability across the entire genome, as well as within specific genomic regions. To ensure the robustness of our analysis, stringent quality control measures were applied to the GWAS summary statistics data. Criteria for inclusion encompassed the absence of missing values, a minor allele frequency ≥1%, P -values falling within the range of 0 to 1, and clear SNP strand orientation. SNP meeting these stringent criteria were then meticulously included in our analysis. The SNP heritability of NSCL/P was calculated using linkage disequilibrium score regression. Additionally, hierarchical linkage disequilibrium score regression to partition SNP heritability within coding regions, promoters, introns, enhancers, and super enhancers were employed, and the enrichment levels within different genomic regions using LDSC (v1.0.1) software were further elucidated., Results: Our study drew upon GWAS summary statistics data obtained from 806 NSCL/P trios, comprising a total of 2 418 individuals from the Chinese population. Following rigorous quality control procedures, 490 593 out of 492 993 SNP were deemed suitable for inclusion in SNP heritability calculations. The observed SNP heritability of NSCL/P was 0.55 (95% CI : 0.28-0.82). Adjusting for the elevated disease pre-valence within our sample, the SNP heritability scaled down to 0.37 (95% CI : 0.19-0.55) based on the prevalence observed in the general Chinese population. Notably, our enrichment analysis unveiled significant enrichment of SNP heritability within enhancer regions (15.70, P =0.04) and super enhancer regions (3.18, P =0.03)., Conclusion: Our study sheds light on the intricate interplay between common genetic variations and the risk of NSCL/P in the Chinese population. By elucidating the SNP heritability landscape across different genomic regions, we contribute valuable insights into the genetic basis of NSCL/P. The significant enrichment of SNP heritability within enhancer and super enhancer regions underscores the potential role of these regulatory elements in shaping the genetic susceptibility to NSCL/P. This paves the way for further research aimed at uncovering novel genetic pathogenic factors underlying NSCL/P pathogenesis.

Objective: To explore the association between polymorphisms of transforming growth factor-β (TGF-β) signaling pathway and non-syndromic cleft lip with or without cleft palate (NSCL/P) among Asian populations, while considering gene-gene interaction and gene-environment interaction., Methods: A total of 1 038 Asian NSCL/P case-parent trios were ascertained from an international consortium, which conducted a genome-wide association study using a case-parent trio design to investigate the genes affec-ting risk to NSCL/P. After stringent quality control measures, 343 single nucleotide polymorphism (SNP) spanning across 10 pivotal genes in the TGF-β signaling pathway were selected from the original genome-wide association study(GWAS) dataset for further analysis. The transmission disequilibrium test (TDT) was used to test for SNP effects. The conditional Logistic regression models were used to test for gene-gene interaction and gene-environment interaction. Environmental factors collected for the study included smoking during pregnancy, passive smoking during pregnancy, alcohol intake during pregnancy, and vitamin use during pregnancy. Due to the low rates of exposure to smoking during pregnancy and alcohol consumption during pregnancy (<3%), only the interaction between maternal smoking during pregnancy and multivitamin supplementation during pregnancy was analyzed. The threshold for statistical significance was rigorously set at P =1.46×10 -4 , applying Bonferroni correction to account for multiple testing., Results: A total of 23 SNPs in 4 genes yielded nominal association with NSCL/P ( P <0.05), but none of these associations was statistically significant after Bonferroni' s multiple test correction. However, there were 6 pairs of SNPs rs4939874 ( SMAD2 ) and rs1864615 ( TGFBR2 ), rs2796813 ( TGFB2 ) and rs2132298 ( TGFBR2 ), rs4147358 ( SMAD3 ) and rs1346907 ( TGFBR2 ), rs4939874 ( SMAD2 ) and rs1019855 ( TGFBR2 ), rs4939874 ( SMAD2 ) and rs12490466 ( TGFBR2 ), rs2009112 ( TGFB2 ) and rs4075748 ( TGFBR2 ) showed statistically significant SNP-SNP interaction ( P <1.46×10 -4 ). In contrast, the analysis of gene-environment interactions did not yield any significant results after being corrected by multiple testing., Conclusion: The comprehensive evaluation of SNP associations and interactions within the TGF-β signaling pathway did not yield any direct associations with NSCL/P risk in Asian populations. However, the significant gene-gene interactions identified suggest that the genetic architecture influencing NSCL/P risk may involve interactions between genes within the TGF-β signaling pathway. These findings underscore the necessity for further investigations to unravel these results and further explore the underlying biological mechanisms.

To assess the growth status of children with non-syndromic oral clefts (NSOC) and explore potential influencing factors. The data of NSOC children aged ≤5 years hospitalized between December 2018 and June 2020 were retrieved and evaluated, including their height, weight, NSOC subtypes and demographic characteristics before reparative surgeries. The growth status of the children was assessed using height-for-age Z-score (HAZ), weight-for-age Z-score (WAZ) and weight-for-height Z-score (WHZ). In total, 504 NSOC children (271 females & 233 males) were included. The proportion of stunting (HAZ <-2), underweight (WAZ <-2) and wasting (WHZ <-2) was 4.96%, 5.16% and 3.97%, respectively. In addition, we observed that HAZ and WAZ decreased with increasing age (both p < 0.01). Moreover, non-syndromic cleft palate only (NSCP) and non-syndromic cleft lip and palate (NSCLP) were associated with lower HAZ and WAZ compared with non-syndromic cleft lip only (NSCL) (all p < 0.01), while NSCLP was associated with a lower WHZ compared with NSCL ( p < 0.01). The growth retardation and low weight rate of NSOC children under 5 years old were higher than the national average level and differed by the age of NSOC children and disease subtypes. Further improvements are warranted to promote the growth status of the NSOC-affected children., Competing Interests: The authors declare no conflict of interest., (©2023 The Author(s). Published by MRE Press.)

The folate-mediated one-carbon metabolism pathway is thought to play an important role in the etiology of non-syndromic oral clefts (NSOFC), although none of the genes in this pathway has shown significant signals in genome-wide association studies (GWAS). Recent evidence indicated that enhanced understanding could be gained by aggregating multiple SNPs effect simultaneously into polygenic risk score (PRS) to assess its association with disease risks. This study is aimed to assess the association between the genetic effect of folate-mediated one-carbon metabolism pathway and NSOFC risks using PRS based on a case-parent trio design. A total of 297 SNPs mapped from 18 genes in the folate-mediated one-carbon metabolism pathway were aggregated from a GWAS of 2458 case-parent trios recruited from an international consortium. We found a PRS based on the folate-mediated one-carbon metabolism pathway was significant among all NSOFC trios (OR = 1.95, 95% CI: 1.66-2.28, p = 2.39 × 10 -16 ), as well as two major subtypes, non-syndromic cleft lip with or without cleft palate (NSCL/P) trios (OR = 1.71, 95% CI: 1.50-1.96, p = 7.66 × 10 -15 ) and non-syndromic cleft palate only (NSCPO) trios (OR = 1.51, 95% CI: 1.36-1.68, p = 2.1 × 10 -14 ). Similar results were also observed in further subgroup analyses stratified into Asian and European trios. The averaged PRS of the folate-mediated one-carbon metabolism pathway varied between the NSOFC case group and its comparison group (p < 0.05) with higher average PRS in the cases. Moreover, the top 5% pathway PRS group had 2.25 (95% CI: 1.85-2.73) times increased NSOFC risk, also 3.09 (95% CI: 2.50-3.81) and 2.06 (95% CI: 1.39-3.02) times increased risk of NSCL/P and NSCPO compared to the remainder of the distribution. The results of our study confirmed the folate-mediated one-carbon metabolism pathway was important in controlling risk to NSOFC and this study enhanced evidence towards understanding the genetic risks of NSOFC., (© 2021 Wiley Periodicals LLC.)

Background: Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a common birth defect with complex etiology. One strategy for studying the genetic risk factors of NSCL/P is to consider gene-gene interaction (G × G) among gene pathways having a role in craniofacial development. The present study aimed to investigate the G × G among cell adhesion gene pathway., Methods: We carried out an interaction analysis of eight genes involved in cell adherens junctions among 806 NSCL/P Chinese case-parent trios originally recruited for a genome-wide association study (GWAS). Regression-based approach was used to test for two-way G × G interaction, while machine learning algorithm was run for exploring both two-way and multi-way interaction that may affect the risk of NSCL/P., Results: A two-way ACTN1 × CTNNB1 interaction reached the adjusted significance level. The single nucleotide polymorphisms pair composed of rs17252114 (CTNNB1) and rs1274944 (ACTN1) yielded a p value of .0002, and this interaction was also supported by the logic regression algorithm. Higher order interactions involving ACTN1, CTNNB1, and CDH1 were picked out by logic regression, suggesting a potential role in NSCL/P risk., Conclusion: This study suggests for the first time evidence of both two-way and multi-way G × G interactions among cell adhesion genes contributing to the NSCL/P risk., (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a common birth defect. Genetic variants causing syndromic orofacial clefts can also contribute to the etiology of NSCL/P. The purpose of the present study was to explore gene-gene (G × G) interaction using common single nucleotide polymorphic (SNP) markers in fibroblast growth factor (FGF) family and its receptors and T-box genes, which were associated with syndromic orofacial clefts. Our study was conducted in 806 Chinese NSCL/P case-parent trios drawn from an international consortium. A total of 252 SNPs in FGF8, FGF10, FGFR1, FGFR2, and TBX5 passed the quality control criteria and were included in the analysis. The interactions between SNPs in different genes were assessed using Cordell's method, which fitted a conditional logistic regression model. The analysis was performed using the R-package trio (Version 3.8.0). Bonferroni correction was used to adjust for multiple comparisons, and the overall significance threshold was set as P = 1.98 × 10 -4 (0.05/252). Conditional logistic regression revealed the most significant interaction between rs2330542 in FGF10 and rs1946295 in TBX5, which remained significant (P = 9.63 × 10 -6 ) after Bonferroni correction. The relative risk of allele C in rs2330542 (FGF10) was 1.02 (95%CI 0.81-1.28), while the relative risk was 1.42 (95%CI 1.03-1.97) when the exposure was a combination of allele C in rs2330542 and allele A in rs1946295 (TBX5). Our findings confirmed the importance of considering G × G interaction when exploring the genetic risk factors of NSCL/P. Further investigations are warranted to validate the potential interaction and reveal the biological function of FGF10/FGFR2/TBX5. Environ. Mol. Mutagen. 2019. © 2019 Wiley Periodicals, Inc., (© 2019 Wiley Periodicals, Inc.)

Non-syndromic cleft lip with or without cleft palate (NSCL/P) is one of common birth defects in China, with genetic and environmental components contributing to the etiology. Genome wide association studies (GWASs) have identified SPRY1 and SPRY2 to be associated with NSCL/P among Chinese populations. This study aimed to further explore potential genetic effect and gene-environment interaction among SPRY genes based on haplotype analysis, using 806 Chinese case-parent NSCL/P trios drawn from an international consortium which conducted a genome-wide association study. After the process of quality control, 190 single nucleotide polymorphisms (SNPs) of SPRY genes were included for analyses. Haplotype and haplotype-environment interaction analyses were conducted in Population-Based Association Test (PBAT) software. A 2-SNP haplotype and three 3-SNP haplotypes showed a significant association with the risk of NSCL/P after Bonferroni correction (corrected significance level = 2.6 × 10 -4 ). Moreover, haplotype-environment interaction analysis identified these haplotypes respectively showing statistically significant interactions with maternal multivitamin supplementation or maternal environmental tobacco smoke. This study showed SPRY2 to be associated with NSCL/P among the Chinese population through not only gene effects, but also a gene-environment interaction, highlighting the importance of considering environmental exposures in the genetic etiological study of NSCL/P.

Objective: Multiple studies have suggested nonsyndromic cleft lip with or without cleft palate (NSCL/P), and lung cancer may have common genetic etiology. Previous studies have showed genetic variants in nicotinic cholinergic receptor genes (CHRNs) may influence risk of lung cancer. We aimed to explore the effect of CHRNs on risk of NSCL/P considering gene-gene (GxG) interaction for these genes., Subjects and Methods: We selected 120 markers in 14 CHRNs to test for GxG interaction using 806 Chinese case-parent trios recruited from an international consortium established for a GWAS of oral clefts., Results: Totally, two pairs of SNPs yielded significant GxG interactions after Bonferroni correction (rs935865 and rs2337980 with p = 4.04 × 10 -5 , rs2741335 and rs3743077 with p = 4.80 × 10 -4 ), and these pairwise interactions were confirmed in permutation tests. In addition, the relative risk (RR) of the putative interaction between rs935865 and rs2337980 was 1.10 (95% CI: 0.92~1.31)., Conclusions: While the single SNP association and the gene-environment interaction analysis of 14 CHRN genes yielded no signal, this study did demonstrate the importance of considering potential GxG interaction for exploring etiology of NSCL/P. This study suggests an important role for particular combinations of SNPs in CHRN genes in influencing risk to NSCL/P, which needs further study., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. All rights reserved.)

Objective: To investigate the age effects of cleft palate repair on middle ear function and hearing level in patients who underwent cleft palate repair at different ages by audiologic examination., Methods: Medical histories were gathered in detail, and audiologic tests (ie, tympanometry and pure tone hearing threshold) were conducted in 126 patients after palatoplasty. The patients were divided into the following 4 groups according to their ages when they underwent cleft palate repair: group I (0-3 years, 73 patients), group II (4-7 years, 29 patients), group III (8-11 years, 16 patients), and group IV (12 years and older, 8 patients). The data regarding tympanograms, hearing levels, and the average hearing thresholds of each group were analyzed using chi-square tests., Results: The prevalence of middle ear dysfunction and hearing loss in the patients who underwent palatoplasty before 3 years old (27.4% and 2.0% respectively) was significantly lower than that in patients who underwent palatopalsty at 12 years or older (75.0% and 43.7%, respectively). Linear-by-linear association revealed that the prevalences of middle ear dysfunction and hearing loss among the 4 groups were significantly different ( P < .05)., Conclusions: The prevalence of middle ear dysfunction and hearing loss tended to increase with advancing age at the time of cleft palate repair. From an audiologist's perspective, palatoplasty at an early age is very beneficial in helping children with cleft palates acquire better middle ear function and hearing level.

Background: Small ubiquitin-like modification, also known as sumoylation, is a crucial post-translational regulatory mechanisms involved in development of the lip and palate. Recent studies reported two sumoylation target genes, MSX1 and TP63, to have achieved genome-wide level significance in tests of association with nonsyndromic clefts. Here, we performed a candidate gene analysis considering gene-gene and gene-environment interaction for SUMO1, MSX1, and TP63 to further explore the etiology of nonsyndromic cleft lip with or without cleft palate (NSCL/P)., Methods: A total of 130 single-nucleotide polymorphisms (SNPs) in or near SUMO1, MSX1, and TP63 was analyzed among 1,038 Asian NSCL/P trios ascertained through an international consortium. Conditional logistic regression models were used to explore gene-gene (G × G) and gene-environment (G × E) interaction involving maternal environmental tobacco smoke and multivitamin supplementation. Bonferroni correction was used for G × E analysis and permutation tests were used for G × G analysis., Results: While transmission disequilibrium tests and gene-environment interaction analysis showed no significant results, we did find signals of gene-gene interaction between SNPs near MSX1 and TP63. Three pairwise interactions yielded significant p values in permutation tests (rs884690 and rs9290890 with p = 9.34 × 10 -5 and empirical p = 1.00 × 10 -4 , rs1022136 and rs4687098 with p = 2.41 × 10 -4 and empirical p = 2.95 × 10 -4 , rs6819546 and rs9681004 with p = 5.15 × 10 -4 and empirical p = 3.02 × 10 -4 )., Conclusion: Gene-gene interaction between MSX1 and TP63 may influence the risk of NSCL/P in Asian populations. Our study provided additional understanding of the genetic etiology of NSCL/P and underlined the importance of considering gene-gene interaction in the etiology of this common craniofacial malformation., (© 2018 Wiley Periodicals, Inc.)

Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common birth defect with a complex and heterogeneous etiology. A recent genome-wide association study (GWAS) among Chinese populations has identified a new region at 16p13.3 as being associated with NSCL/P, which requires further replication. Here, we attempted to replicate and further clarify the genetic association between this region and NSCL/P, as well as testing for potential gene-gene (G × G) and gene-environment (G × E) interactions. We conducted transmission disequilibrium tests on 69 single nucleotide polymorphisms (SNPs) mapping to 16p13.3 among 806 Chinese case-parent trios ascertained through an international consortium where a GWAS of oral clefts was conducted. G × G, as well as G × E interactions involving maternal environmental tobacco smoke (ETS) and multivitamin supplementation, were explored using conditional logistic regression model. We applied Cordell's method as implemented in the R package TRIO to test for possible interactions. While no SNPs showed evidence of linkage and association with NSCL/P after Bonferroni correction, we found signals of G × G interactions between SNPs in 16p13.3. Nine pairs of SNP-SNP interactions attained significance after Bonferroni correction, among which the most significant interaction was found between rs2072346 (ADCY9) and rs11646137 (intergenic region, P = 7.2 × 10 -5 ). Linkage disequilibrium (LD) analysis revealed only low level of LD between these SNPs. This study failed to confirm the significant association between SNPs within 16p13.3 and the risk of NSCL/P, but underlined the importance of taking into account potential G × G interactions for the genetic association analysis of NSCL/P., (© 2017 Wiley Periodicals, Inc.)

Objective: To explore the relationship between hearing level and soft palate movement after palatoplasty and to verify the importance of recovery of soft palate movement function for improving the middle ear function as well as reducing the hearing loss., Methods: A total of 64 non-syndromic cleft palate patients were selected and the lateral cephalometric radiographs were taken. The patients hearing level was evaluated by the pure tone hearing threshold examination. This study also analyzed the correlation between hearing threshold of the patients after palatoplasty and the soft palate elevation angle and velopharyngeal rate respectively., Results: Kendall correlation analysis revealed that the correlation coefficient between hearing threshold and the soft palate elevation angle after palatoplasty was -0.339 (r = -0.339, P < 0.01).The correlation showed a negative correlation. The hearing threshold decreased as the soft palate elevation angle increased. After palatoplasty, the correlation coefficient between the hearing threshold and the rate of velopharyngeal closure was -0.277 (r = -0.277, P < 0.01). The correlation showed a negative correlation. While, The hearing threshold decreased with the increase of velopharyngeal closure rate. The hearing threshold was correlated with soft palate elevation angle and velpharyngeal closure rate., Conclusions: The movement of soft palate and velopharyngeal closure function after palatoplasty both have impact on patient hearing level. In terms of the influence level, the movement of soft palate has a higher level of impact on patient hearing level than velopharygeal closure function.

Objective: To investigate the phonological characteristics of glottal stop on the patients with speech disorders following cleft palate surgery or pharyngoplasty, and to determine the effects of a new method of speech training for glottal stop in chinese., Methods: Using the methods of listening judge and sound spectrograph in acoustic analyses to investigate the category and frequency of glottal stop on consonants in Chinese. A new method of speech therapy was used for 12 patients with glottal stop., Results: The frequency of glottal stop on the unaspirating affricates and unaspirating plosives were the highest in Chinese consonants. Secondly, the aspirating affricates and aspirating plosives, and then, the fricatives, but the nasal consonants were not effected by glottal stop completely. The score of articulations of the 12 patients whom trained through the methods increased from 32% to 85.5%., Conclusions: The glottal stop is one of the main causes to impair the articulations of consonants and speech. The new methods of speech training for glottal stp are effective.

Objective: To investigate the age effects of cleft palate repair on middle ear function and hearing level in patients who underwent cleft palate repair at different ages by audiologic examination. Methods: Medical histories were gathered in detail, and audiologic tests (ie, tympanometry and pure tone hearing threshold) were conducted in 126 patients after palatoplasty. The patients were divided into the following 4 groups according to their ages when they underwent cleft palate repair: group I (0-3 years, 73 patients), group II (4-7 years, 29 patients), group III (8-11 years, 16 patients), and group IV (12 years and older, 8 patients). The data regarding tympanograms, hearing levels, and the average hearing thresholds of each group were analyzed using chi-square tests. Results: The prevalence of middle ear dysfunction and hearing loss in the patients who underwent palatoplasty before 3 years old (27.4% and 2.0% respectively) was significantly lower than that in patients who underwent palatopalsty at 12 years or older (75.0% and 43.7%, respectively). Linear-by-linear association revealed that the prevalences of middle ear dysfunction and hearing loss among the 4 groups were significantly different (P < .05). Conclusions: The prevalence of middle ear dysfunction and hearing loss tended to increase with advancing age at the time of cleft palate repair. From an audiologist’s perspective, palatoplasty at an early age is very beneficial in helping children with cleft palates acquire better middle ear function and hearing level. [ABSTRACT FROM AUTHOR]