The Department of Plastic Surgery of the Yonsei University College of Medicine in Korea studied 2422 cases of cleft lip and cleft palate patients for 20 years An analysis of the date resulted in the following: 1) of the 33,130 live births in our hospital in 20 years (Jan. 1962-Dec. 1981), 44 of the birth certificates specified cleft lip or palate. This is a ratio of 1.33 cases per 1000 live births. 2) The ratios for left to right to bilateral cleft was 3.4:1.9:1.0. Higher percentage of males than females had cleft lip-palate combined, than cleft lip only. A higher percentage of females had cleft palate only. 3) A positive family history was noted in 151 out of 2422 cases; (6.3%). 4) 45% of the patients had an associated congenital malforation of which heart anomaly was the most common. 5) Lip closure was scheduled to be done within 3 months of age; palate closure was scheduled between 12 to 18 months. 6) The triangular flap method was used for the lip repair. The palate was repaired by the KilnerWardill method in all cases. The operative results were satisfactory m both lip controur and speech. Noting the lack of published reports about this topic, especially among the oricental population, we believe this paper will serve to enhance the knowledge of the field of cleft lip and cleft palate patients in Asia.
Cleft Lip/epidemiology* ; Cleft Lip/genetics ; Cleft Lip/surgery ; Cleft Palate/epidemiology* ; Cleft Palate/genetics ; Cleft Palate/surgery ; Female ; Human ; Infant ; Infant, Newborn ; Korea ; Male

Cleft Lip ; epidemiology ; genetics ; Cleft Palate ; epidemiology ; genetics ; Humans ; Risk Factors

Genome-wide association studies (GWASs) are the most widely used method to identify genetic risk loci associated with orofacial clefts (OFC). However, despite the increasing size of cohort, GWASs are still insufficient to detect all the heritability, suggesting there are more associations under the current stringent statistical threshold. In this study, we obtained an integrated epigenomic dataset based on the chromatin conformation of a human oral epithelial cell line (HIOEC) using RNA-seq, ATAC-seq, H3K27ac ChIP-seq, and DLO Hi-C. Presumably, this epigenomic dataset could reveal the missing functional variants located in the oral epithelial cell active enhancers/promoters along with their risk target genes, despite relatively less-stringent statistical association with OFC. Taken a non-syndromic cleft palate only (NSCPO) GWAS data of the Chinese Han population as an example, 3664 SNPs that cannot reach the strict significance threshold were subjected to this functional identification pipeline. In total, 254 potential risk SNPs residing in active cis-regulatory elements interacting with 1 718 promoters of oral epithelium-expressed genes were screened. Gapped k-mer machine learning based on enhancers interacting with epithelium-expressed genes along with in vivo and in vitro reporter assays were employed as functional validation. Among all the potential SNPs, we chose and confirmed that the risk alleles of rs560789 and rs174570 reduced the epithelial-specific enhancer activity by preventing the binding of transcription factors related to epithelial development. In summary, we established chromatin conformation datasets of human oral epithelial cells and provided a framework for testing and understanding how regulatory variants impart risk for clefts.
Chromatin ; Cleft Lip/genetics* ; Cleft Palate/genetics* ; Epithelium ; Genome-Wide Association Study ; Humans

OBJECTIVE: In this study, we used genome-wide association study (GWAS) data to explore whether WNT pathway genes were associated with non-syndromic oral clefts (NSOC) considering gene-gene interaction and gene-environment interaction. METHODS: We conducted the analysis using 806 non-syndromic cleft lip with or without cleft palate (NSCL/P) case-parent trios and 202 non-syndromic cleft palate (NSCP) case-parent trios among Chinese populations selected from an international consortium established for a GWAS of non-syndromic oral clefts. Genotype data and maternal environmental exposures were collected through DNA samples and questionnaires. Conditional Logistic regression models were adopted to explore gene-gene interaction and gene-environment in teraction using trio package in R software. The threshold of significance level was set as 3.47×10^-4 using Bonferroni correction. RESULTS: A total of 144 single nucleotide polymorphisms (SNPs) in seven genes passed the quality control process in NSCL/P trios and NSCP trios, respectively. Totally six pairs of SNPs interactions showed statistically significant SNP-SNP interaction (P < 3.47×10^-4) after Bonferroni correction, which were rs7618735 (WNT5A) and rs10848543 (WNT5B), rs631948 (WNT11) and rs556874 (WNT5A), and rs631948 (WNT11) and rs472631 (WNT5A) among NSCL/P trios; rs589149 (WNT11) and rs4765834 (WNT5B), rs1402704 (WNT11) and rs358792 (WNT5A), and rs1402704 (WNT11) and rs358793 (WNT5A) among NSCP trios, respectively. In addition, no significant result was found for gene-environment interaction analysis in both of the NSCL/P trios and NSCP trios. CONCLUSION Though this study failed to detect significant association based on gene-environment interactions of seven WNT pathway genes and the risk of NSOC, WNT pathway genes may influence the risk of NSOC through potential gene-gene interaction.
Asians/genetics* ; Cleft Lip/genetics* ; Cleft Palate/genetics* ; Genome-Wide Association Study ; Humans ; Wnt Signaling Pathway/genetics*

OBJECTIVE: This study aimed to investigate the clinical phenotype and genetic characteristics of Chinese families with Van der Woude syndrome (VWS). METHODS: Clinical manifestations between 14 families and within each family were recorded. Possible inheritance modes and pathogenic genes were analyzed. Phenotypic distribution and gene frequencies were calculated. RESULTS: Of the pedigrees investigated, an autosomal dominant inheritance pattern was suggested. All patients had typical symptoms. The pathogenic gene was interferon regulatory factor 6 (IRF6). Phenotypic distribution frequencies were as follows: lip pits (91.9%), cleft lip and/or palate (73.0%), and hyperdontia (8.1%). There were significant differences in clinical phenotypes among individuals of different families and individuals of the same family. CONCLUSIONS VWS in a Chinese population was dominantly inherited with high penetrance and variable expressivity. The pathogenic gene was IRF6. VWS in a Chinese population was genotyped as VWS1.
Abnormalities, Multiple ; genetics ; Cleft Lip ; genetics ; Cleft Palate ; genetics ; Cysts ; genetics ; Humans ; Interferon Regulatory Factors ; genetics ; Lip ; abnormalities ; Mutation ; Pedigree ; Syndrome

OBJECTIVE: Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common birth defect, affecting 1.4 per 1 000 live births, and multiple genetic and environmental risk factors influencing its risk. All the known genetic risk factors accounted for a small proportion of the heritability. Several authors have suggested parent-of-origin effects (PoO) may play an important role in the etiology of this complex and heterogeneous malformation. To clarify the genetic association between PTCH1, PTCH2, SHH and SMO in hedgehog (HH) pathway and NSCL/P, as well as testing for potential PoO effects in Chinese case-parent trios. METHODS: We tested for transmission disequilibrium tests (TDT) and PoO effects using 83 common single nucleotide polymorphic (SNP) markers of HH pathway genes from 806 NSCL/P case-parent trios. These trios were drawn from an international consortium established for a genome-wide association studies (GWAS) of non-syndromic oral clefts of multiple ethnicities. DNA samples were collected from each trio. Single marker and haplotype based analysis were performed both in TDT tests and PoO effects. SNPs were excluded if they (ⅰ) had a call rate of < 95%, (ⅱ) had a minor allele frequency (MAF) of < 0.05, (ⅲ) had Mendelian errors over all trios of >5%, (ⅳ) had a genotype distribution in the parents that deviated from the Hardy-Weinberg equilibrium (HWE) (P < 0.000 1). The process was done using Plink (version 1.07, http://pngu.mgh.harvard.edu/~purcell/plink/data.shtml). TDT test was performed in Plink v1.07. A log-linear model was used to explore PoO effects using Haplin v6.2.1 as implemented in R package v3.4.2. Significance level was assessed using the Bonferroni correction. RESULTS: A total of 18 SNPs were dropped due to low MAF, thus leaving 65 SNPs available for the analysis. Thus the Bonferroni threshold was 7.7×10^-4 (0.05/65). Nominal significant association with NSCL/P was found at a SNP (rs4448343 in PTCH1, P=0.023) and six haplotypes (rs10512249-rs4448343, rs1461208-rs7786445, rs10512249-rs4448343, rs16909865-rs10512249-rs4448343, rs1461208-rs7786445-rs12698335, and rs288756-rs288758-rs1151790, P < 0.05). A total of six haplotypes (rs288765-rs1233563, rs12537550-rs11765352, rs872723-rs288765-rs1233563, rs288765-rs1233563-rs288756, rs6459952-rs12537550-rs11765352, and rs12537550-rs11765352-rs6971211) showed PoO effect (P < 0.05). None of the results remained significant after the Bonferroni correction (P>7.7×10^-4). CONCLUSION Neither significant association between SNPs within HH pathway and the risk of NSCL/P nor PoO effects was seen in this study.
Asians ; Cleft Lip/genetics* ; Cleft Palate/genetics* ; Genome-Wide Association Study ; Hedgehog Proteins/genetics* ; Humans ; Patched-2 Receptor ; Smoothened Receptor

Non-syndromic oral cleft (NSOC), a common birth defect, remains to be a critical public health problem in China. In the context of adjustment of childbearing policy for two times in China and the increase of pregnancy at older childbearing age, NSOC risk prediction will provide evidence for high-risk population identification and prenatal counseling. Genome-wide association study and second generation sequencing have identified multiple loci associated with NSOC, facilitating the development of genetic risk prediction of NSOC. Despite the marked progress, risk prediction models of NSOC still faces multiple challenges. This paper summarizes the recent progress in research of NSOC risk prediction models based on the results of extensive literature retrieval to provide some insights for the model development regarding research design, variable selection, model-build strategy and evaluation methods.
Humans ; Cleft Palate/genetics* ; Cleft Lip/genetics* ; Genome-Wide Association Study ; Genetic Predisposition to Disease ; Risk Factors ; Polymorphism, Single Nucleotide

OBJECTIVETo determine if alteration in TP63 is responsible for a Chinese patient with ectrodactyly-ectodermal dysplasia clefting (EEC) syndrome, but without cleft palate/lip.

METHODSScreening of TP63 gene was performed in the patient with EEC syndrome and his family members using PCR-single strand conformational polymorphism (SSCP) analysis, then performed by direct sequencing of the coding region.

RESULTSA C > T substitution at nucleotide position 838 in exon 7 was detected in the patient, and the change predicted a heterozygous missense mutation, Arg280Cys. His parents showed the wild type.

CONCLUSIONSThe results indicate that the de novo mutation Arg280Cys of the TP63 gene observed in the patient maybe contribute to his EEC syndrome.

Asian Continental Ancestry Group ; Cleft Lip ; genetics ; Cleft Palate ; genetics ; Ectodermal Dysplasia ; genetics ; Exons ; Genotype ; Heterozygote ; Humans ; Mutation, Missense ; Transcription Factors ; genetics ; Tumor Suppressor Proteins ; genetics

OBJECTIVETo investigate the relationship between muscle segment homeobox gene-1 (MSX1) and the genetic susceptibility of nonsyndromic cleft lip and palate (NSCLP) in Hunan Hans.

METHODSOne microsatellite DNA marker CA repeat in MSX1 intron region was used as genetic marker. The genotypes of 387 members in 129 NSCLP nuclear family trios were analyzed by polymerase chain reaction (PCR) and denaturing polyacrylamide gel electrophoresis. Then transmission disequilibrium test (TDT) and Logistic regression analysis were used to conduct association analysis.

RESULTSTDT analysis confirmed that CA4 allele in CL/P and CPO groups preferentially transmitted to the affected offspring (P = 0.018, P = 0.041). Logistic regression analysis indicated that the recessive model of inheritance was supported, and CA4 itself or CA4 acting as a marker for a disease allele or haplotype was inherited in a recessive fashion (P = 0.009).

CONCLUSIONSMSX1 gene is associated with NSCLP, and MSX1 gene may be directly involved either in the etiology of NSCLP or in linkage disequilibrium with disease-predisposing sites.

Asian Continental Ancestry Group ; Cleft Lip ; genetics ; Cleft Palate ; genetics ; Genetic Markers ; genetics ; Genotype ; Humans ; Linkage Disequilibrium ; Logistic Models ; MSX1 Transcription Factor ; genetics ; Microsatellite Repeats ; genetics ; Pedigree

OBJECTIVETo study the association of the A2756G polymorphism of the methionine synthase (MS) gene with nonsyndromic cleft lip with or without cleft palate (NSCL/P) in Chinese.

METHODSNinety-seven NSCL/P case-parent triads were selected as the case group. One hundred and four healthy subjects and their biological parents were selected as control group. For all subjects the A2756G polymorphism of the MS gene was examined by PCR-RFLP method.

RESULTSThere was no statistical difference in genotype and allele frequencies for MS A2756G variants among family members between case group and control group. The GG genotype was not detected in the offsprings and mothers. The odds ratio and confidence interval of genotype AG in offspring, father and mother were 1.78(0.74-4.34), 0.80(0.36-1.79) and 1.26(0.54-2.93) respectively. The odds ratio and confidence interval of allele G in offspring, father and mother were 1.70(0.78-3.73), 0.88(0.49-1.75), and 1.23(0.59-2.60) respectively. The G allele did not increase the risk of NSCL/P. Transmission disequilibrium test (TDT) analysis yielded no evidence of linkage disequilibrium (chi-square=0.034,P>0.05). The results of haplotype-based haplotype relative risk (HHRR) analysis (chi-square=0.03,P>0.05) and family-based association tests (FBAT) (Z=0.186, P>0.05) failed to show association between the MS A2756G variant and the risk of NSCL/P.

CONCLUSIONThe A2756G polymorphism of the MS gene was not associated with NSCL/P in Chinese in the present study.

5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase ; genetics ; Asian Continental Ancestry Group ; genetics ; Child ; Cleft Lip ; genetics ; Cleft Palate ; genetics ; Female ; Genotype ; Humans ; Male ; Polymorphism, Genetic