Dear Editor： Increased homocysteine levels due to vitamin B6 or B12 deficiency or genetic defects in folate pathway genes are associated with an increased incidence of non-syndromic cleft lip with or without cleft p...Dear Editor： Increased homocysteine levels due to vitamin B6 or B12 deficiency or genetic defects in folate pathway genes are associated with an increased incidence of non-syndromic cleft lip with or without cleft palate （NSCLP）tlj. Thymidylate synthase （TS） is a folate-dependent enzyme that catalyzes methylation of 2＇-deoxyuridine-5＇-monophosphate （dUMP） to 2＇-deox- ythymidine-5＇-monophosphate （dTMP）, a rate-limiting step in DNA synthesis,展开更多
Introduction: Non-Syndromic Clefts Lip-Palates (NSCLP/CP) are most common congenital malformation in the world, with very important psychic and social impact. Formation of NSCLP/CP arises from the interaction of envir...Introduction: Non-Syndromic Clefts Lip-Palates (NSCLP/CP) are most common congenital malformation in the world, with very important psychic and social impact. Formation of NSCLP/CP arises from the interaction of environmental and genetic factors. This paper provides a review of recent progress in defining the genetic causes of NSCLP. Methods: A literature review was conducted on the Medline data by searching for the following keywords: genes, non-syndromic cleft lip-palate, and genetics of clefts lip-palates, until January 2018. Results: Various genes are identified in different population and country, with the study using case parent’s trio. The aim of this study contributes to review relative gene which has been identify in non-syndromic cleft lip and palate, and to help to have a better understanding of the inheritance pattern of this pathology and the prevention of genetic disease. Conclusion: Although three major genes have been confirmed, the genetic research is necessary to provide an understanding of the pathophysiology of the clefts lip-palates.展开更多
All of 1055 cleft-lip and/or cleft-palate cases with their 1055 families were investigated. As the results." the incidence of siblings of propositi is 2.2% (39/1791). The incidences of the first, second and third...All of 1055 cleft-lip and/or cleft-palate cases with their 1055 families were investigated. As the results." the incidence of siblings of propositi is 2.2% (39/1791). The incidences of the first, second and third degree relatives were 1.53% (60/3927), 0.22% (25/11359), 0.30% (31/10296) respectively. In 17 cases, either of propositi’s parents had cleft, the incidence of cleft among propositi’s siblings was 9.52% (2/21). In 34 cases, the incidence of rest propositi’s siblings beyond those whose one sib had cleft or more is 5% (4/80), whereas both their parents were normal. Based on above, all incidences of different order relatives were higher than population ones. Furthermore, it is demonstrable that the closer the consanguinity is, the higher the incidence is, and if there was cleft in one family, the incidence increased obviously among his siblings or children, revealing apparent family tendency. In this group, the heritability is 46.80%.展开更多
目的:探索非综合征型唇裂伴或不伴腭裂(non-syndromic cleft lip with or without cleft palate, NSCL/P)全基因组常见遗传变异对NSCL/P风险的影响。方法:利用全基因组关联研究(genome-wide association study, GWAS)数据,以全基因组单...目的:探索非综合征型唇裂伴或不伴腭裂(non-syndromic cleft lip with or without cleft palate, NSCL/P)全基因组常见遗传变异对NSCL/P风险的影响。方法:利用全基因组关联研究(genome-wide association study, GWAS)数据,以全基因组单核苷酸多态性(single nucleotide polymorphism, SNP)遗传度和基因组不同分区SNP遗传度评估基因组上常见变异的效应。对GWAS汇总数据进行质量控制,标准包括数据中无缺失值、弱势等位基因频率≥1%、P值在0~1、SNP正负链明确等。利用连锁不平衡得分回归计算NSCL/P的SNP遗传度,采用分层的连锁不平衡得分回归计算基因组编码区、启动子区、内含子区、增强子区和超级增强子区的分区SNP遗传度,并评估不同分区内的富集度,分析工具为LDSC (v1.0.1)软件。结果:纳入中国人群806个NSCL/P核心家系(2 418人)的GWAS数据,490 593个SNP通过质量控制,被纳入到SNP遗传度的计算中。观测样本中NSCL/P的SNP遗传度为0.55(95%CI:0.28~0.82),由于观测样本患病率较高,按中国人群患病率转换为一般人群后SNP遗传度为0.37(95%CI:0.19~0.55)。SNP遗传度在增强子区的富集度为15.70(P=0.04),在超级增强子区的富集度为3.18(P=0.03)。结论:基因组常见变异有助于解释一部分中国人群NSCL/P目前未被解释的遗传度,同时中国人群NSCL/P的SNP遗传度在增强子分区和超级增强子分区中显著富集,提示该区域中可能存在未被发现的遗传致病因素。展开更多
The Patched 1(PTCH1)gene encodes a membrane receptor involved in the Hedge-hog(Hh)signaling pathway,an abnormal state of which may result in congenital defects or hu-man tumors.In this study,we conducted whole-exome s...The Patched 1(PTCH1)gene encodes a membrane receptor involved in the Hedge-hog(Hh)signaling pathway,an abnormal state of which may result in congenital defects or hu-man tumors.In this study,we conducted whole-exome sequencing on a three-generation Chinese family characterized with variable penetrance of orofacial clefts.A rare heterozygous variant in the PTCH1 gene(c.2833C>T p.R945X)was identified as a disease-associated mutation.Structural modeling revealed a truncation starting from the middle of the second extracellular domain of PTCH1 protein.This may damage its ligand recognition and sterol transportation abilities,thereby affecting the Hh signaling pathway.Biochemical assays indi-cated that the R945X protein had reduced stability compared to the wild-type in vitro.In addi-tion,we reviewed the locations and mutation types of PTCH1 variants in individuals with clefting phenotypes,and analyzed the associations between clefts and locations or types of variants within PTCH1.Our findings provide further evidence that PTCH1 variants result in or-ofacial clefts,and contributed to genetic counseling and clinical surveillance in this family.展开更多
目的:探讨MTHFR基因C677T多态性与非综合征型唇腭裂(nonsyndromic cleft lip with or without cleft pa-late,NSCL/P)相关性。方法:收集97个核心家庭和104个对照家庭,用聚合酶链式反应-限制性片段长度多态性方法,进行MTHFR基因C677T位...目的:探讨MTHFR基因C677T多态性与非综合征型唇腭裂(nonsyndromic cleft lip with or without cleft pa-late,NSCL/P)相关性。方法:收集97个核心家庭和104个对照家庭,用聚合酶链式反应-限制性片段长度多态性方法,进行MTHFR基因C677T位点多态性检测;用人群关联研究、传递不平衡检验(transmission-disequlibrium test,TDT)、单倍型相对风险率(haplotype-based haplotype relative risk,HHRR)、家系为基础的关联检验(family-basedas-sociation test,FBAT)等进行统计分析。结果:人群关联研究分析表明,子代、父亲、母亲的病例组和对照组之间基因型和等位基因的分布差异无统计学意义(P>0.05);子代、父亲、母亲组,CT基因型携带者相对于CC基因型携带者的OR分别为1.02(95%CI0.47～2.21)、0.62(95%CI0.29～1.32)、0.66(95%CI0.31～1.40);TT基因型携带者相对于CC基因型携带者的OR分别为1.10(95%CI0.44～2.74)、0.95(95%CI0.39～2.32)、0.68(95%CI0.28～1.66);T相对于C基因的OR分别为1.07(95%CI0.72～1.58)、0.98(95%CI0.66～1.46)、0.83(95%CI0.56～1.24)。携带有突变基因T并不能增加患NSCL/P的危险。病例组核心家庭分析表明,TDT检验χ2=1.817,P>0.05;HHRR检验χ2=1.76,P>0.05;FBAT检验Z=1.348,P>0.05。结论:没有发现MTHFRC677T多态性和NSCLP无关联性,该基因位点的变异可能不会导致中国东北地区人群NSCLP的发生。展开更多
基金funding from the Indian Council of Medical Research(ICMR),Government of India(Project Ref.No.56/15/2007-BMS)
文摘Dear Editor： Increased homocysteine levels due to vitamin B6 or B12 deficiency or genetic defects in folate pathway genes are associated with an increased incidence of non-syndromic cleft lip with or without cleft palate （NSCLP）tlj. Thymidylate synthase （TS） is a folate-dependent enzyme that catalyzes methylation of 2＇-deoxyuridine-5＇-monophosphate （dUMP） to 2＇-deox- ythymidine-5＇-monophosphate （dTMP）, a rate-limiting step in DNA synthesis,
文摘Introduction: Non-Syndromic Clefts Lip-Palates (NSCLP/CP) are most common congenital malformation in the world, with very important psychic and social impact. Formation of NSCLP/CP arises from the interaction of environmental and genetic factors. This paper provides a review of recent progress in defining the genetic causes of NSCLP. Methods: A literature review was conducted on the Medline data by searching for the following keywords: genes, non-syndromic cleft lip-palate, and genetics of clefts lip-palates, until January 2018. Results: Various genes are identified in different population and country, with the study using case parent’s trio. The aim of this study contributes to review relative gene which has been identify in non-syndromic cleft lip and palate, and to help to have a better understanding of the inheritance pattern of this pathology and the prevention of genetic disease. Conclusion: Although three major genes have been confirmed, the genetic research is necessary to provide an understanding of the pathophysiology of the clefts lip-palates.
文摘All of 1055 cleft-lip and/or cleft-palate cases with their 1055 families were investigated. As the results." the incidence of siblings of propositi is 2.2% (39/1791). The incidences of the first, second and third degree relatives were 1.53% (60/3927), 0.22% (25/11359), 0.30% (31/10296) respectively. In 17 cases, either of propositi’s parents had cleft, the incidence of cleft among propositi’s siblings was 9.52% (2/21). In 34 cases, the incidence of rest propositi’s siblings beyond those whose one sib had cleft or more is 5% (4/80), whereas both their parents were normal. Based on above, all incidences of different order relatives were higher than population ones. Furthermore, it is demonstrable that the closer the consanguinity is, the higher the incidence is, and if there was cleft in one family, the incidence increased obviously among his siblings or children, revealing apparent family tendency. In this group, the heritability is 46.80%.
文摘目的:探索非综合征型唇裂伴或不伴腭裂(non-syndromic cleft lip with or without cleft palate, NSCL/P)全基因组常见遗传变异对NSCL/P风险的影响。方法:利用全基因组关联研究(genome-wide association study, GWAS)数据,以全基因组单核苷酸多态性(single nucleotide polymorphism, SNP)遗传度和基因组不同分区SNP遗传度评估基因组上常见变异的效应。对GWAS汇总数据进行质量控制,标准包括数据中无缺失值、弱势等位基因频率≥1%、P值在0~1、SNP正负链明确等。利用连锁不平衡得分回归计算NSCL/P的SNP遗传度,采用分层的连锁不平衡得分回归计算基因组编码区、启动子区、内含子区、增强子区和超级增强子区的分区SNP遗传度,并评估不同分区内的富集度,分析工具为LDSC (v1.0.1)软件。结果:纳入中国人群806个NSCL/P核心家系(2 418人)的GWAS数据,490 593个SNP通过质量控制,被纳入到SNP遗传度的计算中。观测样本中NSCL/P的SNP遗传度为0.55(95%CI:0.28~0.82),由于观测样本患病率较高,按中国人群患病率转换为一般人群后SNP遗传度为0.37(95%CI:0.19~0.55)。SNP遗传度在增强子区的富集度为15.70(P=0.04),在超级增强子区的富集度为3.18(P=0.03)。结论:基因组常见变异有助于解释一部分中国人群NSCL/P目前未被解释的遗传度,同时中国人群NSCL/P的SNP遗传度在增强子分区和超级增强子分区中显著富集,提示该区域中可能存在未被发现的遗传致病因素。
基金This study was supported by the National Natural Science Foundation of China(grant numbers:81870747,81860194,and 31771619)Beijing Municipal Natural Science Foundation(grant number:7182184).
文摘The Patched 1(PTCH1)gene encodes a membrane receptor involved in the Hedge-hog(Hh)signaling pathway,an abnormal state of which may result in congenital defects or hu-man tumors.In this study,we conducted whole-exome sequencing on a three-generation Chinese family characterized with variable penetrance of orofacial clefts.A rare heterozygous variant in the PTCH1 gene(c.2833C>T p.R945X)was identified as a disease-associated mutation.Structural modeling revealed a truncation starting from the middle of the second extracellular domain of PTCH1 protein.This may damage its ligand recognition and sterol transportation abilities,thereby affecting the Hh signaling pathway.Biochemical assays indi-cated that the R945X protein had reduced stability compared to the wild-type in vitro.In addi-tion,we reviewed the locations and mutation types of PTCH1 variants in individuals with clefting phenotypes,and analyzed the associations between clefts and locations or types of variants within PTCH1.Our findings provide further evidence that PTCH1 variants result in or-ofacial clefts,and contributed to genetic counseling and clinical surveillance in this family.
文摘目的:探讨MTHFR基因C677T多态性与非综合征型唇腭裂(nonsyndromic cleft lip with or without cleft pa-late,NSCL/P)相关性。方法:收集97个核心家庭和104个对照家庭,用聚合酶链式反应-限制性片段长度多态性方法,进行MTHFR基因C677T位点多态性检测;用人群关联研究、传递不平衡检验(transmission-disequlibrium test,TDT)、单倍型相对风险率(haplotype-based haplotype relative risk,HHRR)、家系为基础的关联检验(family-basedas-sociation test,FBAT)等进行统计分析。结果:人群关联研究分析表明,子代、父亲、母亲的病例组和对照组之间基因型和等位基因的分布差异无统计学意义(P>0.05);子代、父亲、母亲组,CT基因型携带者相对于CC基因型携带者的OR分别为1.02(95%CI0.47～2.21)、0.62(95%CI0.29～1.32)、0.66(95%CI0.31～1.40);TT基因型携带者相对于CC基因型携带者的OR分别为1.10(95%CI0.44～2.74)、0.95(95%CI0.39～2.32)、0.68(95%CI0.28～1.66);T相对于C基因的OR分别为1.07(95%CI0.72～1.58)、0.98(95%CI0.66～1.46)、0.83(95%CI0.56～1.24)。携带有突变基因T并不能增加患NSCL/P的危险。病例组核心家庭分析表明,TDT检验χ2=1.817,P>0.05;HHRR检验χ2=1.76,P>0.05;FBAT检验Z=1.348,P>0.05。结论:没有发现MTHFRC677T多态性和NSCLP无关联性,该基因位点的变异可能不会导致中国东北地区人群NSCLP的发生。
文摘目的:探索中国人群中转化生长因子β(transforming growth factor-β,TGFB)信号通路基因多态性与非综合征型唇腭裂(non-syndromic oral clefts,NSOC)的关联关系及可能存在的基因环境交互作用。方法:在806个中国汉族人群非综合征型唇裂合并或不合并腭裂(non-syndromic cleft lip with or without cleft palate,NSCL/P)核心家系中,对TGFB信号通路上的10个基因进行了传递不平衡检验以及基因环境交互作用分析。环境因素包括母亲孕早期吸烟、被动吸烟、饮酒及补充多维生素制剂。结果:经过质量控制的筛选,共对343个位点的单核苷酸多态性(single nucleotide polymorphisms,SNPs)进行了传递不平衡检验及交互作用分析,结果显示,共有6个基因中的19个SNPs与NSCL/P之间存在关联(P<0.05),但经过Bonferroni校正后,这些关联均不具有统计学意义。经多重检验校正后,未发现常见孕期环境暴露因素与TGFB信号通路上的基因多态性存在有统计学意义的基因环境交互作用。结论:未发现TGFB信号通路上的基因多态性与NSCL/P之间存在关联。
