非综合征型唇裂伴或不伴腭裂的遗传方式

目的 为探讨非综合征型唇裂伴或小伴腭裂的遗传方式,对其高发家系进行遗传学研究. 方法 采用分离分析法和多基因阈值理论分析法对37个非综合征型唇裂伴或不伴腭裂的高发家系进行分析. 结果先证者的亲属患病率分别是一级亲属为29.89%(26/87),二级亲属为2.70%(4/148);其亲属发病率高低与血缘关系近远相关,与先让者血缘关系越近的亲属患病率越高;非综合征型唇裂伴或不伴腭裂的遗传方式不同于常染色体单基因显性、隐性遗传及性连锁遗传,而符合多基因遗传,其一级、二级亲属加权平均遗传度为(148.40±8.20)%. 结论非综合征型唇裂伴或不伴腭裂的遗传方式为多基因遗传.     

非综合征性唇腭裂部分基因SNPs研究进展

非综合征性唇裂伴或不伴腭裂是人类最常见的先天性畸形之一,是一种遗传、环境因素及两者相互作用所致的多基因多因素遗传疾病.单核苷酸多态性是新一代遗传标记,可被用来寻找各种致病基因,目前认为单核苷酸多态性及其特定组合可能是造成以多基因多因素遗传病为代表的复杂性状疾病易感性的重要原因.     

河北省5个县1993～1996年唇腭裂的流行病学特征

目的 描述河北省5个县1993-1996年先天性唇腭裂的流行病学特征。 方法利用1992年建立的“中美预防神经管畸形合作项目”出生缺陷监测的常规报告资料,研究河北省5个县1993-1996年孕满20周的总出生人群中唇腭裂(包括单纯腭裂、唇裂伴或不伴腭裂)在不同地区、不同时间、不同性别的患病率。 结果 1993-1996年河北省5个县唇腭裂患病率为2.08‰(144/69 131),其中单纯腭裂患病率为0.30‰(21/69 131),唇裂伴或不伴腭裂(唇裂+/-腭裂)患病率为1.78‰(123/69 131);唇腭裂患病率元氏县最高(3.35‰),香河县最低(1.66‰),1993年最高(2.70‰),1995年最低(1.68‰),2月、4月、8月、10月、12月份相对较高,没有明显的季节波动;男性唇腭裂患病率为2.30‰,女性为1.82‰,男女性比为1.38;男性和女性唇裂+/-腭裂患病率分别为2.08‰和1.43‰,二者比较差异有显著性(x2=4.14,P<0.05)。 结论 1993-1996年河北省5个县的唇腭裂患病率持续较高,并在出生人群中存在性别差异。提示本地区可能存在持续的环境危险因素暴露以及唇腭裂遗传性在性别上的差异。     

胎儿唇腭裂畸形的超声诊断价值

目的探讨超声诊断胎儿唇腭裂畸形的价值。方法采用彩超诊断仪对14836名18周以上孕妇进行检查。结果共发现唇腭裂畸形胎儿22例,漏诊3例,检出率88%。结论胎儿唇弓回声中断是胎儿唇裂的主要征象,上唇结节回声消失,鼻小柱向健侧移位,患侧鼻翼内陷是唇腭裂的常见声像图表现,单纯腭裂及唇裂合并腭裂时声像图难以直接显示腭裂。     

探讨腭裂修复的术后体会分析

先天性腭裂是口腔颌面部发育畸形中最为常见的疾病之一，可伴可不伴先天性唇裂。腭裂不仅导致患者颌面部形态畸形和生理功能障碍，而且造成咬合关系紊乱和语言功能障碍等，给患者的日常生活及学习工作等带来不利影响，同时还会造成患者的心理障碍。综合序列治疗腭裂是目前国内外的主流治疗方式，腭裂整复手术是该序列治疗的第一步，为正常吞咽、吸吮、语言、听力等生理功能恢复创造条件。腭裂的治疗方法主要是采用外科手术修复治疗，我科自1999--2011年修复治疗了386例腭裂患者。我们根据患者的不同年龄、腭裂的不同类型、裂隙的宽窄、组织丰满程度等情况，在手术过程中进行了针对性的处理。手术修复治疗取得了成功。术后通过精心的局部及全身护理，降低了腭裂术后并发症的发生，积累了丰富的临床经验。修复腭裂的主要目的是恢复患者的正常语音功能．同时必须考虑到手术可能对上颌骨生长发育带来的不利影响。除术前后配以多科的综合序列治疗来预防和减轻腭裂本身和手术的不利影响之外，通过开展不同的外科修复模式或程序，也是有效减轻和避免消极因素，达到治疗目的的有效手段，并且已在世界范围内得到广泛的应用与总结，其中不乏成功之典范。现结合本单位之经验。作一归纳与总结。以期引起广大临床医生的研究兴趣，积极探索提高腭裂整体治疗水平的方法。     

2型糖尿病的全基因组关联研究进展

2型糖尿病是环境和遗传因素共同作用的结果,遗传因素的研究在2006年以前主要是基于连锁分析和候选基因策略,近年来全基因组关联研究的出现使2型糖尿病遗传易感性的研究进入了一个崭新的阶段,发现了很多新的易感基因或区域,为其病因学研究及防治提供新的思路.     

血管紧张素Ⅰ转换酶基因多态性与2型糖尿病患者伴高血压易感性的研究

血管紧张素Ⅰ转换酶(ACE)是肾素-血管紧张素(RAS)系统的关键酶,其在高血压发病中的作用已得到了肯定.近年来发现在人ACE基因的第16内含子287bp长度片段的缺失或插入基因多态性与高血压关系密切,是高血压的候选基因之一[1].由于2型糖尿病、心血管疾病和高血压病常集结出现,且2型糖尿病患者伴高血压的发生率远远高于一般人群,提示2型糖尿病与高血压有共同的遗传背景[2].因此,我们在2型糖尿病患者中进行ACE基因多态性研究,试图寻找2型糖尿病患者伴高血压易感性与该基因多态性之间的某种相互关系.     

480例先天性唇腭裂患者临床资料分析

目的了解先天性唇腭裂的发病情况并分析其发病因素。方法对480例唇腭裂患者的临床资料进行详细的调查和分析。结果单纯唇裂128例，单纯腭裂118例，合并唇腭裂234例。有遗传史者56例，其它可疑暴露因素330例。男性：女性为1．93：1。结论唇腭例的病因是复杂的，而遗传因素和来自农村文化程度低的有烟酒嗜好的父母及孕妇早期服药、感染、接触毒物。外伤及精神刺激等特定环境因素作用是其致病的危险因素。     

多囊卵巢综合征的基因研究进展

多囊卵巢综合征（ＰＣＯＳ）是育龄妇女最常见的内分泌疾病，病例的家族聚集性提示遗传因素的病因学上起重要的作用，家系研究提示ＰＣＯＳ既有常染色体显性遗传特征，也有Ｘ性连锁遗传特征，通过对ＰＣＯＳ候选基因研究，其结果支持少数基因紊乱的观点，阐述了胰同素基因微卫星在ＰＣＯＳ不排卵病因学方面的重要作用以及胆固醇侧链分裂基因（ＣＹＰ１１ａ）在ＰＣＯＳ妇女过高雄激素分泌方面的机理，提出：ＰＣＯＳ的临床遗传异质性     

血管紧张素I转换酶基因多态性与2型糖尿病患者伴高血压易感性的研究

血管紧张素 转换酶 (ACE)是肾素 -血管紧张素 (RAS)系统的关键酶 ,其在高血压发病中的作用已得到了肯定。近年来发现在人 ACE基因的第 16内含子 2 87bp长度片段的缺失或插入基因多态性与高血压关系密切 ,是高血压的候选基因之一〔1〕。由于 2型糖尿病、心血管疾病和高血压病常集结出现 ,且 2型糖尿病患者伴高血压的发生率远远高于一般人群 ,提示2型糖尿病与高血压有共同的遗传背景〔2〕。因此 ,我们在 2型糖尿病患者中进行 ACE基因多态性研究 ,试图寻找 2型糖尿病患者伴高血压易感性与该基因多态性之间的某种相互关系。1　材料和方法1…     

胎儿唇腭裂产前诊断及预后研究现状

唇腭裂是最常见的颜面部畸形,对于该病的病因迄今尚未阐明,目前多认为该病是由于遗传、环境因素共同作用所致。中孕期通过超声、MRI等辅助检查方法可诊断胎儿唇腭裂。部分胎儿唇腭裂合并其他畸形,部分存在基因、染色体异常,影响患儿出生后生存质量及预后等,因此产前对胎儿唇腭裂的明确诊断至关重要。胎儿唇腭裂宫内手术治疗目前尚处于研究阶段,非综合征性唇腭裂(NSCL/P)患儿于婴幼儿期进行手术治疗后,多数可以康复。笔者拟就胎儿唇腭裂产前诊断及预后研究现状进行阐述,以提高临床对该病的诊治水平。     

Testing candidate genes for non-syndromic oral clefts using a case-parent trio design.

Markers in five candidate genes were examined on 269 case-parent trios ascertained through a child with an isolated, non-syndromic oral cleft (cleft lip, CL; cleft palate, CP; or cleft lip and palate, CLP). Cases and their parents were ascertained through treatment centers in Maryland. Markers at two of the five candidate genes, transforming growth factor beta3 (TGFbeta3) and MSX1, showed consistent evidence of linkage and disequilibrium due to linkage using several statistical tests (e.g., the global chi-square for TGFbeta3 was 21.1 with 12 df, P = 0.03; that for MSX1 was 8.7 with 3 df, P = 0.03). There was little evidence of heterogeneity in the role of TGFbeta3 between different types of oral clefts, but MSX1 did yield marginal evidence for such heterogeneity. MSX1 also showed evidence for interaction between infant's genotype and maternal smoking, giving a likelihood ratio test for heterogeneity between smoker and non-smoker mothers of 7.16 (2 df, P = 0.03). Using a conditional logistic model to test for gene-gene interaction showed no evidence of interaction between TGFbeta3 and MSX1, with both seeming to contribute independently to risk of isolated, non-syndromic oral clefts.     

Evidence for gene-environment interaction in a genome wide study of nonsyndromic cleft palate

Nonsyndromic cleft palate (CP) is a common birth defect with a complex and heterogeneous etiology involving both genetic and environmental risk factors. We conducted a genome-wide association study (GWAS) using 550 case-parent trios, ascertained through a CP case collected in an international consortium. Family-based association tests of single nucleotide polymorphisms (SNP) and three common maternal exposures (maternal smoking, alcohol consumption, and multivitamin supplementation) were used in a combined 2 df test for gene (G) and gene-environment (G × E) interaction simultaneously, plus a separate 1 df test for G × E interaction alone. Conditional logistic regression models were used to estimate effects on risk to exposed and unexposed children. While no SNP achieved genome-wide significance when considered alone, markers in several genes attained or approached genome-wide significance when G × E interaction was included. Among these, MLLT3 and SMC2 on chromosome 9 showed multiple SNPs resulting in an increased risk if the mother consumed alcohol during the peri-conceptual period (3 months prior to conception through the first trimester). TBK1 on chr. 12 and ZNF236 on chr. 18 showed multiple SNPs associated with higher risk of CP in the presence of maternal smoking. Additional evidence of reduced risk due to G × E interaction in the presence of multivitamin supplementation was observed for SNPs in BAALC on chr. 8. These results emphasize the need to consider G × E interaction when searching for genes influencing risk to complex and heterogeneous disorders, such as nonsyndromic CP.     

Using Whole Exome Sequencing to Identify Candidate Genes With Rare Variants In Nonsyndromic Cleft Lip and Palate

Studies suggest that nonsyndromic cleft lip and palate (NSCLP) is polygenic with variable penetrance, presenting a challenge in identifying all causal genetic variants. Despite relatively high prevalence of NSCLP among Amerindian populations, no large whole exome sequencing (WES) studies have been completed in this population. Our goal was to identify candidate genes with rare genetic variants for NSCLP in a Honduran population using WES. WES was performed on two to four members of 27 multiplex Honduran families. Genetic variants with a minor allele frequency > 1% in reference databases were removed. Heterozygous variants consistent with dominant disease with incomplete penetrance were ascertained, and variants with predicted functional consequence were prioritized for analysis. Pedigree‐specific P‐values were calculated as the probability of all affected members in the pedigree being carriers, given that at least one is a carrier. Preliminary results identified 3,727 heterozygous rare variants; 1,282 were predicted to be functionally consequential. Twenty‐three genes had variants of interest in ≥3 families, where some genes had different variants in each family, giving a total of 50 variants. Variant validation via Sanger sequencing of the families and unrelated unaffected controls excluded variants that were sequencing errors or common variants not in databases, leaving four genes with candidate variants in ≥3 families. Of these, candidate variants in two genes consistently segregate with NSCLP as a dominant variant with incomplete penetrance: ACSS2 and PHYH. Rare variants found at the same gene in all affected individuals in several families are likely to be directly related to NSCLP.     

Tobacco smoking and oral clefts: a meta-analysis

OBJECTIVE: To examine the association between maternal smoking and non-syndromic orofacial clefts in infants. METHODS: A meta-analysis of the association between maternal smoking during pregnancy was carried out using data from 24 case-control and cohort studies. FINDINGS: Consistent, moderate and statistically significant associations were found between maternal smoking and cleft lip, with or without cleft palate (relative risk 1.34, 95% confidence interval 1.25-1.44) and between maternal smoking and cleft palate (relative risk 1.22, 95% confidence interval 1.10-1.35). There was evidence of a modest dose-response effect for cleft lip with or without cleft palate. CONCLUSION: The evidence of an association between maternal tobacco smoking and orofacial clefts is strong enough to justify its use in anti-smoking campaigns.     

中国人群WNT代谢通路与非综合征型唇腭裂的亲源效应分析

目的 非综合征型唇裂合并或不合并腭裂（NSCL/P）是一类常见的出生缺陷,遗传致病因素一直是其病因学研究的热点。本研究拟基于家系设计在WNT代谢通路基因中探索亲源效应对NSCL/P发病风险的影响。方法 本研究人群为“唇腭裂的基因组学国际合作组研究”项目在中国地区募集的806个NSCL/P核心家系。利用对数线性模型探索WNT基因及其单体型的亲源效应与疾病的关联,采用Wald检验探索亲源效应与环境因素的交互作用。经过Bonferroni多重检验校正后,统计学检验的显著性阈值设为P<3.47×10^-4。结果 质量控制后共纳入7个基因上144个单核苷酸多态性位点进行分析。结果显示,NSCL/P家系中有8个位点具有潜在的亲源效应（P<0.05）,但经Bonferroni多重检验校正后,均未达到统计学显著性水平（P>3.47×10^-4）。NSCL/P家系中位于WNT9A rs4074668-rs12725747单体型（T-A）具有亲源效应,且经Bonferroni校正后差异仍有统计学意义（P=2.74×10^-4）。但该单体型的亲源效应与环境因素（被动吸烟、复合维生素补充）的交互作用并未达到统计学显著水平。结论 WNT代谢通路基因可能通过亲源效应影响NSCL/P的发生风险。位于WNT9A基因rs4074668-rs12725747单体型（T-A）亲源效应与NSCL/P发病风险存在显著关联。未来仍需其他独立样本验证以进一步确认WNT代谢通路在NSCL/P发生中的作用。     

Oral facial clefts and gene polymorphisms in metabolism of folate/one‐carbon and vitamin A: a pathway‐wide association study

An increased risk of facial clefts has been observed among mothers with lower intake of folic acid or vitamin A around conception. We hypothesized that the risk of clefts may be further moderated by genes involved in metabolizing folate or vitamin A. We included 425 case‐parent triads in which the child had either cleft lip with or without cleft palate (CL/P) or cleft palate only (CPO), and no other major defects. We analyzed 108 SNPs and one insertion in 29 genes involved in folate/one‐carbon metabolism and 68 SNPs from 16 genes involved in vitamin A metabolism. Using the Triad Multi‐Marker (TRIMM) approach we performed SNP, gene, chromosomal region, and pathway‐wide association tests of child or maternal genetic effects for both CL/P and CPO. We stratified these analyses on maternal intake of folic acid or vitamin A during the periconceptional period. As expected with this high number of statistical tests, there were many associations with P‐values<0.05; although there were fewer than predicted by chance alone. The strongest association in our data (between fetal FOLH1 and CPO, P=0.0008) is not in agreement with epidemiologic evidence that folic acid reduces the risk of CL/P in these data, not CPO. Despite strong evidence for genetic causes of oral facial clefts and the protective effects of maternal vitamins, we found no convincing indication that polymorphisms in these vitamin metabolism genes play an etiologic role. Genet. Epidemiol. 2009. © 2008 Wiley Liss, Inc.     

A systematic genetic analysis and visualization of phenotypic heterogeneity among orofacial cleft GWAS signals

Phenotypic heterogeneity is a hallmark of complex traits, and genetic studies of such traits may focus on them as a single diagnostic entity or by analyzing specific components. For example, in orofacial clefting (OFC), three subtypes—cleft lip (CL), cleft lip and palate (CLP), and cleft palate (CP) have been studied separately and in combination. To further dissect the genetic architecture of OFCs and how a given associated locus may be contributing to distinct subtypes of a trait we developed a framework for quantifying and interpreting evidence of subtype-specific or shared genetic effects in complex traits. We applied this technique to create a “cleft map” of the association of 30 genetic loci with three OFC subtypes. In addition to new associations, we found loci with subtype-specific effects (e.g., GRHL3 [CP], WNT5A [CLP]), as well as loci associated with two or all three subtypes. We cross-referenced these results with mouse craniofacial gene expression datasets, which identified additional promising candidate genes. However, we found no strong correlation between OFC subtypes and expression patterns. In aggregate, the cleft map revealed that neither subtype-specific nor shared genetic effects operate in isolation in OFC architecture. Our approach can be easily applied to any complex trait with distinct phenotypic subgroups.     

1988—1992年中国非综合征性唇腭裂发生率的动态变化

目的：了解我国1988－1992年非综合征性唇腭裂发生率的动态变化趋势及流行病学特征。方法：在1988－1992年期间,采用以医院为单位的整群抽样方法,对全国500多所医院孕28周至产后7天的4349例非综合征性唇腭裂病例进行回顾性分析。结果：我国5年非综合征性唇腭裂发生率无显著性差异,城乡发生率也无显著性差异。男性发生率为14．9／万,女性发生率为11．7/万,差异有显著性,非综合征性唇腭裂的性别比为1．3：1。三类非综合征性唇腭裂各自的发生率为：唇裂合并腭裂：7．8／万,单纯性唇裂：3．8／万,单纯性腭裂：1．8/万。结论：我国非综合征性唇腭裂发生率无变化趋势,城乡无差异。男性高于女性,唇裂合并腭裂为最常见类型。