课程文献中心 更多>>

关键词： 全面发育迟缓   智力障碍   分析遗传学病因  

摘要： 目的研究全面发育迟缓/智力障碍(global developmental delay/intellectual disability,GDD/ID)的分子遗传学病因特点,探讨基因检测在诊断GDD/ID患儿中的应用价值。方法收集2017年9月至2019年12月就诊于武汉儿童医院神经内科及康复医学科230例GDD/ID患儿临床资料,同时采集患儿及父母的外周血标本进行基因检测及致病性分析。结果在230例GDD/ID患儿中,全面发育迟缓(GDD)患者203例,智力障碍(ID)患者27例,男性患儿略多于女性(1.57:1)。在合并症方面,GDD/ID合并癫痫患儿114例,GDD/ID合并孤独症谱系障碍者6例,GDD/ID合并肌张力障碍者4例。在61例拷贝数变异(CNV)阳性患儿中,其中GDD患儿52例,检测出67例CNV变异,包括微缺失微重复综合征12例,非染色体微缺失微重复综合征4例,良性CNV改变4例,可能良性CNV改变1例,致病性CNV改变17例,临床意义未明9例,可能致病性改变20例;ID患儿9例,检测出11例CNVs变异,包括微缺失微重复综合征6例,非染色体微缺失微重复综合征1例,可能致病性改变1例,致病性CNV改变1例,临床意义未明1例,良性CNV改变1例。在169例基因突变阳性患儿中,GDD患儿151例,共检测出103个相关基因突变,其中SCN1A基因突变为GDD患儿最常见变异;ID患儿18例,共检测出21个相关基因突变,基因分布较分散。在所有基因突变阳性患儿中,共检测出115个智力障碍相关基因,其中癫痫性脑病相关基因38个,常染色体显性遗传智力障碍基因37个,常染色体隐性遗传智力障碍基因21个,X连锁智力障碍基因19个。在染色体微缺失微重复综合征患儿中,Angelman/Prader-Willi患儿最多;在癫痫性脑病患儿中,SCN1A新发突变患儿最多;在女性全面发育迟缓患儿中,MECP2基因突变患儿最多。结论GDD/ID病因复杂,遗传学因素占比较多,且患儿常共患癫痫、孤独症谱系障碍、注意缺陷多动障碍等疾病,临床上要注意对这类患儿及时诊断及鉴别诊断。完善分子遗传学相关检查,能够明确部分GDD/ID患儿的病因,有助于对此类患儿进行早期识别、综合治疗及预后评估。

关键词： 反复妊娠丢失   CCNB3基因   卵母细胞减数分裂   基因突变   反复妊娠丢失   KIF22基因   配子   减数分裂   非整倍体  

摘要： 目的胚胎染色体异常是导致人类反复妊娠丢失(Recurrent pregnancy loss,RPL)的常见病因之一,其中卵母细胞非整倍体形成是导致胚胎染色体异常出现的关键因素。因此,本研究旨在探讨是否存在致病基因突变通过影响卵母细胞减数分裂过程导致染色体分离错误从而引起反复妊娠丢失的发生。 方法本研究先通过对6个近亲婚配后代的URPL女性进行了全外显子组测序,对选出的候选基因在132个独立发病的URPL女性样本中进行了散发验证,并通过Sanger测序确认致病突变。对筛选出的所有突变位点进行等位基因频率,位点致病性,保守性的分析。利用分子实验探讨突变位点引起CCNB3功能变化与卵母细胞减数分裂发生错误的关系。 结果在所有纳入的138个URPL研究样本中发现了CCNB3基因在3个患者中的致病突变。分别是两个罕见纯合错义突变(A1261T和T1280I)和一个复合杂合突变(P119Q,L710W),通过对所有突变位点的家系信息和生物信息学分析,选择A1261T位点进行后续研究。发现该位点突变会降低CCNB3基因m RNA水平的表达,并推测该突变在减数分裂过程中和CDK1和CDK2的结合能力降低。 结论CCNB3基因致病突变位点A1261T可能会通过影响增加卵母细胞减数分裂过程染色体分离错误从而引起反复妊娠丢失的发生。 目的反复妊娠丢失(Recurrent pregnancy loss,RPL)是严重损害育龄夫妻生殖健康的复杂疾病,其中胚胎染色体异常(非整倍体多见)被认为是最重要的病因之一。本研究旨在探讨KIF22基因突变和减数分裂中卵母细胞非整倍体形成在增加RPL风险中的作用。 方法选取一对近亲婚配家系RPL患病兄妹作为研究对象。对两名患者进行全外显子组测序,通过Sanger测序确认致病突变。进一步采用实时荧光定量PCR、Western blot、小鼠卵母细胞显微注射、免疫荧光、单细胞扩增和拷贝数变异分析,更好地探讨KIF22功能障碍对非整倍体的影响。 结果鉴定出KIF22基因中一个纯合错义突变c.848G>A(p.R283H)。多种生物信息学软件预测该突变具有致病性,Western blot证明R283H突变降低KIF22的表达水平。进一步的功能实验结果表明,Kif22蛋白的缺失不影响卵母细胞的发育过程、一般形态和染色体中期排列,但增加了卵母细胞第一次减数分裂的非整倍体率。 结论推测KIF22致病突变在人类中可能通过增加减数分裂期间配子的非整倍体率,从而导致人类反复妊娠丢失疾病的发生。

摘要： Breast cancers are the most common malignancies and leading causes of cancer mortality among women worldwide. Global breast cancer statistics reveal vast international and interethnic differences, which are attributed to non-genetic risk factors such as dietary pattern. Several lines of evidence indicate a role of the aryl hydrocarbon receptor (AhR) in breast cancer initiation and promotion of aggressive tumor phenotypes. The studies documented in this dissertation investigate the effects of the soy isoflavone genistein on oncogenic activity of the AhR in multiple in vitro and in vivo model systems. Cell culture studies investigating the effect of genistein on AhR-dependent epigenetic regulation of BRCA1 were performed in HCC38 triple negative breast cancer (TNBC) and MCF7 luminal A breast cancer cells. The effects of lifetime exposure to dietary genistein on carcinogen induced mammary tumors were investigated in a mouse model of BRCA1 mutation carriers (Brca1+/-) and wildtype littermates. The Brca1+/- model was derived using Brca1+/F22-24 mice and CRE-LOX recombination driven by transgenic expression of Cre under control of a mouse mammary tumor virus (MMTV) promoter construct. Cell culture studies demonstrated genistein reversed BRCA1 epigenetic silencing in HCC38 cells, which was attributed to antagonism toward overexpressed and hyperactive AhR. Mouse studies suggested the effect of lifetime exposure to dietary genistein on carcinogen-induced mammary tumorigenesis is dependent on genotype (Brca1+/+ vs. Brca1+/-). In Brca1+/+ mice, the genistein diet suppressed tumor growth, whereas tumor growth was enhanced in Brca1+/- mice administered genistein. These collective studies indicate the potential utility for genistein to influence epigenetic regulation of BRCA1 and antagonize AhR in mammary tumorigenesis.

关键词： Waardenburg综合征   SOX10基因   遗传性耳聋   基因突变   内耳畸形  

摘要： [目的]Waardenburg(WS)综合征是一种先天性常染色体显性遗传疾病,临床上通常以单侧或双侧感音神经性听力损失,皮肤、毛发及虹膜色素缺失或分布异常为主要表现,并可依据其表型将其分为4型。由于WS是目前最常见的综合征型听力疾病,具有高度的遗传异质性,经证已发现PAX3、MITF、SNAI2、EDN3、EDNRB、SOX10六个基因的突变与WS的发病有关。本研究通过对一个WS耳聋家系进行研究,初步探索该耳聋家系的相关突变基因,分析该家系听力学及遗传学特征,为该耳聋家系提供一定的遗传及婚育指导。[方法]本研究的一名先证者(男孩,16岁),来自于云南省建水县,通过对其表型进行研究,我们发现该先证者的表型符合WS2。我们以该患者为中心进行家系信息调查,追踪到了一个具有16名成员的WS家系,该家系中共有2名WS耳聋患者。随后,采集所有家系成员的基本信息,向2名符合WS表型的家系成员询问更加详细的发病史,如发病时间、耳毒性药物使用史、WS相关表型、耳聋进展史、家族史以及是否有人工耳蜗手术史等,并对这两名患者进行全身体格检查、听力学检查(纯音测听、声导抗、听性脑干反应)及影像检查(颞骨CT及内耳MRI),并使用WPS2019绘制家系图谱。在征得其家系成员同意后,收集该家系中3名成员(包括2名WS耳聋患者在内)即先证者及其父母的外周静脉血3-5ml。使用QIAamp DNA提取试剂盒提取3名成员外周血DNA后,送至广州金域医学检验所进行基因测序,将提纯后的DNA接上相关引物经PCR扩增,最后将扩增纯化后的最终文库放到TruSight One测序版上经NextSeq500测序仪对 WS 相关基因(PAX3、MITF、SNAI2、EDN3、EDNRB、SOX10)的外显子区进行测序,测序结果与人类基因突变数据库、dbSNP、1000人基因组计划、ClinVar、ESP6500数据库进行比对,通过计算机软件(ANNOVAR)分析其治病突变位点。随后对先证者及其父母的突变位点行PCR扩增和Sanger测序验证,[结果](1)该家系中有两名WS患者,分别为先证者(Ⅲ-4)及其母亲(Ⅱ-4),两者都患有双耳极重度感音神经性耳聋,都具有右侧虹膜色素减退的表现,且W值<1.95(内眦无外移),根据其表型两名患者被诊断为Ⅱ型Waardenburg综合征(WS2);先证者的颞骨CT及内耳MRI提示其双侧半规管畸形。(2)基因测序结果显示该家系中的两名WS2患者均携带SOX10基因(NM06941.3)第2号外显子c.255G>A杂合无义突变,软件预测该突变可能会导致该基因所编码蛋白质的第85号氨基酸翻译为终止密码子,使得蛋白质翻译提前终止;先证者的父亲未检测到相关耳聋基因突变。[结论](1)该家系中的两名WS2患者均携带SOX10(c.255G>A)杂合无义突变,检索人类基因突变数据库、dbSNP、1000人基因组计划、ClinVar、ESP6500数据库均未见该突变被收录,综合考虑该变异为此家系种的致病突变;(2)根据WS常染色体显性遗传特点及孟德尔遗传规律,我们推测SOX10(c.255G>A)突变在此家系中的遗传方式为常染色体显性遗传,且先证者(Ⅲ-4)有很大可能将致病基因遗传给下一代。(3)基因测序技术广泛用于云南省WS患者的分子遗传诊断具有一定的应用价值和前景。

ISBN: (纸本)9787519275990

摘要： Schizophrenia is an extensively studied complex psychotic illness, due to the lack of efficient treatment and global prevalence. By means of interdisciplinary research, representative and large study samples, neuroimaging genetics consortia aim to unravel the underlying mechanism of schizophrenia. Despite the wide geographical spread of the members of these consortia, Sub-Saharan African (SSA) populations are largely underrepresented. This literature review aims to pool useful literature and expert opinions to better understand whether this is problematic and whether the incorporation of the SSA population could be used to neuroimaging genetics research of schizophrenia. First, brain-behaviour associations seemed to be predominantly found in frontal and temporal regions. Second, robust associations between genetic risk for schizophrenia and differences in structural and functional brain measures were reported. Third, extrapolation of results derived from European ancestry- to SSA populations may be problematic, due to differences in genetic architecture. The high genetic diversity across SSA populations and the homogeneous genetic nature within SSA subpopulations are suggested to enable the development of genetic prediction models and reliable gene-trait associations. The issues faced by the SSA population in genetic schizophrenia research could, however, complicate the use of these benefits. Finally, some differences seem to exist in schizophrenia epidemiology and prognosis in SSA. In conclusion, extrapolation of schizophrenia research outcomes derived from European ancestry study samples to SSA populations should be carefully considered due to the cross-population differences. However, future collaboration with the SSA population in schizophrenia research could provide deeper insight into the relation between neuroimaging and genetics in schizophrenia due to the unique use of the distinct genetic architecture of this population. Provided that the limitations of th

摘要： Rise of commercial gene tests and whole-genome sequencing becoming easier and cheaper brings many benefits to health care, but also challenges. The challenges include storing, sharing and managing huge amounts of data, analyzing genetic data to find rele-vant information, and interpreting and visualizing complex genetic data. The issue of data privacy is also a major concern in medical genetics. Efficient and well-designed software can help with these challenges. In my thesis, I strive to provide a systematic mapping of the literature on medical genetics software and answer questions about what types of re-search approaches and technological focuses there are in scientific articles on the subject, is data privacy addressed in the articles, and what types of journals the articles are published in. The results show that validation is the most common research approach. This result is possibly partly due to the inclusion criteria and categorization approach used. Preprocessing and analysis of genetic data is the most common technological focus in the papers, likely due to genetic data and analysis of it being very complex and requiring dif-ferent kinds of software to help with it. Data privacy is not addressed in most of the papers, which could partly be due to it not deemed an issue in all types of software. Most of the articles were published in journals related to medical genetics, which is probably due to the genetics professionals using the software reading more journals related to their field.

摘要： Genes are the functional units of heredity. However, the functions of many genes remain unknown, which impedes the understanding of the underlying mechanism of complex traits and diseases. Systems genetics approaches try to understand the complexity underlining phenotypic traits using high-throughput experimental and computational approaches. In this thesis, I describe a list of novel systems genetics approaches to identify gene functions based on publicly available datasets. In Chapter 2, I focused on the multi-omics datasets collected from the BXD mouse cohort, which is one of the most studied mouse genetic reference populations. Over the past 40 years, the BXD community has generated tremendous amounts of data covering different omics layers, making the BXD GRP a perfect data source to conduct systems genetics analyses to discover biological insights. By integrating the data from different omics layers, I developed phenome-wide association study (PheWAS) and expression-based PheWAS (ePheWAS) to reveal the associations between genes and phenotypic traits, as well as mediation and reverse-mediation analysis to identify the regulatory connections between genes. In Chapter 3, I analyzed the transcriptome datasets from six different model organisms, ranging from yeast to human. It is commonly believed that genes with similar functions tend to have similar expression patterns. Therefore by using the co-expression patterns of genes, one can annotate a gene from its correlating genes with known functions. I proposed here a new systems genetics method, termed gene-module association determination (G-MAD), which assigns novel functions of genes and proposes new components of pathway modules. Several new associations, including DDT as a novel mitochondrial protein, were experimentally validated. In addition, G-MAD was further extended to determine the interconnection between pathway modules, for example those between mitochondria and proteasome, as well as ribosome and lipi

关键词： 多发性骨髓瘤   老年人   细胞遗传学  

摘要： 目的探讨老年多发性骨髓瘤(MM)的遗传学特点。方法回顾性分析103例老年MM病人的细胞遗传学特征,并与同期167例非老年MM病人的核型进行对比分析。结果 1q21扩增是MM最常见的遗传学异常,老年组及非老年组病人阳性率分别为59.2%和54.5%。老年组病人IGH重排阳性率为34.0%,非老年组病人为47.3%,2组差异具有统计学意义(P=0.03),但进一步分析显示,具有高危预后意义的t(4;14)和t(14;16)的阳性率在2组间差异无统计学意义。老年组及非老年组17p-阳性率分别为13.6%和12.6%。结论老年MM病人更易合并1q21扩增异常,IGH重排阳性率较非老年病人明显低,但高危细胞遗传学异常老年组与非老年组无明显差异。

关键词： 遗传疾病   临床遗传学   遗传检测   人生态度   知识缺乏   普通人  

摘要： 过去十年,随着遗传检测技术的进步,临床遗传学科迎来了飞速发展,遗传疾病也在不知不觉间渐渐进入了公众的视野。尽管如此,我们对于遗传疾病的认知依然有很长很长的路要走——这是一个技术走在意识之前的时代,并且是远远地走在前面。普通人对遗传疾病具有“与生俱来”的恐惧,这是由知识缺乏、社会环境和人生态度共同带来的结果,令人感到无奈。