由21三体综合征的核型引起的思考

不同的医学遗传学教材上对21三体综合征的概念及核型说法不一, 作者在查阅了大量教材的基础上, 对21三体综合征的概念及核型等问题进行了认真的思考, 并提出了自己的观点, 认为21三体综合征的核型应该为两种类型: 即三体型和嵌合型, 而先天愚型的核型应该为3种类型: 即三体型、嵌合型和易位型。     

两种细胞来源的21-三体综合征诱导多能干细胞系的建立及比较

21-三体综合征是染色体异常导致的疾病,通过重编程21-三体综合征患儿两种组织来源的细胞成为多能干细胞,比较两种组织来源的细胞建立21-三体综合征诱导多能干细胞（T21-iPSCs）系的效率,为进一步研究21-三体综合征发病机制提供细胞模型,并为选择高效制备T21-iPSCs的组织类型提供理论依据。该实验利用慢病毒介导4种转录因子（Oct4、Sox2、Klf4、c-Myc）分别诱导人21-三体综合征的羊水细胞和胎儿皮肤成纤维细胞,建立诱导多能干细胞系（Trisomy 21 human amniotic fl uid induced pluripotent stem cells,T21 hAF-iPSCs;Trisomy 21 human dermal fi broblast induced pluripotent stem cells,T21 hDF-iPSCs）,T21 hAF-iPSCs及T21 hDF-iPSCs在蛋白和mRNA水平上均表达人胚胎干细胞的多能性分子标记,如Oct4、Nanog等,具有在体外及体内分化三个胚层的能力,其在培养过程中能维持异常核型并能维持自我更新状态。结果发现,利用羊水细胞建立T21-iPSCs效率高于皮肤成纤维细胞,羊水细胞可能是制备T21-iPSCs的理想细胞类型。     

湖南地区1013例亲子鉴定中的STR突变位点研究

对亲子鉴定常用的ABI公司Indentifiler荧光标记复合扩增试剂盒中的15个短串联重复序列及D14S306、D16S3391、D5S2500、D12S391、D13S796、D1S518位点的突变现象进行研究.在1013例认定亲子关系案例中,对发现有一个基因位点发生突变的案例增加8个常染色体STR（short tandem repeat）基因座检测,使其父权相对机会（RCP）大于99.999%以上,并对突变位点进行测序.在1013例认定亲子关系案例中,发现11例有一个基因位点发生突变,8次突变事件为父源性突变,突变位点包括vWA、FGA、D14S306、D13S317、D21S11、CSFIPO、D16S3391;其余3例突变来源不明,包括FGA、D13S796、D3S1358.以vWA和FGA的突变率最高,为0.15%,平均突变率为（0.09±0.370×10^-3）%.本鉴定所常用的21个基因座,突变率低,具有较高的推广价值.     

21三体综合征及其产前筛查的研究现状和发展方向

简要介绍了目前21三体综合征产前筛查所采取的孕母血清标记物结合B型超声波筛查的方法,比较了不同组合的检出率等指标,并指出产前筛查可能的发展方向。     

儿童巴特综合征药物治疗一例分析暨文献复习

目的:加强对儿童巴特综合征药物治疗的认识,探讨医院药学部门的处方点评模式。方法:分析我院2015年12月的1张巴特综合征患者处方的合理性,并复习相关文献。结果:本张处方初评时被判定为不合理处方,经过临床药师与临床医师的沟通和查阅相关文献,复评时将此处方改判为合理处方,证明了我院三级处方点评模式可以提高药师审查处方的能力,确保处方点评合理、公平。结论:表面上看用药不合理的处方并不一定是真正的不合理,要深入分析处方的内涵,才能对处方进行准确的判定。三级处方点评模式能促进药师学习掌握专业知识技能,提高判断处方的能力。     

9;21相互易位携带者生育多例9p部分三体患者细胞遗传学分析

在河南南阳收集到一个家系4代23人, 其中6人患先天性智力障碍, 具有轻度的面部和小母指畸形等特点, 先证者伴随有癫痫的发生。采用常规的外周血培养染色体G带分析, 发现先证者的核型为：46, XY, der(21) t(9; 21) (9p22.2; 21q22.3)pat, 是部分9p三体。对该家系其他成员的染色体进行分析, 发现所有患者均为部分9p三体, 异常染色体均来自9号与21号染色体平衡易位携带者染色体相互易位的异常分离, 因此这是一个部分9p三体综合征家系。而重复区段发生在9号染色体短臂远端一半区域(9pter→9p21)内, 该区是关键区, 导致智力障碍和面容轻微畸形。     

非典型恶性综合征1 例报告暨文献复习

目的:探讨恶性综合征的病因、发病机制、临床表现及治疗。方法:回顾性分析1例非典型恶性综合征患者1例,结合文献进行分析讨论。结果:患者因高龄、全身状况差、长期并联合应用多种抗精神病药物、合并应用多种其他药物而诱发,表现为肌张力增高,心率增快,血压增高,经过停用抗精神病药,给予甲磺酸溴隐亭片、盐酸金刚烷胺片及对症支持治疗,患者病情好转。结论:恶性综合征是抗精神病药物治疗的严重并发症,其临床表现可无发热等典型表现,且可出现各系统症状,可能首诊于多个科室,各科临床医师均应熟悉该病的临床表现,以便及时作出诊断,及时治疗,改善患者预后。     

1例7 p21.2→pter部分三体综合征患者及其表型定位研究

采用人类染色体G显带技术、高分辨显带技术、荧光原位杂交技术(FISH),对一例7p21．2→pter部分三体综合征患者的染色体进行研究,并综合文献报道的14例7P部分三体综合征的临床资料,就7p部分三体综合征患者的核型与表型的相关关系、核型与疾病基因的相关关系等问题进行探讨。通过1例染色体7p21．2→pter部分三体患者的染色体分析、表型定位研究和相关文献复习比较,探索染色体区带与表型的关系。结果表明,7p21．2→p22是7p部分三体综合征的关键片段,生殖器畸形、髋关节脱位与7p15重复有关,心脏畸形与7p多个基因作用有关,颅缝早闭基因可能位于7p21．2→p21．3。     

B型尼曼-匹克病一例附文献复习

目的:报道一例B型尼曼-匹克病患者的病例资料,提高对该病的认识。方法:观察1例B型尼曼-匹克病患者的临床表现、骨髓涂片及骨髓活检结果,并进行相关的文献复习。结果:B型尼曼-匹克为自幼发病,无神经系统受损表现,伴有肝脾肿大、外周血三系降低,骨髓涂片及活检结果可见尼曼-匹克细胞。结论:尼曼-匹克病是一种罕见的鞘磷脂沉积性遗传性疾病,临床表现多样,骨髓、肝脾淋巴结病理及基因检测是确诊的关键方法,此病预后差,无特效治疗药物。     

True vs. false inv(Y)(p11q11.2): a familial instance concurrent with trisomy 21

A boy with Down syndrome due to a free trisomy 21 also had a metacentric Y chromosome with an arm euchromatic and the other heterochromatic inherited from his phenotypically normal father. This chromosome was mitotically stable and hybridized with the DYZ3 probe precisely at its primary constriction; in addition, a subtelomeric Xp/Yp probe gave the expected signal near the end of the euchromatic arm. So, the proband's karyotype was 47,X,inv(Y)(p11q11.2),+21. Given the high frequency of both chromosome anomalies, we regard its concurrence as a mere coincidence. This observation, along with previous reports, allows us to classify the apparent pericentric inversions of the Y chromosome into two types: "true" inversions characterized by an alphoid single centromere and mitotic stability, and "false" inversions in which a nonalphoid centromere has taken over the usual alphoid centromere; indeed, these chromosomes are dicentric and mitotically unstable. Finally, the inv(Y) polymorphism in man compares with that documented in other mammal species, in which the rearranged Y chromosome neither impairs the fertility nor has other phenotypical consequences.     

HLA分型技术在亲子鉴定中的应用

本文对ＨＬＡ分型实验用于亲子鉴定进行了研究,应用统计学公式计算出ＨＬＡ单倍型检测的平均亲子概率为９４０６％,并对５例要求亲子鉴定的家庭进行检测。结果表明：３例亲子关系成立,１例否定,１例可疑     

Distribution of extracellular matrix components in nuchal skin from fetuses carrying trisomy 18 and trisomy 21

We have investigated histologically the elevations of the skin in dorsal and lateral neck (nuchal) regions of human fetuses carrying karyotypes of trisomy 18 (Edwards' syndrome) and trisomy 21 (Down's syndrome). Cavities filled with interstitial fluid were found in the dermis, epidermal basement membrane and occasionally in the epidermis of trisomy-18 fetuses, but were not delineated by an epithelium or basement membrane as judged by the absence of immunostaining for laminin, collagen IV and collagen VII. Dilated vessels were also found at the interface between dermis and subcutis. Neither normal fetal skin nor that of trisomy-21 fetuses contained cavities or dilated vessels. In order to detect possible alterations of the extracellular matrix in trisomy-18 and trisomy-21 skin, the distribution of glycoproteins, glycosaminoglycans and proteoglycans was studied immunohistochemically. In trisomy-21 and control skin, the dermis stained intensely for fibronectin, whereas the subcutis reacted only weakly. In trisomy-18 skin, the stronger staining for fibronectin appeared in the subcutis, and the prevailing collagen type was collagen III, collagen type I being absent. In the skin of trisomy-21 fetuses, collagen VI was more irregularly arranged and densely packed, whereas collagen I was more widely spaced than in normal fetuses. More hyaluronan was present in the dermis and subcutis of trisomy-21 fetuses than in that of trisomy-18 and control fetuses. A correlation seems to exist between undelimited cavities and collagen III in trisomy-18 skin, and between hyaluronan and the specific arrangement of collagen in trisomy-21 skin.Abbreviations bm Basement membrane - ep epidermis - d dermis - sc subcutis - hf hair follicle - c capillary This article is dedicated to Professor Dr. Konrad Märkel on the occasion of his 70^th birthday     

A possible cause of non-disjunction of additional chromosome 21 in Down syndrome

Summary A possible cause of non-disjunction of chromosome 21 in Down Syndromes has been cytogenetically evaluated by examining the parents by Ag-staining technique. In all the cases studied so far, the contributing parents have active ribosomal cistrons on both chromosomes 21 i.e. both chromosomes are stained positively by silver staining. These results show that the active NORs might play an essential role in meiotic non-disjunction. Furthermore, the preliminary results demonstrate that the acrocentric associations of homologous and non-homologous nature involving chromosome 21 are the most frequent in the contributing parent which may further indicate the role of multiple cellular factors affecting the associations in promoting the non-disjunction in addition to active NORs. The possible mechanisms regarding the non-disjunction of chromosome 21 have been described.Presented at the 34th Annual Meeting of the American Society of Human Genetics, Norfolk, VA, USA     

Detection of mosaicism in lymphocytes of parents of free trisomy 21 offspring

Down syndrome (DS) resulting from free trisomy 21 (FT21) has been largely associated with advanced maternal age. However, approximately 60% of FT21 cases are born to young couples. Thus, the etiological factors responsible for these FT21 children must differ from those proposed for maternal age-related FT21. These factors have not been defined. In this study, we analyzed the chromosomes of peripheral blood lymphocytes from three groups of couples aged ≤35 years, to identify chromosomal trisomies: Group I included 5 couples with normal offspring; Group II included 22 couples with one FT21 child; and Group III consisted of 3 couples with recurrent FT21. A total of 13,809 metaphases were analyzed with G-banding and 60,205 metaphases were analyzed with FISH using a 13/21 centromeric probe. Aneuploidy was significantly more frequent in Groups II and III. The frequencies of hyperdiploid cells were 0.19, 0.49 and 0.96% in Groups I–III, respectively. FISH analysis showed that trisomy 21 cell percentages were 0.08, 0.21 and 0.76 for Groups I–III, respectively, and were very similar to those obtained with G-banding. Trisomy 21 mosaicism was found in 2/22 couples with one FT21 offspring, and in 2/3 couples with recurrent FT21. Our data suggest that mosaicism is an important cause of FT21 offspring in young couples, and that aneuploidy is more frequent among couples with FT21 offspring. This may be related with age and other undetermined intrinsic and extrinsic factors.     

Mice Transgenic for Copper/Zinc Superoxide Dismutase Exhibit Increased Markers of Biogenic Amine Function

Abstract: Mice that are transgenic for and overexpress human copper/zinc superoxide dismutase were used to investigate the role of this enzyme in the pathophysiology of Down's syndrome (DS; trisomy 21). Previous studies have indicated that overexpression of copper/zinc superoxide dismutase leads to deficits in peripheral markers of neurochemical function, which are consistent with the hypothesis that this enzyme plays a role in the pathophysiology of DS. We have measured concentrations of amino acids and biogenic amines (catecholamines, serotonin, and their metabolites), uptake of biogenic amines into crude synaptosomes, and activities of synthetic enzymes in both control mice and mice transgenic for human copper/zinc superoxide dismutase that overexpress it by two- to fivefold above control values. We find that these transgenic mice exhibit higher concentrations of the biogenic amines in specific brain regions, with little or no change in amino acid concentration. Furthermore, tyrosine hydroxylase activity is increased in the striatum of the transgenics, whereas glutamic acid decarboxylase and choline acetyltransferase activities are unchanged in all but one brain region. These findings indicate that over-expression of copper/zinc superoxide dismutase, by itself, is not sufficient to cause the synaptic neurochemical deficits reported in DS.     

Quantitative proteomic analysis of amniocytes reveals potentially dysregulated molecular networks in Down syndrome

Background

Down syndrome (DS), caused by an extra copy of chromosome 21, affects 1 in 750 live births and is characterized by cognitive impairment and a constellation of congenital defects. Currently, little is known about the molecular pathogenesis and no direct genotype-phenotype relationship has yet been confirmed. Since DS amniocytes are expected to have a distinct biological behaviour compared to normal amniocytes, we hypothesize that relative quantification of proteins produced from trisomy and euploid (chromosomally normal) amniocytes will reveal dysregulated molecular pathways.

Results

Chromosomally normal- and Trisomy 21-amniocytes were quantitatively analyzed by using Stable Isotope Labeling of Amino acids in Cell culture and tandem mass spectrometry. A total of 4919 unique proteins were identified from the supernatant and cell lysate proteome. More specifically, 4548 unique proteins were identified from the lysate, and 91% of these proteins were quantified based on MS/MS spectra ratios of peptides containing isotope-labeled amino acids. A total of 904 proteins showed significant differential expression and were involved in 25 molecular pathways, each containing a minimum of 16 proteins. Sixty of these proteins consistently showed aberrant expression from trisomy 21 affected amniocytes, indicating their potential role in DS pathogenesis. Nine proteins were analyzed with a multiplex selected reaction monitoring assay in an independent set of Trisomy 21-amniocyte samples and two of them (SOD1 and NES) showed a consistent differential expression.

Conclusions

The most extensive proteome of amniocytes and amniotic fluid has been generated and differentially expressed proteins from amniocytes with Trisomy 21 revealed molecular pathways that seem to be most significantly affected by the presence of an extra copy of chromosome 21.     

Practical application of fluorescent quantitative PCR on Trisomy 21 in Chinese Han population

Objective To apply the fluorescent quantitative PCR method on the detection of Trisomy 21 by D21S11 locus and make a foundation for rapid prenatal diagnosis of Trisomy 21. Methods About 409 controls (39 amniotic fluid samples and 370 peripheral blood samples) and 35 patients (4 amniotic fluid samples and 31 peripheral blood samples) with Trisomy 21 were tested using fluorescent quantitative PCR by amplification of DNA fragment on D21S11 STR locus. The results were compared with conventional cytogenetic analysis to confirm the utility of this method. And the allele frequency distributions of D21S11 STR locus were analyzed. Results The 95% reference interval of fluorescent intensity ratios of peak heights of PCR products amplified from two alleles on D21S11 locus ranged from 0.84 to 1.42 (1.13 ± 0.29) in heterozygous controls. About 19 out of 35 patients showed a “diallelic“ pattern and their height ratio of fluorescent peaks of PCR products amplified from two alleles in patients with “diallelic” patterns were all outside of the 95% reference range of controls. The PCR products of DNA from 12 patients presented the third allele. No sample with the “monoallelic“ pattern was found. Four chimeras diagnosed by cytogenetic method could not be diagnosed by this method. There were 17 and 11 alleles found in controls and patients, respectively. About 343 out of 409 controls were heterozygous and the heterozygosity was 83.86%. We did not find any significant differences in the frequency distributions of alleles on D21S11 locus between controls and patients. But there were significant differences in the frequency distributions of alleles on D21S11 locus between controls and patients. But there were significant differences in the frequency distributions of alleles on D21S11 locus among different populations. Conclusions The fluorescent quantitative polymerase chain reaction method was rapid, accurate, and only small amount of starting material was needed, it could be applied in rapid prenatal diagnosis of Trisomy 21. D21S11 was a good marker with high heterozygosity for the screening of Trisomy 21. And the frequency distributions of alleles on D21S11 locus were significantly related to ethnic background. This work was supported by grants from the National Natural Science Foundation of China (30200107) as well as the Dominant Youth Fund from Wuhan University School of Medicine