Translocation (14;21)(q11;q22) in a woman with history of abortions and a child with Down's syndrome

A translocation (14;21)(q11;q22) was observed in a woman with history of abortions and in her child with Down's syndrome. This appears to be the first report of such a translocation with no centric fusion between the acrocentric chromosomes leading to a count of 45 chromosomes in the carrier and giving birth to a Down's syndrome child.     

HL-A frequencies in Down's syndrome.

HL-A antigen frequencies were examined in 76 Down's syndrome individuals and 733 normal Caucasians. 10 antigens of the first locus and 15 antigens of the second locus were defined, using a microlymphocytotoxicity technique. No significant differences were observed between the normal and Down's syndrome samples, in contrast to a previous report (Boxer and Yokoyama, 1972) of decreased HL-A antigen frequencies in Down's syndrome individuals. Our results therefore suggest that there is no relationship between trisomy 21-associated immune aberrations and altered HL-A antigen frequencies.     

Reexamination of paternal age effect in Down's syndrome

Summary The recent discovery that the extra chromosome in about 30% of cases of 47, trisomy 21 is of paternal origin has revived interest in the possibility of paternal age as a risk factor for a Down syndrome birth, independent of maternal age. Parental age distribution for 611 Down's syndrome 47,+21 cases was studied. The mean paternal age was 0.16 year greater than in the entire population of live births after controlling for maternal age. There was no evidence for a significant paternal age effect at the 0.05 level. For 242 of these Down's syndrome cases, control subjects were selected by rigidly matching in a systematic manner. Paternal age was the variable studied, with maternal age and time and place of birth controlled. There was no statistically significant association between paternal age and Down's syndrome. After adjustment for maternal age, these two studies were not consistent with an increase of paternal age in Down's syndrome.     

Unusual genotypes in the COL6A1 gene in parents of children with trisomy 21 and major congenital heart defects

Collagen type VI is a candidate for a role in the pathogenesis of congenital heart defects (CHD) in Down's syndrome. Three restriction fragment length polymorphisms of the COL6A1 gene were used to determine COL6A1 genotypes in 50 families of affected children with trisomy 21 (29 with congenital heart defects and 21 without) and 37 unrelated volunteers. We found seven unusual genotypes in the parents of affected children with Down's syndrome, five being unique to the parents of children with trisomy 21 and CHD. There were no unusual genotypes associated with other chromosome 21 loci. No single COL6A1 genotype was associated with CHD. Thus, the unusual genotypes unique to parents of affected children suggest that genetic variation in the COL6A1 gene region contributes to the pathogenesis of CHD in Down's syndrome.     

Trisomy 21q223 and Down's phenotype correlation evidenced by in situ hybridization

Summary Two cases of trisomy 21q223 with the Down's phenotype were analysed by in situ hybridization with specific probes previously located in the sub-bands 21q221 (SOD-A) and 21q223 (BCEI and COL6A). These studies give evidence that the clinical picture of Down's syndrome is at least to a great extent correlated with trisomy for the 21q223 band.     

多重实时荧光PCR相对定量法快速诊断唐氏综合征

为了建立一种基于多重实时荧光相对定量PCR技术并应用之于唐氏综合征分子诊断, 选择21号染色体上唐氏综合征特异区域基因片段(DSCR3)为目的基因, 以12号染色体上的磷酸甘油醛脱氢酶基因(GAPDH)为参照基因, 设计合成两对引物以及分别以不同荧光标记的TaqMan探针, 在同一个反应管中进行扩增。以相对定量指标△CT值区分唐氏综合征患者与正常人。采用EB 病毒转化技术, 把唐氏综合征患者外周血B 淋巴细胞转化成永生淋巴母细胞系作为标准品。通过优化反应条件, 使得目的基因和参照基因的扩增效率基本一致, 接近100%, 模板浓度在3～300 ng/μL范围内, △CT值的变异系数小于15%, 浓度在30 ng/μL时, 变异系数最小(＜10%), 以该浓度的DNA作为模板进行批内和批间实验的△CT值重复性好, 变异系数分别为9.8%和13.3%。运用建立的方法检测20例唐氏综合征患者的血标本和30例正常人的血标本, 正常人△CT值范围是-1.90～-1.30, 患者的△CT值范围是-2.95～-2.15, 两组之间无交叉重叠, 有明显差异(P＜0.001)。唐氏综合征患者永生细胞系建系成功 ,染色体核型和DNA 分析表明建系前后遗传是稳定的。因此, 实时荧光定量PCR比较△CT值的相对定量法快速诊断唐氏综合征是可行的。     

Moderate Down's syndrome in three siblings having partial trisomy 21q22.2→qter and therefore no SOD-1 excess

Summary Three mentally retarded siblings with moderate stigmata of Down's syndrome were found to have a partial trisomy 21q22.2qter resulting from a maternal translocation t(4q+;21q-). By the exclusion of any excess of SOD-1 in them, we can confirm the nonessentiality of the sub-band 21q22.1 and of the SOD-1 excess for most of the Down's syndrome stigmata including the mental retardation. However, the sub-band 21q22.1 in triplicate might be required for the completion of the full syndrome, as for example is shown by the incomplete dermatoglyphic pattern on the palms in the patients.     

Satellite association in Down's syndrome

Summary The frequency of association of acrocentric chromosomes is examined in 20 Down's syndrome children, their parents, and 60 controls. Chromosome 21 enters into satellite associations most frequently, and chromosome 15 least. The parents of Down's syndrome children do not show any increased tendency for satellite association of chromosome 21 or indeed any other acrocentric.     

Understanding mental retardation in Down's syndrome using trisomy 16 mouse models

Mental retardation in Down's syndrome, human trisomy 21, is characterized by developmental delays, language and memory deficits and other cognitive abnormalities. Neurophysiological and functional information is needed to understand the mechanisms of mental retardation in Down's syndrome. The trisomy mouse models provide windows into the molecular and developmental effects associated with abnormal chromosome numbers. The distal segment of mouse chromosome 16 is homologous to nearly the entire long arm of human chromosome 21. Therefore, mice with full or segmental trisomy 16 (Ts65Dn) are considered reliable animal models of Down's syndrome. Ts65Dn mice demonstrate impaired learning in spatial tests and abnormalities in hippocampal synaptic plasticity. We hypothesize that the physiological impairments in the Ts65Dn mouse hippocampus can model the suboptimal brain function occuring at various levels of Down's syndrome brain hierarchy, starting at a single neuron, and then affecting simple and complex neuronal networks. Once these elements create the gross brain structure, their dysfunctional activity cannot be overcome by extensive plasticity and redundancy, and therefore, at the end of the maturation period the mind inside this brain remains deficient and delayed in its capabilities. The complicated interactions that govern this aberrant developmental process cannot be rescued through existing compensatory mechanisms. In summary, overexpression of genes from chromosome 21 shifts biological homeostasis in the Down's syndrome brain to a new less functional state.     

Multiple birth and Down's disease]

The frequency of twinning among newborns with Down's syndrome (2,11+/-0,6%)was significantly higher than in the general populaltion (0,73+/-0,3%). The increase in the rate of multiple births of children with trisomy-21 occurred due to almost three-fold excess in the frequency of dizygotic (discordant) twin pairs over the expected level. The increase in the frequency of dizygotic twins with Down's syndrome was explained by the combined effect of two independent factors: the increase in probability of dizgotic twins natality and the enhanced rate of children birth with trisomy-21, which depended on the increase in mother's age.     

Familial transmission of a (21q22q) translocation.

A large family is described in which a (21q22q) Robertsonian translocation is segregating through three generations. The assessment of the risk of a translocation carrier producing an offspring with Down's syndrome is calculated from the data in this family and eight others reported in the literature. The risk when the translocation carrier is a female is approximately 6 in 100, or 0.06. For the male translocation carrier the risk can only be guessed, since the patients with Down's syndrome born to these parents were probands. The risk for Down's syndrome from the combined data of male and female translocation carriers in 3 is 100, or 0.03.     

Dermatoglyphics of Down's syndrome patients in Malays--a comparative study

There has been no recent report on the dermatoglyphics of the Malays (normal population as well as patients with Down's syndrome). A study on the frequencies of the dermal patterns (dermatoglyphics) of the digits, palms and hallucal areas was done therefore in 40 Malay patients with Down's syndrome and 200 unrelated normal controls. Only the patients with the standard 21 trisomy karyotype were included in the study. Comparison was made with the published data on studies done in various racial groups. Significant differences of the dermal patterns were found not only between the controls but also among patients of different races.     

Identification of G group anomalies in Down's syndrome by quinacrine dihydrochloride fluorescence staining

Summary 9 patients with regular trisomic Down's syndrome, 3 female carriers from different t (DqGq) families and 2 carriers from the same t (21q22q) family were examined by quinacrine dihydrochloride fluorescence microscopy. A G group chromosome with a highly fluorescent band on its long arm was found in triplicate in all patients. The same chromosome was missing in the (DqGq) translocation carriers being involved in the translocation with a D chromosome. It was also missing in the (21q22q) carriers. This supports the suggestion that it is always the same chromosome which is involved in both regular and translocation Down's syndrome.Quinacrine dihydrochloride is an easily available stain, which can be used for identification of human metaphase chromosomes.     

Offspring of patients with Down syndrome

An incident of birth of a child in 16-year-old patient with typical phenotype of Down's syndrome is described. The karyotype of the proband is 47, XX + 21, while that of the child is 46, XX. Analysis of the literature data and the author's observations showed that the total ratio of trisomics and non-trisomics in the offspring of women with Down's syndrome is 9:18, which considerably differs from theoretically expected and suggests that selection against anomalous gametes exists.     

Genetic epidemiology of Down's syndrome in Shetland

Summary Pedigrees of all known cases, on Shetland, of Down's syndrome, cytogenetically confirmed as trisomy 21, and of a control for each patient matched by birth date, sex and birth place, were traced over a minimum of eight generations. Mean kinship coefficients in all pairs of Down's syndrome patients and in all pairs of controls were similar. The kinship between the father and mother of each case shows that the parents are more closely related than the general level of relationship in the population, suggesting some recessive element in the etiology. It is argued that the effect of the resulting increased homozygosity would be to prevent the loss of the conceptus that occurs in the majority of trisomy 21 conceptions.     

人类PKNOX1基因一种新剪接型全长cDNA的克隆与表达分析

为了寻找新的Down’s综合征相关基因,利用生物信息学分析与实验技术相结合的方法,从定位于Down’s综合征关键区内(21q22．3)的EST(GenBank登录号H77399)出发,从人类睾丸组织cDNA文库内克隆到含同源盒结构域转录因子PKNOX1的一种新剪接型全长cDNA,命名为PKNOX1B,GenBank登陆号AYl42115。PKNOX1B基因跨越58．4kb,全长cDNA约2．8kb,有11个外显子和10个内含子,编码405个氨基酸残基的酸性蛋白质,分子量为44．628kDa,等电点6．28。PKNOX1B与PKNOX1的前9个外显子及9个内含子完全相同,由于PKNOX1B在第10与11外显子之间发生了差异剪接,以致其在3’端cDNA序列被截短约2kb,所编码的蛋白质在C端较PKNOX1短30个氨基酸残基。但PKNOX1B保留了与PKNOX1完全相同的同源盒结构域,因而它可能与其他含同源盒结构域基因家族成员一样参与了发育的遗传调控。RT-PCR结果显示PKNOX1B除骨髓组织外在人体组织广泛表达。在睾丸组织中PKNOX1可见5kb,2．9kb,2kb 3种转录本,而在其他组织中仅发现2个较大的转录本,2kb的转录本在睾丸组织呈现特异性的表达,它有可能参与了精子的发生过程。     

Immunological aberrations in patients with aneuploid chromosome abnormalities and in their parents

Summary Studies of autoantibody reactions towards different organs in patients with aneuploid sex chromosome aberrations have been controversial, and no conclusions can be drawn at present. If the findings by certain authors of increased thyroid autoantibody titers in patients with Down's syndrome as well as in the mothers are confirmed by further studies, this might indicate that the increased thyroid autoantibody titers found in mothers of patients with Down's syndrome in some way might be aetiologically connected with the risk of non-disjunction resulting in trisomy 21.     

Overproduction of human Cu/Zn-superoxide dismutase in transfected cells: extenuation of paraquat-mediated cytotoxicity and enhancement of lipid peroxidation.

The 'housekeeping' enzyme Cu/Zn-superoxide dismutase (SOD-1) is encoded by a gene residing on human chromosome 21, at the region 21q22 known to be involved in Down's syndrome. The SOD-1 gene and the SOD-1 cDNA were introduced into mouse L-cells and human HeLa cells, respectively as part of recombinant plasmids containing the neoR selectable marker. Human and mouse transformants were obtained that expressed elevated levels (up to 6-fold) of authentic, enzymatically active human SOD-1. This enabled us to examine the consequences of hSOD-1 gene dosage, apart from gene dosage effects contributed by other genes residing on chromosome 21. Human and mouse cell clones that overproduce the hSOD-1 had altered properties; they were more resistant to paraquat than the parental cells and showed an increase in lipid peroxidation. The data are consistent with the possibility that gene dosage of hSOD-1 contributes to some of the clinical symptoms associated with Down's syndrome.     

Tandem duplication chromosome 21 in the offspring of a ring chromosome 21 carrier

A direct tandem duplication chromosome 21 was found in a boy with Down's syndrome. The proband's mother and grandmother both carried a ring chromosome 21. The observed duplication chromosome in the child may be explained either by recombination between the maternal ring and the mother's normal chromosome 21 or by break of a double-sized ring chromosome 21.     

Meiosis I non-disjunction as the main cause of trisomy 21

Summary The relative roles of Meiosis I and Meiosis II non-disjunctions in the causation of trisomy 21 have been assessed by analysing the distribution of polymorphic phenotypes of the chromosomes 21 in a group of individuals with Down's syndrome. The data suggest that the majority of cases of trisomy 21 are due to meiosis I non-disjunctions.