先天性智能低下儿的染色体脆性位点探讨

对１０４例先天性智能低下儿和３７例正常儿分别进行叶酸敏感型染色体脆性位点表达、外周血淋巴细胞培养、染色体制备和核型分析，结果为：智能低下儿染色体脆性位点表达率明显高于正常儿（Ｐ＜０．０１）。脆性位点在各组（Ａ－Ｇ）和Ｘ染色体表现众数为Ａ、Ｃ组，表达率较高为Ａ、Ｃ组和Ｘ染色体。本文研究不仅得出了染色体脆性位点的表达和分布，而且进一步说明了染色体脆性位点的检测对智能低下儿的诊断提供了有价值的实验资料。     

智力低下儿童X染色体脆性位点及FMR1基因突变的研究

目的探讨智力低下（Mental Retardation,MR）儿童染色体遗传学原因。方法选择智力低下患儿及其父母作为研究对象,采用细胞遗传学方法检测X染色体脆性位点,以及采用多重连接探针扩增（Multiplex ligation—dependent Probe Amplificaton,MLPA）技术分析FMRl（Fragile X mental retardation gene1）基因的缺失与重复。结果266例患儿共查出X脆性综合征18例,与父母同一脆性位点的7例,其中6例为FMRl基因突变。结论MR患儿可与表型正常的父母有同-X染色体脆性位点,但FMRl基因突变是X脆性综合征（Fragile X syndrome,Fra X）临床表型的真正原因。     

儿童出生季节与智商关系探讨

对５２９９名儿童作了出生季节及受孕时期与智商关系的分析。结果表明：弱智儿春季出生（夏季受孕）者比例最高；夏季出生（秋季受孕）者比例最低（Ｐ＜０．０５）。智力处于临界状态的儿童秋季出生（冬季受孕）者比例最高，冬季出生（春季受孕）者比例最低（Ｐ＜０．０５）．智力超常儿童及智力优秀儿童春夏秋冬各季节出生者无显著性差异（Ｐ＞０．０１）。文中也讨论了其他因素的作用。     

早孕期绒毛细胞短期培养的染色体脆性位点研究

筛选１０２份人工流产的绒毛标本，分组进行短期培养及染色体脆性位点（ＦＳ）的研究，结果表明：Ｍ１９９加ＭＴＸ（２组）（终浓度为４×１０～（－８）ｍｏ１／Ｌ）与单纯Ｍ１９９（１组）比较，染色体畸变率（ＣＡＲ）和脆性位点表达率（ＦＲ）差别均有显著意义（Ｐ＜０．０５）；Ｍ１９９加ＢｒｄＵ（终浓度为２×１０～（－４）ｍｏ１／Ｌ）（３组）与Ｍ１９９加ＭＴＸ比较ＦＲ差别有极显著意义（Ｐ＜０．０ｌ）；ＲＰＭＩ１６４０加ＭＴＸ（终浓度８×１０～（－８）ｍｏ１／Ｌ）（４组）与２组比较中期分裂相数差别有显著意义（Ｐ＜０．０５）。     

35例智力低下儿童染色体脆性部位分析

３５例智力低下儿童染色体脆性部位分析张晓珍，余继英，霍晓春，饶兆英近年来，对脆性Ｘ综合征的研究引起了医学遗传学界的广泛关注。脆性Ｘ染色体（ＦｒａＸ）与Ｘ连锁智力低下（ｍｅｎｔａｌｒｅｔａｒｄａｔｉｏｎ，ＭＲ）有关，进而使人们对罕见型脆性位点发生极大兴...     

正常人群中染色体随体联合的分布频率

本文研究了２００ 对完全随机的正常夫妇的外周血淋巴细胞Ｇ 带染色体随体联合频率（ＳＡｆ）,其近端着丝点染色体ＳＡｆ 男性２－６６％ 、女性２－６７％ ,每个细胞平均出现随体联合数男性１－２２ ±０－０３、女性１－２２ ±０－０６,男女之间差异不显著（Ｐ＞０－０５）。在随体联合中Ｄ组染色体所占频率（ＤＳＡｆ） 男性０－６３ ±０－０１ 、女性０－６５ ±０－０１;Ｇ 组染色体所占频率（ＧＳＡｆ） 男性０－３７±０－０１、女性０－３５ ±０－０１ ,男女之间差异不显著（Ｐ＞０－０５）。     

非小细胞肺癌患者外周血染色体稳定性研究

在非小细胞肺癌患者外周血培养液中加入诱变剂，结果发现患者染色体畸变率（１４％）较正常对照组明显增高，主要的畸变有１ｐ－、６ｑ、７ｐ－、７ｑ－。说明患者染色体不稳定，并且有一定的遗传基础。此外，患者脆性位点表达率（９４．９％）明显高于正常对照组（３４．１％）（Ｐ〈０．０１）。患者染色体断裂点有７２％与脆性位点一致。两者可能有共同的遗传基础。     

皮下埋植Norplant Ⅰ 型避孕药囊妇女的细胞遗传学研究

对２９例皮下埋植ＮｏｒｐｌａｎｔⅠ型避孕药囊（芬兰产）已４年的妇女和１９例未埋药的正常妇女的外周血淋巴细胞培养后进行了细胞遗传学分析。研究结果分析表明：埋药组染色体畸变率明显高于对照组染色体畸变率，且有统计学意义（Ｐ＜０．０１）；埋药组ＳＣＥ频率平均值高于对照组ＳＣＥ频率平均值，且有统计学意义（Ｐ＜０．０５）；埋药组细胞微核率平均值虽高于对照组细胞微核率平均值，但无统计学意义（Ｐ＞０．０５）。研究结果提示：应引起对于长期皮下埋植ＮｏｒｐｌａｎｔⅠ型是否存在致突变作用问题的重视和研究。     

自血光量子疗法对颅脑损伤者外周血脆性位点的影响

我们对接受自血光量子疗法治疗的颅脑损伤病人外周血脆性位点（ＦＳ）进行分析，并与正常人做对照。结果对照组与实验组治疗前比较无显著性差异（Ｐ＞０．０５）。说明此病与ＦＳ无关。实验组治疗后３年与治疗前比较有显著性差异（Ｐ＜０．０５）；治疗结束时与治疗前比较有高度显著性差异（Ｐ＜０．０１）。治疗后３年与治疗结束时有显著性差异（Ｐ＜０．０５）。前二者说明ＦＳ的升高与紫外线照射血液回输有关，后者说明３年后ＤＮＡ有恢复趋势。     

学龄前与学龄期正常儿童甲襞微循环比较

对学龄前（３～６岁）和学龄期（７～１２岁）二组正常儿童甲襞微循环进行比较，结果表明：学龄前组管袢数目较学龄组少（Ｐ＜０．０５），而乳头下静脉丛出现率较学龄组高（Ｐ＜０．０１），其余指标二组比较无显著性差异（Ｐ＞０．０５），指出不同年龄组的儿童甲襞微循环正常值存在一定差异     

The clinical significance of fragile sites on human chromosomes

Fragile X syndrome is now a well established common clinical entity and most of those who are aware of the condition probably know that it takes its name from a rare fragile site (FRAXA) on the X chromosome. This is the best known fragile site and its clinical significance is clear. Similar, but a little less known is FRAXE, a fragile site close to that associated with fragile X syndrome, but in this case associated with a mild form of non-specific X-linked mental retardation. These are the only two fragile sites that are unequivocally of clinical significance. A fragile site within the CBL2 oncogene on chromosome 11 has been mapped very close to the deletion breakpoint in a handful of patients with Jacobsen syndrome. It is doubtful that parents with FRA11B are at increased risk of having children with Jacobsen syndrome, but this cannot be ruled out. The common fragile sites have been implicated in oncogenesis since shortly after their discovery in the early 1980s. While a couple of these are within genes that have been implicated in cancer it is unclear whether either the fragile sites, or the genes in which they are located are important in cancer. It may be that the common fragile sites are regions of genomic instability and that this instability is increased in malignant cells, analogous to the enhanced instability seen at microsatellite loci in a number of tumours. Since we all have the common fragile sites there is no suggestion that they give anyone an increased risk of developing malignant disease. In dealing with patients who are found to have fragile sites, other than FRAXA, FRAXE and possibly FRA11B, considerable reassurance can be given that they are not at increased risk of having children with congenital disease or developing disease themselves because of their fragile sites.     

Novel aphidicolin-inducible common fragile site FRA9G maps to 9p22.2, within the C9orf39 gene

Common fragile sites represent a component of normal chromosome structure that form gaps and breaks on metaphase chromosomes after partial inhibition of DNA synthesis. In humans, cytogenetic locations of 89 common fragile sites are listed in the Genome Database; however, the exact number of fragile sites remains unknown. The application of high resolution mapping approaches continues to reveal new common fragile sites in the human genome. Here, we identified a novel aphidicolin-inducible common fragile site FRA9G, which maps to chromosomal band 9p22.2. We have characterized the structure of the fragile DNA sequence that extends over a genomic region of approximately 300 kb within the C9orf39 (chromosome 9 open reading frame 39) gene. Analysis of incidence in healthy individuals showed that FRA9G is commonly expressed in the population. Heterozygous BRCA2 mutation carriers exhibit an almost sevenfold increase of FRA9G expression compared to an unrelated control population group. Identification of a novel aphidicolin-inducible common fragile site at 9p22 may have implications for understanding the mechanism of genetic instability in tumorigenesis and other genetic disorders.     

Chromosome instability in lymphocytes from two patients affected by three sequential primary cancers: the role of fragile sites

The chromosomal aberration rate and the expression of fragile sites induced by aphidicolin were evaluated in metaphase chromosomes obtained from peripheral blood lymphocytes of two untreated patients with multiple primary cancers. Spontaneous aberrations of chromosome number and structure and chromosome fragility were compared with controls with the use of the same methods. Chromosomal aberration rates and expression frequencies of fragile sites were significantly higher in the patients than in normal control subjects. In the patients, all but one structural chromosome aberration involved at least one fragile site. Our results suggest that fragile sites may be unstable regions of the human genome, which might play an important role in the genetic instability associated with cancer predisposition.     

Common fragile sites in couples with recurrent spontaneous abortions

Recently, increased spontaneous chromosome instability was reported in couples with recurrent spontaneous abortions but without constitutional chromosome aberrations. Therefore, we investigated the frequency and distribution of aphidicolin-induced common fragile sites in couples with recurrent spontaneous abortions and no children and in age-related control couples. The breakage rate was significantly elevated in the abortion-prone couples; the women in the abortion couples had an especially higher breakage rate than the control women. Breakpoints cluster to those chromosome regions where common fragile sites have been localized. No preference of a particular common fragile site was demonstrated in the abortion couples. Our findings appear to support the hypothesis of increased chromosome instability in at least some couples with recurrent spontaneous abortions. As long as the nature of aphidicolin-induced common fragile sites is not completely understood, the significance of these findings remains unclear.     

Specific extra chromosomes occur in a modal number dependent pattern in pediatric acute lymphoblastic leukemia

Children with acute lymphoblastic leukemia (ALL) and high hyperdiploidy (>50 chromosomes) are considered to have a relatively good prognosis. The specific extra chromosomes are not random; extra copies of some chromosomes occur more frequently than those of others. We examined the extra chromosomes present in high hyperdiploid ALL to determine if there were a relation of the specific extra chromosomes and modal number (MN) and if the extra chromosomes present could differentiate high hyperdiploid from near-triploid and near-tetraploid cases. Karyotypes of 2,339 children with ALL and high hyperdiploidy at diagnosis showed a distinct nonrandom sequential pattern of gain for each chromosome as MN increased, with four groups of gain: chromosomes 21, X, 14, 6, 18, 4, 17, and 10 at MN 51-54; chromosomes 8, 5, 11, and 12 at MN 57-60; chromosomes 2, 3, 9,16, and 22 at MN 63-67; chromosomes 1, 7 13, 15, 19, and 20 at MN 68-79, and Y only at MN >or=80. Chromosomes gained at lower MN were retained as the MN increased. High hyperdiploid pediatric ALL results from a single abnormal mitotic division. Our results suggest that the abnormal mitosis involves specific chromosomes dependent on the number of chromosomes aberrantly distributed, raising provocative questions regarding the mitotic mechanism. The patterns of frequencies of tetrasomy of specific chromosomes differs from that of trisomies with the exception of chromosome 21, which is tetrasomic in a high frequency of cases at all MN. These results are consistent with different origins of high hyperdiploidy, near-trisomy, and near-tetrasomy.     

An integrated mBAND and submegabase resolution tiling set (SMRT) CGH array analysis of focal amplification, microdeletions, and ladder structures consistent with breakage-fusion-bridge cycle events in osteosarcoma

Osteosarcoma (OS) is characterized by chromosomal instability and high-copy-number gene amplification. The breakage-fusion-bridge (BFB) cycle is a well-established mechanism of genomic instability in tumors and in vitro models used to study the origins of complex chromosomal rearrangements and cancer genome amplification. However, until now, there have been no high-resolution cytogenetic or genomic array studies of BFB events in OS. In the present study, multicolor banding (mBAND) FISH and submegabase resolution tiling set (SMRT) array comparative genomic hybridization (CGH) were used to identify and map genomic signatures of BFB events in four OS cell lines and one patient tumor. The expected intermediates associated with BFB-dicentric chromosomes, inverted duplications, and intra- and interchromosomal amplifications-were identified. mBAND analysis provided detailed mapping of rearrangements in 1p, 6p, and 8q and showed that translocation junctions were often in close proximity to fragile sites. More detailed mBAND studies of OS cell line MG-63 revealed ladderlike FISH signals of equally spaced interchromosomal coamplifications of 6p21, 8q24, and 9p21-p22 in a homogeneously staining region (hsr). Focal amplifications that concordantly mapped to the hsr were localized to discrete genomic intervals by SMRT array CGH. The complex amplicon structure in this hsr suggests focal amplifications immediately adjacent to microdeletions. Moreover, the genomic regions in which there was deletion/amplification had a preponderance of fragile sites. In summary, this study has provided further support for the role of the BFB mechanism and fragile sites in facilitating gene amplification and chromosomal rearrangement in OS.     

The expression frequency of common fragile sites and genetic predisposition to colon cancer

The expression frequency of common fragile sites induced by aphidicolin (Apc), bromodeoxyuridine (BrdU), and caffeine was evaluated on prometaphase chromosomes obtained from the peripheral blood lymphocytes of 32 patients with colon cancer, 30 of their clinically healthy family members and 30 age-matched normal controls. The proportion of damaged cells (P < 0.001), the mean number of chromosomal aberrations and the expression frequencies of fragile sites were significantly higher in the patient and relative groups compared to the control group. Our findings show an increased genetic instability in patients with colon cancer and their first-degree relatives. In addition, common fragile sites can be used as a suitable marker for determining genetic predisposition to cancer.     

Common fragile sites: their prevalence in subjects with constitutional and acquired chromosomal instability

Chromosomal fragile sites that are inducible by methotrexate and aphidicolin are frequent in the human population. To assess the frequency and distribution of these common fragile sites, we performed a cytogenetic survey on lymphocytes from subjects known to be particularly prone to breakage because of constitutional chromosomal instability, the possession of a rare fragile site, or Fanconi anemia. Furthermore, a group of cancer patients was included in this study in view of possible acquired chromosomal instability. Lymphocyte chromosomes from several healthy donors were analyzed under identical conditions. We found that methotrexate- and aphidicolin-induced fragile sites are widespread in the general population, showing a similar breakpoint distribution. Ten fragile sites (3p14, 16q23, 2q32, 6q25, 4p16, 4q31, 14q24, 1p31, 20p12, 7q21) were observed in at least 40% of the individuals among the different groups. Our data point out a significantly increased breakage induced by aphidicolin in lymphocytes from cancer patients and, to a lesser extent, from rare fragile sites carriers. These results suggest that common fragile sites are enhanced in some constitutional and acquired conditions.     

In vivo micronuclei in uncultured T-lymphocytes of male railroad transit workers and referents

In the biomonitoring of human genotoxic effects, micronuclei (MN) usually are scored in phytohaemagglutinin-stimulated cultured lymphocytes. MN also can be examined in uncultured lymphocytes, which facilitates the analysis of genotoxic damage incurred in vivo. Characterization of MN in cultured lymphocytes by fluorescence in situ hybridization (FISH) has shown a clear over-representation of the X and Y chromosomes in the MN of males. However, it is not known if this phenomenon also occurs in vivo. The purpose of the present study was to assess the frequency and composition of MN formed in vivo from immunomagnetically isolated uncultured T-lymphocytes of men. To evaluate the possible effects of genotoxic exposure on in vivo MN, we examined 17 railroad workers occupationally exposed to complex chemical mixtures and 14 referents, all nonsmokers. The results showed similar total frequencies of micronucleated cells among the exposed workers and the referents. When the MN were characterized by FISH, there were no significant differences between the exposed and referents with regards to the frequency of centromere-positive or centromere-negative MN. Centromeric label was observed in 69% of all MN, indicating that most of the MN contained whole chromosomes (or chromatids). 80% of the centromere-positive MN harbored autosomes, 12% Y chromosomes, and 8% X chromosomes. The occurrence of the Y- and X-chromosomes in MN was, respectively, 5.5- and 3.8-times greater than would be expected assuming an equal contribution by all chromosomes. Thus, sex chromosomes appear to be over-represented in lymphocyte MN of men in vivo, confirming previous results obtained in vitro.     

Frequency of the fragile X syndrome in Chinese mentally retarded populations is similar to that in Caucasians.

Fragile X syndrome is recognized as the most common inherited cause of mental retardation in western countries. The prevalence of the fragile X syndrome in Asian populations is uncertain. We report a multi-institutional collaborative study of molecular screening for the fragile X syndrome from 1,127 Chinese mentally retarded (MR) individuals. We found that 2.8% of the Chinese MR population screened by DNA analysis had the fragile X full mutation. Our screening indicated that the fragile X syndrome prevalence was very close to that of Caucasian subjects. In addition, we found that 62.5% of fragile X chromosomes had a single haplotype for DXS548-FRAXAC1 (21-18 repeats) which was present in only 9.7% of controls. This unique distribution of microsatellite markers flanking the FMR1 CGG repeats suggests that the fragile X syndrome in Chinese populations, as in the Caucasian, may also be derived from founder chromosomes.