Abnormal skin fibroblast cytogenetics in four dysmorphic patients with normal lymphocyte chromosomes.

Four patients with features suggestive of chromosome disorders but with normal lymphocyte karyotypes were found to have chromosome aberrations in skin fibroblast karyotypes. Although mosaicism for chromosome abnormalities in lymphocyte cultures is common, apparent restriction of mosaicism to one tissue is unusual. We suggest that after examination of lymphocyte karyotypes, certain patients warrant cytogenetic evaluation of a second tissue, usually cultured skin fibroblasts.     

Trisomy 21 Down syndrome

Summary In a series of 374 families with Down syndrome progeny, structural chromosome rearrangements were detected in the parents of six children with regular trisomy. The aberrations were reciprocal translocations and inversions. In all three informative families, the parent who transmitted the extra chromosome was not the one with the structural rearrangement. Among the three non-informative families there was one in which both parents carried different reciprocal translocations. In two other families a chromosome aberration was detected: a triple X mother and a father with a Philadelphia chromosome. Omitting the four parents with possible biased asccrtainment, 0.4% had a chromosome rearrangement. When the parents with constitutional chromosome aberrations and those with mosaicism, described previously, are combined, the frequency of chromosomally abnormal parents lies between 1.9% and 3.2%. When correlated with parental transmission of the extra chromosome, mosaicism rather than structural rearrangements appears to be of ctiologic significance.     

Incidence of major chromosome aberrations in 12,319 newborn infants in Tokyo

Summary In order to ascertain the frequency of chromosome aberrations among newborn infants in Japan, a chromosome survey of a large number of newborn infants is in progress. A consecutive series of 12,319 newborn babies, 6382 male and 5937 female, have been screened for clinical manifestations of autosomal aberrations and for sex chromatin and sex chromosome aberrations. Chromosome studies were carried out on 694 infants with suspected chromosome aberrations. The clinically abnormal infants were screened by conventional staining, and banding techniques have been used in the part of the study performed since 1974. Of the clincally abnormal infants, 25 had abnormal karyotypes, including two males with a 47,XXY complement, one female with a 45,X complement, three male infants with a 47,XYY complement, two with trisomy 13 syndrome, three with trisomy 18 (including one case of mosaicism), eleven with Down's syndrome (including one case of mosaicism), one with B5p partial trisomy, one with cri-du-chat syndrome, and one with Y/D translocation. The overall results are comparable to those of previous population cytogenetic studies only in the autosomal trisomies and sex chromosome abnormalities and in that the observed frequencies were comparable to those found in studies in Caucasians.To whom offprint requests should be sent     

Tissue-specific placental mosaicism for autosomal trisomies in spontaneous human abortuses: mechanisms of formation and phenotypic effects]

The frequencies of autosomal trisomies in extraembryonic human tissues were estimated in the cases of different abnormalities of prenatal development, from the confined placental mosaicism (CPM) with either relatively normal embryogenesis or restricted intrauterine growth to spontaneous abortion. A tissue-specific compartmentalization was found to be characteristic of cell lines with trisomies for individual autosomes. Analysis of various phenotypical effects of chromosomal aberrations associated with mosaicism is necessarily required to understand the mechanisms and factors responsible for tissue chromosomal mosaicism. Based on analysis of the cell karyotype during prenatal diagnosing of chromosome aberrations in tissues of both extraembryonic and embryonic origin, in 1996, Wolstenholme proposed a model of CPM for individual chromosomes. According to the model, the distribution of cell lines with autosomal trisomies between extraembryonic tissues depends on the ratio between meiotic and mitotic mutations early in embryonic development. However, the model cannot be used to study tissue chromosomal mosaicism in spontaneous abortions, because little information is available on cell karyotype in embryonic tissues themselves after intrauterine fetal death. In this work, a model of tissue-specific chromosomal mosaicism was suggested based on the data on cell karyotype determined in extraembryonic tissues alone, which can be helpful in evaluating the contribution of tissue chromosomal differences into the etiology of early intrauterine death. Along with the experimental evidence, comparative analysis of the two models indicated that the meiotic chromosome nondisjunction plays the major role in trisomy formation and the resultant spontaneous arrest of embryonic development. Other factors responsible for tissue-specific distribution of chromosomal aberrations are also discussed. These are differences in cell proliferative activity, as well as changes in compartmentalization and migration of cells with abnormal karyotypes.     

Tissue-Specific Placental Mosaicism for Autosomal Trisomies in Human Spontaneous Abortuses: Mechanisms of Formation and Phenotypical Effects

The frequencies of autosomal trisomies in extraembryonic human tissues were estimated in the cases of different abnormalities of prenatal development, from the confined placental mosaicism (CPM) with either relatively normal embryogenesis or restricted intrauterine growth to spontaneous abortion. A tissue-specific compartmentalization was found to be characteristic of cell lines with trisomies for individual autosomes. Analysis of various phenotypical effects of chromosomal aberrations associated with mosaicism is necessarily required to understand the mechanisms and factors responsible for tissue chromosomal mosaicism. Based on analysis of the cell karyotype during prenatal diagnosing of chromosome aberrations in tissues of both extraembryonic and embryonic origin, in 1996, Wolstenholme proposed a model of CPM for individual chromosomes. According to the model, the distribution of cell lines with autosomal trisomies between extraembryonic tissues depends on the ratio between meiotic and mitotic mutations early in embryonic development. However, the model cannot be used to study tissue chromosomal mosaicism in spontaneous abortions, because little information is available on cell karyotype in embryonic tissues themselves after intrauterine fetal death. In this work, a model of tissue-specific chromosomal mosaicism was suggested based on the data on cell karyotype determined in extraembryonic tissues alone, which can be helpful in evaluating the contribution of tissue chromosomal differences into the etiology of early intrauterine death. Along with the experimental evidence, comparative analysis of the two models indicated that the meiotic chromosome nondisjunction plays the major role in trisomy formation and the resultant spontaneous arrest of embryonic development. Other factors responsible for tissue-specific distribution of chromosomal aberrations are also discussed. These are differences in cell proliferative activity, as well as changes in compartmentalization and migration of cells with abnormal karyotypes.     

DNA reparation parameters during epigenetic effect of the rad201(G1) mutation in Drosophila

Cell estimates of genetic damage repair were obtained to characterize the epigenetic effect of the rad201(G1) mutation. The estimates included morphological defects (malformations); the frequency of chromosome aberrations in somatic cells; and somatic mosaicism, reflecting double-strand break repair via conversion. The range and frequency of malformations significantly differed between the rad201(G1) epigenetic effect and irradiation. A high pupal lethality, detected upon P-element mobilization, was not associated with an increase in the frequency of cells with chromosome aberrations, while somatic mosaicism was far greater. The results are discussed in the context of differences between radiation and P-element mutagenesis.     

Prenatal diagnosis and characteristics of chromosome aberrations in families with genetic risk

Characteristics of the chromosomal aberrations diagnosed in 959 prenatal tests in the II trimester of pregnancy is presented. Chromosomal aberrations were diagnosed in 33 tests (3.4%). Twenty one out of these aberrations (2.2%) were of labile character. Six aberrations resulted from the parental segregation, translocation or chromosomal inversion. In 12 cases fetus inherited stable aberration from one of parents. It amounted to 1.2% of all tested cases. Chromosomal aberrations were diagnosed in 2.7% cases tested due to the risk related to the mother's age. Half of them was trisomy of chromosome 21. Chromosomal aneuploidy in the progeny of families with a child with the same abnormality was diagnosed in 1.6% of cases. Chromosomal mosaicism was diagnosed in 2.2% of cases including 0.2% of cases with true mosaicism and 1.98% of cases with pseudomosaicism. Incidence and type of the diagnosed chromosomal aberrations coincided with foreseen aberrations for each group of the genetic risk.     

Cell estimates of genetic damage repair under the epigenetic effect of the rad201(G1) mutation in Drosophila

Cell estimates of genetic damage repair were obtained to characterize the epigenetic effect of the rad201(G1) mutation. The estimates included morphological defects (malformations); the frequency of chromosome aberrations in somatic cells; and somatic mosaicism, reflecting double-strand break repair via conversion. The range and frequency of malformations significantly differed between the rad201(G1) epigenetic effect and irradiation. A high pupal lethality, detected upon P-element mobilization, was not associated with an increase in the frequency of cells with chromosome aberrations, while somatic mosaicism was far greater. The results are discussed in the context of differences between radiation and P-element mutagenesis.     

Genetic analysis of mitomycin C-induced interchange in Drosophila melanogaster females

A genetic analysis of an array of mitomycin-induced rearrangements in immature Drosophila oocytes is reported. Induced aberrations were recovered representing detachments of the compound-X chromosome, Y chromosome fragments, X chromosome loss and mosaicism. The spectrum of rearrangements induced by mitomycin C was very similar to that induced by X-ray treatment of immature oocytes. This work suggests that mitomycin C has two modes of action. The drug is radiomimetic for it induces the types of aberrations recovered after X-irradiation. Mitomycin C also seems to have a delayed effect which is reflected in the relatively high recovery of mosaics.     

Cytogenetic investigations on Werner's syndrome, Acrogeria and Keratosis Palmo-Plantaris

The frequencies of sister chromatid exchanges and of aspecific chromosome aberrations have been investigated in the lymphocytes from a Werner patient, from an Acrogeria patient and from three members of a family with Keratosis Palmo-Plantaris. These investigations point out that: 1) the SCE frequency is significatively enhanced in Werner as in KPP lymphocytes, 2) the frequency of aspecific chromosome aberrations is increased only in Werner lymphocytes, without evidence of variegated translocation mosaicism. The findings confirm that SCE and chromosome aberrations do not necessarily result from the same genetic damage and that SCE may represent the cytological evidence of unexcised non fatal DNA lesions, which occasionally may be responsible for carcinogenesis.     

Gonosomale Mosaike

With an incidence of approximately 0.2?% in newborns gonosomal chromosome aberrations are of major relevance for clinical genetics. They frequently occur as numerical and/or structural gonosomal mosaicism. The correlation between genotype and phenotype is poor most probably due to different levels of mosaicism in different tissues and they represent a great challenge especially in prenatal diagnostics, requiring genetic counseling by an experienced clinical geneticist. Postnatally, gonosomal mosaicism in females often leads to the clinical symptoms of Turner’s syndrome (especially short stature and infertility) with an potentially increased risk for gonadoblastoma if an XY cell line is present. In males with Klinefelter’s syndrome mosaicism is also frequent (up to 20?%). Mosaicism in 47,XYY and 47,XXX karyotypes is rarely reported perhaps due to the innocuous phenotype seldom being an indication for chromosome analysis.     

The genomically mosaic brain: Aneuploidy and more in neural diversity and disease

Genomically identical cells have long been assumed to comprise the human brain, with post-genomic mechanisms giving rise to its enormous diversity, complexity, and disease susceptibility. However, the identification of neural cells containing somatically generated mosaic aneuploidy – loss and/or gain of chromosomes from a euploid complement – and other genomic variations including LINE1 retrotransposons and regional patterns of DNA content variation (DCV), demonstrate that the brain is genomically heterogeneous. The precise phenotypes and functions produced by genomic mosaicism are not well understood, although the effects of constitutive aberrations, as observed in Down syndrome, implicate roles for defined mosaic genomes relevant to cellular survival, differentiation potential, stem cell biology, and brain organization. Here we discuss genomic mosaicism as a feature of the normal brain as well as a possible factor in the weak or complex genetic linkages observed for many of the most common forms of neurological and psychiatric diseases.     

Formation of uniparental disomy 7 delineated from new cases and a UPD7 case after trisomy 7 rescue. Presentation of own results and review of the literature

Maternal uniparental disomy for the entire chromosome 7 (matUPD7) has been reported several times in Silver-Russell syndrome (SRS) and growth-restricted patients. Here we present our results from the analysis of an abortion with confined placental mosaicism (CPM) for trisomy 7 which showed a maternal meiotic origin of the trisomy in the placenta and rescue to maternal UPD7 in foetal membrane. Furthermore, two newly detected SRS cases with maternal UPD7 revealed isodisomy and partial heterodisomy, respectively. Summarising these results with those published previously on the origin of UPD7, similar numbers of isodisomy (n=11) and cases with complete or partial heterodisomy (n=12) have been reported. In respect to the different formation mechanisms of UPD, complete isodisomy should be the result of a post-zygotic mitotic segregation error, whereas heterodisomic UPDs should be caused by trisomic rescue after meiotic non-disjunction events. In maternal UPD7, 50% of cases seem to be caused by post-zygotic mitotic segregation errors, which is similar to the situation in trisomy 7. This result corresponds to the situation in trisomy 8 but is in contrast to observations in the frequent aneuploidies. Thus, the different findings in these aberrations reflect the presence of multiple factors that act to ensure normal segregation, varying in importance for each chromosome.     

Prenatal diagnosis of chromosome abnormalities

Prenatal diagnosis of chromosome abnormalities can be performed on three different samples; chorion villi (CVS), amniotic fluid (AFS) and fetal blood (FBS). We are presenting data from our own experience on the chromosome analysis of 957 CVS, 1000 AFS and 927 FBS. A total of 69 chromosome abnormalities have been detected in the CVS, 38 in the AFS and 115 in the FBS. The type of abnormalities and their frequencies are compared between the three sampling methods. Our findings are in agreement with published data, and the higher incidence of chromosomal aberrations in the FBS group reflect the greater efficiency with which aneuploidies associated with more severe congenital malformation can be detected by ultrasound.Finally, we reported 18 cases of mosaicism in CVS, 76 in AFS and 31 in FBS. Of these cases, only 10 represented a true mosaicism of the fetus, 98 cases have been classified as pseudomosaicisms and 7 identified as maternal contamination. We have encountered 9 cases of mosaicism confined to the chorionic villi and 1 case limited to the amniotic fluid cells. There appeared to be a similarity between trisomies involved in chorion confined mosaicisms and pseudomosaicism cases of the AFS.The chromosome complement of the placenta may play an important role in the development of the pregnancy, and although a mosaic result in prenatal diagnosis could present difficulties in the prediction of the ffetal karyotype, it might give important information on the general condition of the fetus.     

Trisomy 7, trisomy 10, and loss of the Y chromosome in short-term cultures of normal kidney tissue

Numerical chromosome aberrations are common in several types of malignant tumors. Recently, trisomy 7 and loss of the Y chromosome were described in cultures from nonneoplastic tissue, making the significance of these aberrations as cancer-associated changes doubtful. We herein report the mosaic occurrence of trisomy 7 in four consecutive short-term cultures initiated from normal kidney tissue. Smaller clones with trisomy 10 were present in three cases, and the only culture established from a male also showed mosaic loss of the Y chromosome.     

Chromosome mosaicism in a population sample.

An analysis has been made of mosaicism found in the different types of chromosome abnormalities among the 19000 persons examined at the Cytogenetic Laboratory, Risskov. The percentage with mosaicism was 36 in both triple-X and Turner's syndrome, it was 7 and 11% in XYY and Klinefelter's syndrome, respectively, and 2 in autosomal abnormalities. We found a mosaicism frequency of 11% in population studies with 5 cells analyzed primarily compared with 7% in other studies, in which 10-50 cells were analyzed primarily. (The difference is not significant.) The total frequency of mosaicism was 8%. The first cell with the chromosome aberration establishing the mosaicism was found among the first 5 cells in 40 of the 44 cases with mosaicism, and all but one of the 44 cases would have been established as mosaics, if the guidlines indicated by Bochkov et al. (1974) had been followed; that is 11 cells analyzed primarily, and if one of these cells has a chromosome aberration, the number of cells analyzed is increased to 17; if 2 cells have the same chromosome aberration, the number of cells analyzed is extended to 23, and if 3 cells with the same chromosome aberration is found among these 23 cells, the mosaicism is established. Aneuploid or structural chromosome abnormalities present in all cells may be detected by analysis of 2-3 cells of good quality. Mosaicism with 2 or more cell clones with different chromosome patterns are extremely difficult to detect, if the percentage of cell clones with chromosome aberration is low. The incidence of chromosome abnormalities found in all cells in newborn children in the different studies is very similar as shown in a recent survey of 6 different studies by Jacobs et al. (1974). The incidence of mosaicism varies according to the frequency of artefactual aneuploidy, the variety of tissue studied, number of cells analyzed from each tissue as well as the acuity of the observer and the checking procedures.     

The most frequent chromosomal abnormalities in karyotypes of patients with reproductive problems

Results of cytogenetic and molecular-cytogenetic inspection of 210 matrimonial pairs with the problems of reproduction are presented. Different types of chromosomal aberrations have been detected in the karyotypes of the patients in 46 (10.95%) cases. Such structural chromosomal aberrations as pericentric inversions, Robertsonian translocations, balanced reciprocal translocations, and marker chromosomes as well prevailed the numerical chromosomal aberrations (89.13% and 10.87% cases accordingly). In the general group of the inspected patients there were 19 cases (4.52%) characterized by the low level of X and Y chromosome mosaicism. The authors suppose that the patients with the exposed chromosomal abnormalities need the differentiated approach at their treatment.     

Chromosomal disorders in women with spontaneous abortions

The results of examination of 120 women with spontaneous abortions are presented. The cytogenetic analysis showed that in karyotypes of the patients there are chromosome aberrations of different types: translocations (17.5%), monosomy (13.3%), trisomy (10%), mosaicism (5.8%) and other forms (4.1%). Phenotypic manifestation of chromosome anomalies with spontaneous miscarriages (abortions) is discussed in the work.     

46,XX,der(2)t(2;10)(2pter-->2q37::10p13-->10pter)[127]/45,X,der(2)t(2;10) (2pter-->2q37::10p13-->10pter)[23]. Karyotype-phenotype correlation and genetic counselling in complex karyotypes

We describe a female child with complex cytogenetic anomalies consisting in partial trisomy of the short arm of chromosome 10, terminal deletion of the long arm of chromosome 2 and--at the same time--a mosaicism for X monosomy. To our knowledge, this is the first case reported in which 10p trisomy is associated to a 2qter deletion. Due to the scarcity of cases reported with pure trisomy, it has not been possible to define the 10p+ syndrome precisely yet. Comparison of our proband's phenotype to both the 2q37 deletion and 10p trisomy showed more features described in 2q37- subjects than in 10p+ ones. We also discuss the difficulties of genetic counseling in children with complex aberrations.     

Aberrant meiosis and spindle abnormalities in Paspalum paspaloides (Michx.) Scribn (Gramineae)

Meiotic chromosome behaviour was studied in two collections of Paspalum paspaloides (Michx.) Scribn. In one of these chromosome mosaicism, restitution nuclei, multinucleate microsporocytes and multipolar and divergent spindles were observed. Chromosome mosaicism resulted from abnormal cell cleavage. In microsporocytes exhibiting chromosome mosaicism, the number of univalents per cell decreased as the chromosome number per cell increased. The increase in chromosome number brought it close to the euploid number (2n=60). Chromosome mosaicism never involved any increase above the cuploid number. In the other collection, meiosis was relatively normal.The work has been carried out at the Department of Botany, Gorakhpur University.