Search

Timely diagnosis of chromosomal aneuploidies plays an important role in determining the proper approach to the management of pregnancy. This article outlines the current ideas on the likelihood of occurrence of obstetric pathology, depending on the number of cells with genetic aberration, especially in the placenta. Such obstetric complications include fetal growth retardation, premature birth, and some forms of preeclampsia. The article describes the prenatal examination techniques, which help obtain timely information about the development of the fetus and predict pregnancy complications, more specifically, non-invasive prenatal DNA screening as a new technique with its advantages and limitations, based on the analysis of DNA of placental origin. It also highlights other latest diagnostic tools that allow to get more accurate information about placental mosaicism and the development of pathology. We have reviewed publications over the past 10 years, which are devoted to the factors responsible for the formation of placental mosaicism, the prenatal diagnostic procedures required for an accurate diagnosis, and the likelihood of obstetric pathology in case of prolonged pregnancy complicated by genetic aberrations. Foreign studies confirm the direct dependence of the likelihood of obstetric pathology on the number of cells with genetic aber ration. In accordance with the above study results, it would be only right to note that placental insufficiency can be observed in any case of genetic aberration, especially if a large volume of cells is involved in the pathological process at an early stage of differentiation. In addition, the article discusses the issue of need of thorough prenatal diagnosis to prevent the development of pregnancy pathology, including the use of the latest technologies and minimizing invasive methods.

Factors determining the phenotype formation in patients with abnormal karyotype (including those with Down’s syndrome) have been discussed for several decades. Earlier, we considered factors affecting phenotype formation in patients with chromosomal aberrations (Grinberg, 1978, 1982; Grinberg, Kukharenko, 1992). We believe that the general concept of the phenotypic manifestation of chromosomal disbalance must take into account the following factors:1. The alteration in the number of chromosomes, in addition to specific effects connected with the dose of the genes located in a particular chromosome is accompanied by a nonspecific effect, which is manifested in the oppression of growth and development of the organism.2. Birth defects observed in persons with chromosomal aberrations are persisting conditions, which are normal at earlier developmental stages. The main effects of chromosomal aberrations are hypomorphic. Nevertheless, these birth defects actually do not differ from developmental defects caused by particular genes and teratogenic environmental factors.3. The phenotypic manifestation of chromosomal imbalance may be based on disturbances of the basic and elementary events in morphogenesis, occurring at the cell level. Such events are proliferation and migration of cells, specific reception, and induction relationships.4. It is supposed that changes of metabolic homeostasis in cells with abnormal karyotypes favor the manifestation of the latent variability of structures that support the basic morphogenetic functions in cells. It is conceivable that chromosomal aberrations strengthen the evolutionarily conditioned variability towards the delay of maturation of cellular and tissue structures, which is the key link in the pathogenesis associated with chromosomal imbalance.

The paper describes a clinical and anatomical case of partial trisomy of the long arm of 17 chromosome in a baby aged 1 month and 4 days with the karyotype 46,XY, dup(17)(q21q24) from a dichorionic diamniotic twin born after in vitro fertilization. Intrahepatic bile duct hyperplasia was first detected in the patient with this chromosomal abnormality. Histological and immunohistochemical examinations of the liver were conducted using antibodies to Ki-67, CK-pan, CK8, CK 18, Vim, SMA, CD31, CD34, HER-2/neu.

It was studied the frequency of cells with cytogenetic abnormalities in the synovial fluid cells of the knee joint in patients of different age groups suffering from chronic arthritis associated with Lyme borreliosis (CAALB) or post-traumatic arthritis (PTA), depending on the polymorphism of the GSTM1 gene of glutathione-S-transferase. The study included 135 residents of the north of the Tomsk and Tyumen regions, 68 of whom suffered from CAALB, and the rest of the 67 patients who made up the control group were diagnosed with PTA. The results of this study have demonstrated that there are significant age-related differences in the frequency of cytogenetic abnormalities of the synovial fluid cells of the knee joint between young and elderly patients of СAALB. The integrative assessment of clinical and cytogenetic parameters in the group of elderly СAALB patients with mutant GSTM1 (0/0) allele, as compared with the other groups, enable to conclude that there are significant positive correlations between the indices of the severity disruption of articular locomotor function and the frequency of synovial fluid cells with trisomy of chromosome 7.

It is known that up to 50% spontaneous abortions (SA) in the first trimester of pregnancy are associated with chromosomal abnormalities. We studied mosaic forms of chromosomal abnormalities in 650 SA specimens using interphase mFISH and DNAprobes for chromosomes 1,9, 13/21, 14/22, 15, 16, 18, X, and Y. Numerical chromosomal abnormalities were discovered in 58.2% (378 cases). They contained combined chromosomal abnormalities (aneuploidy of several chromosomes or aneuploidy in combination with polyploidy in the same specimen) in 7.7% (29 cases) or 4.5% of the entire SA sample; autosomal trisomy, in 45% (18.2% in chromosome 16, 8.9% in chromosomes 14/22, 7.9% in chromosomes 13/21, 3.1% in chromosome 18, and 1.4% in chromosome 9). Chromosome X aneuploidy was found in 27% cases, among which 9.6% represented chromosome X monosomy. Polyploidy was observed in 22.9% cases. In 5.1% cases, we observed mosaic form of autosomal monosomy Among the SA cases with chromosomal abnormalities mosaicism was observed in 50.3% (approximately 25% of the entire SA sample). The results of the present study indicate that significant amount of chromosomal abnormalities in SA cells are associated with disturbances in mitotic chromosome separation, which represents the most common cause of intrauterine fetal death. It was also shown that original collection of DNA probes and the technique of interphase MFISH could be useful for detection of chromosomal mosaicism in prenatal cell specimens.

Analysis of chromosomal abnormalities in bone marrow cells in 116 children with diagnosis of acute myeloid leukemia (AML) was performed. Frequency of evolution of clonal chromosome abnormalities in AML constituted 42,3%. The most abundant among them were numerical abnormalities of chromosomes 8, 9, and 21 as well as secondary structural abnormalities in region 12p12, 9p22, 9q22, 9q34, 11q14-23, and 16q22. Numerical abnormalities were registered in 26,7% cases. The basic mechanism of leukemic clone evolution was trisomy, deletion and monosomy. The frequency of evolution was 7 times higher in the age group up to 2 years and twice higher in the age group up to 5 years. The high frequency of evolution was established at t(15;17)(q22;q22) and the absence at inv(16)(p13q22). The patients with clonal evolution died earlier, before reaching remission, that can be connected with heavy initial state and high frequency of relapse. Conception of abnormality clone evolution was proposed at some stages: I--appearance of balanced rearrangement; II--trisomy; III--lose of chromosomal material. Appearance of unbalanced genome in evolution possess an advantage in proliferate activity and can be connected with the answer on chemotherapy. Identity of abnormal chromosome structure at diagnosis and relapse of disease can be an evidence of the influence of chemical agent on establishment of some types of evolution of chromosome abnormalities in leukemic cells in AML in children.

Aim: To analyse clinical implications of chromosome 8 trisomy in Ph-negative cells of the bone marrow in patients with chronic myeloid leukemia (CML) treated with inhibitors of tyrosinkinases (ITK)., Material and Methods: A total of 386 patients with CML (chronic phase--288, acceleration phase--77) received imatinib (400-800 mg/day). Because of resistance and/or intolerance some patients were switched to ITK II (nilotinib, dasatinib, bozutinib). This study included 8 CML patients (7 in a chronic phase, 1 in acceleration phase) treated with BCR-ABL ITK inhibitors of the first (imatinib) and the second line (ITK-II). The standard cytogenetic examination, on demand--investigation of the interphase nuclei with FISH, in some cases morphological, cytochemical and histological examinations of the bone marrow were made., Results: The existence of a Ph-negative clone with trisomy of chromosome 8 had no negative effect on the course of the disease. The patients showed a stable hematological and cytogenetic response and no need in changing treatment policy. In long-term follow-up Ph-negative clone with trisomy of the chromosome 8 persisted without a clear trend to rise in most patients., Conclusion: Detection of a Ph-negative clone with chromosome 8 trisomy at early stages suggests parallel existence of Ph-positive and Ph-negative clones. None of the patients had myelodisplasia.

The paper presents results of a revision of data of both conventional chromosome testing and a study of cytogenetic (QFQ) markers in families with Down syndrome. Retrospective analysis of 151 families found eight families with a carrier of gonadal mosaicism. In all cases, the mother was younger than 35 years old. Therefore a prevalence of parental mosaicism in young couples was estimated to be 6.5% (8/123). Conventional diagnostic testing, not followed by analysis of segregation of QHQ markers, would have resulted in a prevalence of only 1%. A comparison of the results ofcytogenetic analysis with those expected using molecular polymorphisms suggests that cytogenetic testing cannot be entirely replaced by molecular testing. A combination of both methods should be applied when gonadal mosaicism is suspected.

We present the prenatally identified case of mosaicism of chromosome 16 trisomy. A patient with the pregnancy complicated in the first trimester by the threat of breaking was refered to the high risk group according to the results of the screening program. The ultrasonic research revealed a number of phenotypical pathologies in 19-weeks-old fetus such as congenital heart disease (ventricular septal defect), hyperechoic bowel, single umbilical artery and some other ones. Cytogenetical and FISH analyses of the placental villi revealed karyotype with chromosome 16 trisomy. The further research of amniotic fluid cells revealed the karyotype of fetus as mos47,XX,+16 / 46,XX. The pathologoanatomic research of the abortus has verified the multiple congenital malformations.

Methylation pattern peculiarities revealed by immunocytochemical analysis of metaphase chromosomes from preimplanted human embryos with monoclonal antibodies against 5-methylcytosine are described. Chromosomes of 2-8-cell triploid human embryos are undermethylated, if compared to those from PHA-stimulated fetal cord blood lymphocytes. Hemimethylation (asymmetric labeling of sister chromatids) is typical for the most of embryonic chromosomes at 2-cell--blastocyst stages due most probably to a passive loss of methylation during initial cleavages. Diffuse labeling and sister chromatid exchanges are two other cytogenetic peculiarities revealed by immunofluorescent staining of early human embryos. Hypomethylation of pericentromeric heterochromatin of chromosomes 1, 9, 16 and different methylation status of some homologous chromosomes may distinguish them from metaphase chromosomes of lymphocytes. M-banding pattern typical for chromosomes from adult and cord blood lymphocytes initially appears in embryonic metaphase chromosomes as early as at a 8-cell stage to be established for most part of chromosomes of the karyotype at the morula-blastocyst stage only.

Prometaphase and metaphase chromosome analyses performed on 70 consecutive men with primary infertility (for a period of at least 2 years) revealed 8 (11.42%) men with some kind of chromosomal abnormality. The highest frequency of abnormal karyotypes (10%) was found among patients with azpospennia and the most frequent anomaly was 47, XXY chromosomal constitution, found in 6 (8.57%) patients. All the chromosomal aberrations found in this study was sex chromosomal type and we did not find any autosomal aberration. All patients with numerical chromosomal anomalies had azoospermia. The incidence of structural aberration in our study was 1.42%. Fifteen patients had different chromosomal variants (21.38%). We suggest that men with azoospermia should be considered for cytogenetic investigation and we report that "variants of the Y chromosome" have no influence on the sperm count (million/ml) and fertility of men.

Despite the great efforts contributed to studies on the trisomy 21 etiology, basic mechanisms of nondisjunction are still poorly understood. Even less is known about mosaic variant of trisonomy 21. In this paper, some problems of masaicism are considered: (1) estimation of the prevalence of mosaicism in patients affected with Down syndrome, (2) determination of population rate of parental mosaicism, (3) evaluation of the role of ovarian mosaicism in etiology of Down syndrome, (4) origin of the extra chromosome, (5) mechanisms of production of mosaic lines, (6) phenomenon of skewed sex ratio (female predominance, in fetuses particularly), (7) effect of maternal age.

Comparative genomic hybridization (CGH) technique was used to examine a set of ten spontaneous abortions whose cell cultures were characterized by the lack of proliferation in vitro, and thereby, were not available for the analysis by means of routine cytogenetic methods. Five abortions (50%) had aneuploidy of autosomes, including trisomy 10, 14, 18, and 21, and monosomy 22. The latter variant of unbalanced chromosomal abnormalities is rarely detected in spontaneous abortions by use of conventional cytogenetic methods. The results were validated by using fluorescent in situ hybridization (FISH) analysis with centromere-specific DNA probes. Embryos with trisomy 10 and monosomy 22 displayed mosaicism with the frequencies of abnormal cell clones constituting 68 and 33% respectively. The advantages and limitations of the applying of CGH technique for detection of genomic abnormalities in both nonmosaic and mosaic forms are discussed.

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.

The results of comprehensive clinical examination and molecular cytogenetic analysis of a patient carrying chromosome 3p+ in 69% of the peripheral blood lymphocytes are presented. Using microdissection of the metaphase chromosomes followed by DOP-PCR, a DNA library specific for the abnormal chromosome was obtained. By fluorescence in situ hybridization (FISH) of this DNA library with chromosomes from the patient and a healthy donor, the aberrant chromosome was identified as der(3)t(3;10)(3p25;q24.3). Since this chromosome was present in only a proportion of patient's cells studied and no chromosome aberrations were revealed in cells of his parents, the der(3)t(3;10) is suggested to appear de novo. The cells carrying der(3)t(3;10) are monosomic for a proportion of 3p25 and trisomic for 10q24.3-->qter. The developmental malformations revealed in the patient, such as the specific features of facial skeleton, mental retardation, microcephaly, and others are similar to those described previously in patients with partial 3p monosomy and 10q trisomy.

By means of in situ nick-translation technique, methylation patterns of pericentric heterochromatin of chromosomes 1, 9 and 16 in extraembryonic (chorion) and embryonic cells of 5-8 week old human fetuses with normal karyotype (5), and in one specimen with trisomy for chromosome 16 were studied. Fixed metaphase chromosomes from direct chromosome preparations were digested with either endonuclease Msp I or its isoshizomer Hpa II recognizing and restricting the same sDNA sequence C decreases CGC with Hpa II, but not Msp I sensitive to methylation state of internal cytosin. According to our results, heterochromatin of extraembryonic, but not embryonic cells is hypomethylated. An obvious difference was registered in signal strength between homologous regions in iq12 of both parental chromosomes 1 in early (5-6 week old), but not in more advanced fetuses. Methylation pattern difference was detected in pericentric chromatin of triple copies of chromosome 16 in extraembryonic tissues of the 47,XY, + 16 fetus. These results are in line with a hypothesis of intraheterochromatin location of "early" genes governing initial stages of embryonic development in humans.

Progress in prevention of chromosome aberrations is due to utilization of molecular cytogenetic diagnostic methods. The purpose of this trend of clinical cytogenetics is development and utilization of new highly effective methods for analysis of chromosome aberrations. Molecular cytogenetic methods (fluorescent in situ hybridization-FISH) are used for pre- and postnatal identification of chromosome aberrations in mentally retarded children and congenital diseases. These studies are carried out after classical cytogenetic analysis, if it proves to be of no avail. FISH diagnosis pre- and postnatally detects autosomal trisomy, gonosome aneuploidy (including mosaic forms), marker chromosomes, structural chromosome aberrations, including fragile X chromosome syndrome. Rapid (15-30 min) FISH with an original collection of centromere, telomere, and site-specific DNA probes (plasmid, cosmid, PAC and YAC clones) is recommended for molecular cytogenetic diagnosis. FISH diagnosis is an effective complex of methods for pre- and postnatal identification of chromosome aberrations and a necessary supplement to classical cytogenetic diagnosis. Molecular studies of chromosome aberrations are significant for theoretical and applied studies, for they help detect patients with specific chromosome syndromes from a vast group of children with undifferentiated mental retardation and congenital diseases.

Seven families with translocations t(11; 22) identified at our Institute and analysis of the literature showed that the imbalance resulted from such translocations is always due to nondisjunction 3:1. Nondisjunction occurs more often in the 1st meiotic division, and is more rare in the second one. Expressed prezygotic selection against spermia with an additional chromosome greatly increases the risk of having an imbalanced child for the women-carriers as compared to men-carriers. The phenotype of the patients with +der(22)t(11; 22) is composed of the features characteristic for trisomy 22q (cleft lip and palate, preauricular papillomas and fistulas, rectal atresia or stenosis) and trisomy 11q (long philtrum with the upper lip hanging over, renal al; asia and hypoplasia). Diaphragmatic hernias are found to be common for the patients with +der(22)t(11; 22).

Four cases of cytogenetic prenatal diagnosis of fetuses with chromosomal aberrations are presented: (1) the Patau syndrome; (2) and (4) the Down syndrome; (3) the Klinefelter syndrome. Cordocentesis has been shown to be expedient for rapid and accurate determination of fetus karyotype. Indicative for cytogenetic examination were ultrasonic data, maternal age, the values of AFP, HGG and nonconjugated estreol in maternal serum. Comparison of ultrasonic examination of fetuses with the data on abortus autotopsia was undertaken. The results demonstrate importance of ultrasonic, cytogenetic, biochemical and morphological research in prenatal malformation diagnosis.

The new type of trisomy (2n = 61, XX, +19) was found in the heifer with prognathia inferior syndrome. Correlations between trisomy of different types and phenotypic abnormalities are discussed.

Analysis of the functional nature of mutations can be based on their manifestation in organisms with a deletion or a duplication of a particular chromosome segment. With the use of reciprocal translocation T(16;17)43H it is feasible to produce mice with tertiary trisomy for proximal region of chromosome 17. The mutations on chromosome 17 we tested included brachyury (T), hairpin tail (Thp), kinky (Fuki), quaking (qk), tufted (tf), as well as tct (t-complex tail interaction) and tcl (t complex lethal), that are specific for t haplotypes. The set of dominant and recessive mutations was assigned to two groups, one obligatory manifesting itself in the phenotype independently of the number of normal alleles in di- and trisomics, and the other facultative, phenotypically manifesting itself, depending upon the dosage of mutant alleles. A model was derived from analysis of the interaction of the T and Thp mutations with t haplotypes which is to explain the morphogenetic effects of the mutations observed in mice of different genotypes. The tir gene is postulated to reside on chromosome 17 within its framework. It is suggested that the gene dosage ratio at the tir and tct loci determines tail length.

The hairpin-tail (Thp) deletion in chromosome 17 is lethal when inherited from the mother. Heterozygotes with this deletion, paternal in origin, are viable. The Thp maternal effect is related to a deficiency of Tme gene located in the Thp deleted region. Herein, the viability of mice with tertiary trisomy of chromosome 17Ts(17(16))43H with different doses of the paternal and maternal Tme alleles is analysed. It is demonstrated that the presence of an additional copy of the region with Tme in the female gamete entirely compensates Thp maternal lethality. We failed to compensate the absence of the Tme gene in the chromosome of maternal origin with a double dose of Tme derived from the father. Thus, evidence was obtained indicating that there are sharp differences between the activities of the paternal and maternal alleles of the Tme gene, due to chromosome imprinting.

The properties of the t haplotypes, specific mutant states of the proximal region of chromosome 17 in the house mouse keep renewing interest. One such property is increased transmission of the t haplotype from heterozygous t/+ males to their offspring. By means of reciprocal translocation T (16; 17)43H, we have constructed males with tertiary trisomy 17 (+T43/++/RB7+) carrying Robertsonian translocation Rb(16.17)7Bnr. The offspring of these males was viable when sperm of +T43/++ and Rb7+ was used. The segregation patterns in the offspring of t-bearing trisomics were analysed on days 16-18 of embryonic development. It was found that in the case when the t haplotype is on the normal acrocentric (male male ++T43/+t12+/Rb7++), its presence in the gamete +t12+/++T43 does not produce meiotic drive. However, when t6 is on Rb7, meiotic drive was equal to 80%. It is concluded that the presence of a normal homolog and a t-bearing chromosome in sperm does not result in meiotic drive. Possible mechanisms of meiotic drive of the t haplotypes are discussed.

Changeability of major + arteries and their main branches has been studied in 159 preparations of the upper extremities of fetuses, newborns and children of suckling age with trisomies of 13, 18, and 21 chromosomes, anencephaly in newborns, died at asphyxia or birth injury without any visible developmental defects. Manifestation of anatomical changeability in the human being is under an essential influence of peculiarities of genotypes. In morphogenesis of the upper extremity arteries genes of 13, 18 and 21 chromosomes participate. Trisomies of 13, 18 chromosomes cause more manifested and specific changes in morphogenesis of some structures, and trisomy 21 and mutant genes, producing anencephaly , only increase variability of their structure.

The paper analyses results of pathomorphologic studies of eyes of 28 fetuses and newborns died from multiple malformations due to the Patau (trisomy 13) syndrome. Ocular malformations were recorded in 25 observations (89%). The most frequent and typical ocular malformations in this syndrome were microphthalmia, typical colobomas of the uveal tract, dysplasia of the retina, persistence and hyperplasia of the primary vitreous body, cataract and luxation of the lens.

The activity of five enzymes (AIP, AcP, GOT, LDH, MDH) was investigated in four cell strains derived from spontaneous abortuses with C-trisomy (three cell strains with trisomy 7, one--with trisomy 9). Significant differences in the activity of three enzymes were revealed. In all the strains AIP activity was lower and GOT activity--higher than in diploid strains. Lowering of AcP level was found in three strains (two cell strains with trisomy 7, one--with trisomy 9). The data obtained are evaluated as a result of disturbed regulatory interrelations in an abnormal genome.

Pathogenetic examinations of 96 mentally retarded children with multiple somatic anomalies and developmental defects (but without Down's disease) were carried out. Changes of the caryotype were discovered in 36 children (37.5%). In 21 children (22.0%) there were true autosomal aberrations 1/4 of which were tri- and monosomies, mainly in the form of mosaicism, and 3/4 were non-balanced structural reconstructions of the autosomes. In about 1/3 of the cases the structural anomalies were inherited by the children from their phenotypically healthy parents who had balanced translocations or inversions. In 15 children (15.6%) chromosomal variations were discovered. No differences between the clinical manifestations of the mental retardation in children with true autosomal aberrations and chromosomal variations were noted.

From 866 embryos of mice heterozygous by Roberstsonian translocations 54 ones (6,2%) had trisomy of one of translocated chromosomes. The frequency of trisomy is unique for each translocation, dependent on other chromosomal redistributions in the karyotype and on sex of heterozygous individuals. Trisomy of all the autosomes studied (N 1, 5, 8, 9, 14, 15, 17, 19) results in a characteristic complex of non-specific malformations which includes general delay in development, reduction of the cephalic portion of the nervous tube, cranio-fascial malformations, hypertrophy of the heart cavities. In a number of cases autosomal trisomy (N 15,8) is responsible for certain specific disturbances of morphogenesis. The excess of majority of autosomes (N 5, 8, 9, 15, 16 and 17) causes death of embryos in the period of active organogenesis. Embryos with trisomy of the 1st, 14th and 19th pairs of autosomes in certain cases reach the fetal period but have severe malformations and are non-survival. In mice karyotype there seems to be no autosomes whose trisomy is compatible with postnatal development. Signs of similarity and difference in manifestation of numericle chromosomal aberrations were noted in embryogenesis of mice and man. Principle possibility of modelling chromosomal embryopathy of man in mice with Robertsonian translocations is supposed.

The activity of nonspecific phosphomonoesterases in cerebellar structure of newborns and infants with trisomies in the 13th (5 cases) 18th (4) and 21st (14) chromosomes was investigated. In all trisomies, changes of phosphatase activity in the cerebellar structures were demonstrated which were particularly marked with alkaline phosphatase. The activity of this enzyme increased not only in the vascular endothelium but in a number of cellular structures as well: in the external embryonal and internal granular layers of the cortex, in the nuclei of Purkinje cells and neurons of the nucleus dentatus, in the foci of heterotopia of cortical cells into the white matter and nucleus dentatus. In Edwards' syndrome the activity of alkaline phosphatase in cellular elements of the cerebellum was slightly higher than in the control group. Changes in the activity was observed in the cells of the external embryonal layer, neurons of the nucleus dentatus and in the cells of the heterotopic foci. In autosomal trisomies dystopic cells have dissimilar levels of phosphatase activity and stain mosaically which seems to confirm the assumption of their dissimilar differentiation.

Clinic-cytogenetic analysis of the patient with distal 15q trisomy is presented. Proband's mother and grandmother are carriers of the balanced translocation t (15; 16) (q24; p13). Phenotypically normal proband's mother has a second cell clone with repaired marker chromosome 15 which participates in the balanced translocation of the main cell line. It is supposed possible to repair translocated human chromosomes as a result of mitotic recombination process.

Antisera to diploid, trisomic and triploid embryonic fibroblast-like cells were obtained after hyperimmunization of rabbits. Immunoelectrophoretic analysis with these antisera revealed up to 9 water-soluble antigens in embryonic cells, which were present in skin fibroblasts from adult donors as well. Trisomic and triploid strains did not differ from the diploid ones by the spectrum of water-soluble antigens. The content of the number of antigens (especially of cathode fractions) in trisomic cells was significantly low as compared with those in control diploid cells, whereas in triploid ones it differed slightly. All the strains were characterized by the presence of proteins immunologically identical to alpha-globulin of human serum.

When using heterozygotic carries of reciprocal or Robertsonian translocations and new methods permitting to identify homologous chromosomes in the karyotype, it is possible to obtain mouse embryos with trisomy and monosomy of any of the autosomes. This allows to analyze the effect of excess or deficiency of genetic material concerning definite linkage groups on morphogenetic processes. The cleavage and formation of blastocyst are not controlled by the zygote chromosomes; beginning from the late blastocyst stage in Muridae all or almost all autosomes display the functional activity. At these stages embryos with monosomy are eliminated whereas the embryos with autosome trisomy survive till later stages. No dependence was found between the time of embryonic death and the size of autosome in excess. The importance of data obtained by means of new methods of cytogenetic analysis is discussed.

Male mice heterozygous for double translocations, involving chromosome 17, T(16, 17)43H (reciprocal) and Rb (16, 17)7 Bnr (Robertsonian), as well as mice with partial trisomy for centromeric region of chromosome 17(Ts17(16)T43H) are fertile but demonstrate a high rate of sterile matings. On the 3rd day of gestation in the progeny of males heterozygous for double translocations chromosomal aberrations were shown in 9,5% of all cleaving embryos. The number of blastomeres in embryos with partial trisomy or monosomy of chromosome 17 or 16 corresponds well to that in embryos with normal karyotype. Partial trisomy Ts17(16)T43H does not affect cleavage and early postimplantation development but may cause growth retardation during major organogenesis. Some of these embryos are probably eliminated by the end of gestation or soon after birth. Mice with translocation T43H are useful tools for studying the action of different parts of chromosome 17 at different stages of ontogenesis.

A review of recent studies on mammalian embryos, mostly mice, with chromosomal aberrations. Morphological, biochemical and cytological studies on mice with polyploidy, aneuploidy and some structural aberrations are discussed. Some types of chromosomal aberrations, especially monosomy for individual chromosomes (2, 5, 7, or 17), are already evident during early cleavage and are inevitably lethal by the morula stage. A direct relationship exists between the duration of survival and chromosome aberrations (trisomy and monosomy) for every chromosome. Differential gene activity of the mouse autosomes becomes evident already at the very early developmental stages. Some feasible causes of the early death of embryos with autosomal monosomy are discussed and a hypothetical mechanism for the activation of homologous autosomes at the early developmental stages is proposed. Perspectives of future studies in cytogenetics of mammalian development are outlined.

Rare mosaicism of chromosome No 18 is described. The proposita is 5.5 years old and has two cell clones: 50% of cells are monosomic for 18p and 50% have isochromosome i18q. The ratio of these clones (1:1) is found to be similar at the age of the proposita 2.5 and 5.5 years. The proposita has some phenotypic characters of both 18p- (ptosis, epicanthus, deformed carious teeth, falled back sternum etc.) and trisomy 18q (contraction of external auditory meatus, femur luxatus congenitus etc.) syndromes. A possible mechanism for the origin of such a mosaicism is discussed.

Spontaneous leucosis was cytogenetically studied in subsequent generations (from 1 to 150) of AKR mice. By means of the differential staining technique of chromosomes, large variations in chromosome numbers were found in the karyotypes of leucotic cells of different generations, and the formation of cell clones containing different marker chromosomes as well as the dominance of a hyperdiploid clone with 41-42 chromosomes was revealed. Chromosome analysis of such hyperdiploid cells of the 150th generation has indicated that the supernumerary chromosomes (in 88.0% of cases examined) belong to the smallest chromosomes of the mouse karyogramm (to the 18-19th chromosome pairs or to chromosomes smaller than those of 19th pair). Similar trisomy was also observed in hypodiploid and pseudodiploid leucosis cells. It is suggested that the cell clone with trisomy for the smallest chromosomes is specific to the spontaneous lympholeucosis in AKR mice as well as to the leucosis transplanted to isogenic mice for a number of subsequent generations. Increased rate of hyperdiploid cells was associated with a generalization of leucosis. It was concluded that the development rate and the severity of transplanted lympholeucosis in AKR mice was determined by the domination of the cell clone with trisomy for the 18-19th chromosome pairs in the population of leucotic cells.

Ontogenetic changes of normal diploid cells and cells with chromosomal aberration (strain LHC-162; 47, XY, +7) were studied in prolonged cultivation in stationary phase. Cultivated cells were human found to possess their specific type of ontogenetic changes for each culture; the dynamics of these changes depended on the density of cellular population. Two morphologically different cellular subpopulations differing by the degree of cell nucleus heterochromatinization (normal strains) and three different cellular subpopulations in the aberrant strain (47, XY, +7) were discovered in studying the cell nucleus.

Morphology of the immune system organs was studied in 13 babies with autosomal trisomies (Down's, Edwards', and Patau's syndromes) dying in the perinatal period and having no morphological signs of infectious diseases. The control group included 5 babies without congenital malformations and 12 babies with unclassified multiple malformations. Hypoplasia of the lymphoid tissue was demonstrated in autosomal trisomies (the relative weight of the thymus decreased 2-fold; the spleen, lymph nodes and the intestinal tract deficient in lymphocytes). In Down's disease hypoplasia was most marked; besides, a 3-fold increase in the average area of Hassall's bodies as compared with that in Patau's and Edwards' syndromes and in the controls was observed. Babies with congenital malformations of non-chromosomal origin had no significant differences in the condition of the immune system organs as compared with babies without malformations which indicates the influence of chromosomal pathology on the formation of the immune system in the intrauterine period.

According to the cytogenetic studies chromosome anomalies frequency in 209 children who died in the perinatal period was 7.2 per cent. These cases were found to consist of 8 autosome trisomies, 5 anomalies in sex chromosome system, 1 case of triploidy and 1 case of structural reorganization. Accounting for the elimination of chromosome anomalies during the early periods of fetus development, the frequency of chromosome lethals was shown to be 6.44 X 10(-2) in registered pregnancies and 54.89 X 10-2 in conceptions.

The embryos with trisomy for chromosome 19 were obtained in the crosses of mice heterozygous by two different Robertsonian translocations. The development of these embryos was markedly delayed, in some of them abnormalities of the cranial region of nervous tube and the eyes were observed. The rate of 3H-uridine incorporation into 28S and 18S rRNA in the trisomic embryos both in the in vivo and in vitro experiments was decreased in 1.3-1.4 times, on the average, as compared with th control embryos. The concentration of cytoplasmic RNA in the tissue of trisomic embryos suffered no significant changes. The absence of active nucleolus-forming regions in chromosome 19 upon translocation Rb(5; 19)1Wh and the preservation of nucleolus-forming function of chromosome 19 involved in the centric fusion RB(9;19)163H were demonstrated by means of specific staining with silver nitrate. Possible causes of developmental delay of the trisomic embryos and of absence of the dose effect of ribosomal genes in them are discussed.

On the basis of data on antropological and psychological investigation of 30 XXY males, 30 X0 females and 10 XXX females comparative characteristics of phenotypes of patients are given. The persons with X monosomy (the absence X- or Y-chromosomes) are observed to have decreased total sizes of body, to retain the ability to compensate congenital mental defects, to use standard methods of the adaptation to social environment and to assimilate standard norms of social behaviour. The persons with trisomies XXY and XXX (the presence of the additional heterochromatic X-chromosome) have the tendency to an increase of the longitudinal body sizes independently on sex; they have a delayed development of mental functions and reduced possibilities to compensation of these functions; they also have different degrees of disorganization of the social behaviour and the disadaptation to social environment. It is found that the patients with numerical anomalies of human X-chromosome (both the lack and the excess of chromosome material) have a disturbance of development of the sex dimorphism and sex dipsychism.