Origin of trisomies in human spontaneous abortions

Summary Chromosome heteromorphisms of 34 trisomic abortuses and their parents were compared to determine the origin of the extra chromosome. Fourteen of the trisomies were maternal in origin, ten resulting from a first-meiotic-division error and four from either first- or second-meiotic-division errors. No paternally derived trisomy was identified.     

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.     

Cytogenetic studies in spontaneous abortuses

Summary In a series of 450 products of conception received for cytogenetic analysis, tissue culture was attempted on 309, and karyotypes were established using banding techniques in 154 singleton specimens. Abnormalities of karyotype were identified in 19%; of these abnormalities, 48% were autosomal trisomies. Gestational age was decreased in the abnormal specimens, and their developmental age was retarded by comparison with their gestational age. Factors contributing to the relatively low incidence of abnormality are examined. The major factor appears to be the clinical interest of collaborating staff, leading to selection, either intentional or unintentional, of particular phenotypes and hence a non-random series. A negative relationship is suggested between frequency of monsomy X and autosomal trisomy, both being associated with maternal age.     

Mosaic trisomies in human spontaneous abortions

Summary Data from a cytogenetic survey of spontaneous abortions were examined to determine the incidence and origin of mosaic trisomies in this population. The overall frequency of mosaicism among trisomies was approximately 5%, but the level of mosaicism varied significantly among trisomies, being much higher for the nonacrocentric than for the acrocentric trisomies. Evidence from chromosome heteromorphism analysis suggests that the extra chromosome in mosaic trisomies usually has a meiotic origin.This work was supported by Grant HD 07879 and Fellowship HD 05576 from the National Institutes of Health     

Anatomic and chromosomal anomalies in 639 spontaneous abortuses

Summary A total of 639 spontaneous abortuses collected in a maternity hospital were set up in culture. This sample included 565 unselected consecutive abortuses and 74 selected abortuses ascertained by morphology and/or clinical history. Among these, 339 were incomplete specimens with no recovered embryo or fetus, 110 were anatomically apparently normal and 190 were grossly abnormal. In the unselected series, 565 specimens were cultured and 402 were karyotyped; 215 (53.5%) were chromosomally abnormal. In the selected series, 74 specimens were set up in culture and 45 were karyotyped; 26 (57.7%) had an abnormal karyotype. In all, successful karyotyping was done on 447 abortuses (70%), of which 339 were studied with banding. One or more major chromosome abnormalities were detected in 241 (54%) of the karyotyped cases, 230 of which were numerical anomalies and 11 structural anomalies. Numerical anomalies included primary autosomal trisomies (31% of the total karyotyped), 45,X (10%), triploidy (6.5%), and tetraploidy (1.8%). Of the 22 types of autosomal trisomies possible, all except those for 1, 5, 17, and 19 were identified. An abortus with a 49,XX,+2,+5,+8 karyotype was detected. The excess autosomal material present in the triple trisomic abortus corresponded to 10% of the haploid autosomal complement. Of the 11 abortuses with structural abnormalities, seven were inherited while the other four were sporadic. The survival rate of 45,X conceptuses was estimated to be one in 300.     

Three cases with enlarged acrocentric p-arms and two cases with cryptic partial trisomies.

In three cases, banding analysis revealed a normal karyotype except for an enlarged short arm of one chromosome 13 or 15. To clarify whether this enlargement was due to a heteromorphism or to a cryptic chromosomal trisomy, so-called cenM-FISH probe sets containing a microdissection-derived probe specific for the acrocentric human p-arms were applied. The results enabled us to confirm in one case and to exclude in two cases that the enlargement on the suspect chromosome was due to a p-arm polymorphism. M-FISH and/or microdissection were used to resolve the nature of the rearrangements, i.e., partial trisomies 6 and 19.     

Congenital defect rates among spontaneous abortuses: twenty years of monitoring

A 20-year study of 1,124 spontaneously aborted embryos and fetuses found 214 (19.0%) to have a localized defect or identifiable syndrome. No clear trend of change over time was noted. The rate is compared with other studies of spontaneously aborted specimens and is approximately ten times higher than in newborns. Forty (3.6%) had neural tube defects and 30 (2.7%) had a clinically recognized chromosomal phenotype. Fifteen had Turner's phenotype, four trisomy 18, and 11 triploidy. Amniotic bands occurred in eight. Two had bilateral renal agenesis. Thirty had some form of facial cleft.     

Comparative analysis of chromosomal nucleolar organizing region activity in spontaneous and medical abortuses]

Comparative analysis of functional activity of silver stained nucleolar-organizing regions (NOR) activity was carried out in human fibroblasts of 70 spontaneous and 50 medical abortuses. The NOR activity was significantly higher in spontaneous abortuses compared with medical ones. This phenomenon which was observed in female, but not in male abortuses, did not depend upon the tissue origin of fibroblasts (embryonic or extraembryonic) and was due to increase of the NOR activity of the all acrocentric chromosomes to the level at which individual differences in the NOR activities among some acrocentrics were smoothed. It has been suggested that the ribosomal genes activity in different sex is likely to be differently involved in polygenic systems determining vitally important features of organism that may lead to different selection intensity in different sex resulted in deviation of the ribosomal gene copy number from the optimum. The possible role of changes in DNA methylation at the genome level in activation of ribosomal genes in spontaneous abortuses is discussed.     

Karyotypes of spontaneous human abortuses and several aspects of their phenotypic presentation]

In all, 172 human spontaneous abortuses were examined: 75 cases from the 1st trimester of pregnancy (all were karyotyped), and 97 ones--from 2nd and 3rd trimesters (59 cases were karyotyped). 31 cases of chromosomal anomalies were revealed. The incidence of chromosomal anomalies among the 1st and 2--3rd trimesters of spontaneous abortuses was 40.0+/-7.5 and 1.0+1.0%, resp. The general incidence of chromosomal anomalies among this series of spontaneous abortuses was equal to 18.0+/-2.9%. The question of phenotypical manifestations of chromosomal aberrations in spontaneous abortuses is discussed. The influence of gene structure of aberrant chromosomes on phenotypes of abortuses is supposed.     

The absence of uniparental X-chromosome inheritance in spontaneous abortuses with a 46,XX karyotype

The problem of the presence of imprinted regions on the X-chromosome and the possible influence of the imprinted expression of X-linked genes on the embryonic development in man remains largely unsolved. A comparison of the uniparental inheritance of chromosomes or of their regions having different phenotypic manifestations provides an instrument with which to study the phenomenon of genomic imprinting at the chromosomal level. Assuming that the imprinted inactivation of X-chromosomes is functionally significant for embryonic development, we have studied several polymorphic micro- and minisatellite loci of X-chromosomes in 52 fetuses with karyotype 46,XX, which were spontaneously aborted during the first trimester of pregnancy. The purpose was to determine the contribution of uniparental disomy for the X-chromosome in any disturbances of the embryonic development. We found that inheritance of X-chromosomes was biparental in the studied embryos, suggesting the absence of any significant contribution of the parental origin of the X-chromosome to embryonic mortality occurring between 4 and 12 weeks of development.     

Collagen and fibronectin synthesis by trisomic and triploid fibroblasts from human spontaneous abortuses

Summary Collagen and fibronectin synthesis by trisomic and triploid fibroblasts derived from human spontaneous abortuses was studied. It was demonstrated that the level of fibronectin and collagen production in fibroblasts with trisomy 7, trisomy 9, and triploidy was reduced as compared with diploid cells. A correlation between this observation and an increased rate of intracellular ¹⁴C-procollagen degradation was also established for the anomalous strains. No difference in hydroxylation of ¹⁴C-proline residues in 1() and 2() collagen chains and no fluctuation in the collagen type (): type ratio was found in the strains with the abnormal karyotypes. It was concluded that differentiation of the abnormal fibroblasts was impaired. The data also favour the hypothesis that the deficiency of the fibroblasts in producing proteins may account for a variety of anatomic abnormalities of embryos.     

Congenital heart disease among spontaneous abortuses and stillborn fetuses: prevalence and associations

The prevalence, range, and associations of congenital heart disease (CHD) were studied among 400 spontaneous abortuses between 9 and 40 weeks' gestation. Fifty-two (13.0%) cases of CHD were detected. To minimize selection bias the specimens were grouped by external appearance and the prevalence expressed accordingly. CHD was detected in 21 (7.3%) of 289 externally normal and 31 (27.9%) of 111 externally abnormal fetuses. Ventricular septal defect (VSD) was the most frequent CHD found in isolation as well as in combination with extracardiac malformations. Seventy-five percent of isolated CHD was VSD. Forty (69.2%) of the 52 cases of CHD were associated with extracardiac malformations. Chromosomal syndromes were responsible for a minimum of 19.2% of the cases and suspected in up to 36.5%. The most frequent associations involved the musculoskeletal system, central nervous system, abdominal wall, and kidneys. In contrast, studies of liveborn infants have reported 70% of CHD as isolated defects, including many CHD infrequently seen among spontaneous abortuses. This suggests that fetuses with isolated CHD often survive to term, and CHD does not significantly affect the survival of the fetus in utero. Ventricular septum formation may be particularly susceptible to hemodynamic changes and may be indicative of an underlying pathologic condition that also leads to a spontaneous abortion.     

rDNA and acrocentric chromosomes in man

Summary A malformed female infant was found to have a 46,XX complement with a chromosome 8 shorter than normal with a secondary constriction and satellites on the short arm. Chromosome studies on the clinically normal father showed a balanced translocation between chromosome 8 and 13, i.e., 46,XY,t(8;13) (p21 p12). The proposita, carrier of the unbalanced form of the translocation, resulted partially monosomic for short arm of chromosome 8 (8p-) and partially trisomic for short arm of chromosome 13.The levels of DNA complementary to rRNA (normal in the father who had 10 NOR and increased in the proposita who had 11 NOR) confirmed our interpretation of the rearrangement.     

Anatomic and chromosomal anomalies in 944 induced abortuses

Summary A total of 944 induced abortuses, 922 of which apparently were anatomically normal and 22 of which were anatomically abnormal, were set up in culture. Of these abortuses, 910 (96.4%) were successfully karyotyped. The study can be divided into two periods. In the initial period, specimens without recovered fetal tissues were excluded, and no chromosome anomalies were found among the 182 abortuses karyotyped. In the later period of sutdy, abortion specimens both with and without recovered fetal tissues were included, and 23 chromosomally abnormal abortuses, 9 of which were without recovered fetal tissues, were found among the 728 abortuses karyotyped. This gives a chromosome abnormality rate of 3.2%. The mean ovulation age for the 728 abortuses was 63.4 days (range 33–109 days). The mean maternal age was 28.4 years (range 15–48 years). The chromosomally abnormal abortuses included 13 (10 nonmosaic and 3 mosaic) trisomics, 7 triploids, 2 abortuses with balanced D/D translocations and an abortus with an XXq- karyotype. Among the 616 abortuses in which both amniotic and fetal tissues were karyotyped, there was complete karyotypic agreement between the two tissues. Among the 339 abortuses in which tissue samples from both sides of the body were analyzed, complete agreement was also found. Factors that may influence the prevalence of abnormal karyotypes in induced abortuses are discussed.