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Chromosomal mosaicism during prenatal diagnosis has been a major concern. Nondisjunctional events can lead to mosaicism in a number of ways, including failure of chromosomal pairing, failure to separate, anaphase lag and abnormal segregation. We provide a concise review on various types of mosaicism with their clinical significance.
Genetic defects of the zygote, such as chromosome aberrations, are the most frequent causes of abnormal embryonic development and spontaneous abortion. However, the underlying mechanisms remain unknown. Chromosome aberrations likely cause changes in placental morphology and function (such as size, shape, vascularity, and the presence of trophoblastic inclusion). We postulated that chromosome aberrations may affect rates of cell proliferation or programmed cell death (apoptosis) during the differentiation of chorionic villi. To address these questions, we evaluated cell proliferation using a monoclonal antibody to Ki-67 (a cell-cycle marker) and apoptosis using the in situ end-labeling method (TUNEL) on paraffin-embedded placental tissues. Tissues were obtained from spontaneous abortions in early gestational periods with normal (11 cases) and abnormal karyotypes (15 cases), as well as eight normal control placentas from elective abortions. Apoptotic cells were found in the stroma of all cases, but were significantly higher in number in the stroma of chromosomally abnormal versus chromosomally normal spontaneous abortions. The apoptotic index of the trophoblasts was not significantly different between groups. Cell proliferation was higher in muscularized blood vessels in chromosomally normal placentas (both elective and spontaneous abortions) versus chromosomally abnormal spontaneous abortions. Cell proliferation was different in the trophoblast and stroma between the groups but to a lesser degree than in blood vessels. The morphological and biological data presented here suggest that: (1) chromosomally abnormal spontaneous abortions may occur because of different mechanisms than chromosomally normal spontaneous abortions, (2) apoptosis of the stromal cells and cell proliferation in blood vessels and stroma play an important role in the differentiation and functioning of villi, and (3) these changes could explain the etiology of spontaneous abortion and growth retardation of chromosomally abnormal embryos.
OBJECTIVE: To evaluate the gestational outcome of pregnancies screen-positive for both neural tube defects (NTD) and Down syndrome (DS) ('dual positivity'). METHODS: Among 10,667 mid-trimester women screened for DS and NTD with alpha-fetoprotein (AFP), unconjugated estriol (uE3), and human chorionic gonadotropin (hCG), delivered up to July 1996, we have selected cases with both an unexplained AFP value > or = 2.5 multiples of median (MoM) and a DS risk > or = 1:250. All these pregnant women were managed with amniocentesis and/or CVS, ultrasound scans, and Doppler velocimetry. We have collected all data about the gestations with 'dual positivity' and no obvious explanation for these findings (cases with fetal malformations related to raised AFP). RESULTS: Twelve women (1.1:1,000) showed unexplained 'dual positivity'. Abnormal karyotypes were found in 3 fetuses, and pregnancies were terminated: there were 2 triploidies with partial hydatiform mola, and 1 DS. In 9 cases the fetal karyotype was normal, but a confined placental trisomy 16 was found in 4. Of the 9 continuing gestations, 8 displayed fetal growth retardation (FGR). One gestation ended with fetal death at 27 weeks. All 9 fetuses were morphologically normal, and 8 were small for gestational age. CONCLUSIONS: 'Dual positivity' at NTD/DS screening may anticipate pregnancy complications. The finding of trisomy 16 confined to the placenta and FGR in 4 cases suggests that at least some fetuses with growth restriction may suffer from a distinct placental disease. Maternal serum screening may have implications different from DS and NTD, as demonstrated by the 2 cases with triploidy and incomplete hydatiform mola, the 4 cases with placental trisomy 16, and the 4 cases of FGR of the 5 fetuses without chromosome abnormalities. As the pathologic outcome of these pregnancies is more important than the mere serum screening results, we feel that these cases need a strict work-up, including CVS, amniocentesis and ultrasound studies to better address the obstetrical management.
OBJECTIVE: To describe the ultrasound findings and its relationship with the cytogenetic study and the origin of the extra haploid chromosome set in four 69,XXX cases. METHODS: Four pregnant women were referred because of abnormal 2nd trimester ultrasound. Karytoypes, FISH and DNA analysis were performed. RESULTS: All cases presented asymmetrical intrauterine growth retardation, marked oligohydramnios and placental alterations and showed a 69,XXX karyotype. In three cases, DNA analysis allowed to establish the origin of the extra haploid chromosome set. CONCLUSIONS: At least three fetuses had a maternal extra haploid chromosome set. Thus, it has been possible to establish the main ultrasonographic markers and to observe the survival of the fetus until the second trimester when they have a maternal origin.
We present a case where the embryo showed an increased nuchal edema and a metabolic disorder. At 31 weeks of gestation the fetus developed a cardiomegaly and a hydrops. In this case, a long-chain 3-hydroxacyl-coenzyme A dehydrogenase deficiency (LCHAD deficiency) was confirmed by biochemical investigations in cultured chorionic villus cells and by DNA analysis. This metabolic disease causes a reduced production of mitochondrial trifunctional proteins and is a very rare autosomal-recessive disease.
OBJECTIVE: Investigation of the normal frequency of tetraploid metaphases in semidirect (STC) and cultured (LTC) chorionic villi. METHODS: Fifty metaphases in STC- and in LTC-villi slides of 100 women of advanced maternal age were screened for tetraploidy. RESULTS: Up to three tetraploid metaphases were encountered in 27% of the STC-villi preparations; the scores fitted a Poisson distribution. In all LTC-villi preparations tetraploid cells were seen; the scores fitted a log-Gaussian distribution. CONCLUSIONS: On the basis of these distributions, we propose a protocol for the management of tetraploid metaphases in chorionic villi, strongly reducing the number of prenatal follow-up investigations.
OBJECTIVE: Prenatal paternity testing can be performed following invasive prenatal diagnosis with amniocentesis or CVS. Coelocentesis is a new technique that could be used as an alternative method early in the first trimester of pregnancy. The aim of this study is to investigate the potential use of the DNA extracted from coelomic cells in the prenatal paternity testing. METHODS: Coelocentesis was performed in 20 singleton pregnancies at 7-9 weeks of gestation immediately before surgical termination of pregnancy. Chorionic cells from the placenta and blood cells from the parents were processed by the standard salt extraction method. Two loci, TPO and Apo B, were used for paternity testing in the DNA of coelomic cells, chorionic cells and blood cells. RESULTS: There was concordance in the results obtained from the coelomic cells and chorionic villi. In two cases only the polymorphisms used were not conclusively informative for paternity exclusion. CONCLUSIONS: Coelomic cells are potentially useful for early paternity testing.
In a dizygotic pregnancy within monochorionic placenta, findings consistent with chimerism were detected. Monochorionicity was confirmed by a combination of ultrasound, histological evaluation and DNA technology. Etiologic hypotheses are offered to explain this rare circumstance.
OBJECTIVES: CVS is the earliest procedure for cytogenetic analysis but the quality of metaphases obtained does not allow the characterization of subtle chromosomal anomalies. We report the application interphase fluorescence in situ hybridization for the rapid prenatal diagnosis of a subtle structural chromosome anomaly in trophoblast cells. METHODS AND RESULTS: The foetus was karyotyped because of a paternal complex chromosomal anomaly 46,XY,inv(2)(q14.3q35),ins(10;2)(q25;q36.1q36.1). Fluorescence in situ hybridization analyses were performed on interphase nuclei and metaphase chromosomes from uncultured chorionic villi using bacterial artificial chromosomes specific for the 2q chromosomal region. Direct conventional cytogenetics showed an apparently normal male karyotype, whereas fluorescence in situ hybridization analysis showed a deletion of the chromosomal region 2q36.1 and a paracentric inversion of the chromosome 2q leading to a partial monosomy 2q36.1. CONCLUSION: This strategy allowed us to offer an early and rapid chromosomal analysis for this couple leading to a better management of the pregnancy. This report demonstrates that interphase fluorescence in situ hybridization can be used in direct CVS for a rapid and early prenatal diagnosis of complex chromosomal rearrangements.
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The results of two French collaborative studies are reported with respect to chromosomal and biochemical analyses following the ultrasonographic detection of a fetal anomaly. Overall, chromosomal anomalies were observed in 14.8%, ranging from 8.6% in isolated single malformations to 40.5% in multiple fetal malformations associated with intrauterine growth retardation. Acetylcholinesterase (AChE) electrophoresis was performed on the amniotic fluid of 64 cases of ultrasonographically diagnosed isolated hydrocephalus. 8 cases of previously unsuspected open neural tube defects were diagnosed by AChE. Digestive microvillar enzyme assays were useful in the precise diagnosis of suspected gastrointestinal anomaly. The correlation of the results of ultrasonography and chromosomal and biochemical analyses is the basis for the diagnosis and the prognosis of pregnancy.
The cystic fibrosis transmembrane regulator gene, one of the most commonly mutated in the European population, was cloned in 1989 and since then has been extensively analysed in patients of various ethnic backgrounds. We have screened the entire coding sequences of the cystic fibrosis transmembrane regulator gene and identified many mutations and polymorphisms. In this paper we propose a general strategy to improve prenatal diagnosis and genetic counselling of cystic fibrosis (CF). As this approach based on denaturing gradient gel electrophoresis is adaptable to different populations, it greatly increases the sensibility and specificity of CF prenatal diagnosis.
Despite the rapid advancement and increasing utilization of prenatal diagnostic technologies, there has been a paucity of investigation into the psychological, socioeconomic, and demographic features associated with the choices women make about both the uptake of services, and the actions taken after fetal abnormalities are discovered. From 1986 through 1991 we have completed four studies initiating a proposed comprehensive evaluation of these factors. The first two studies concentrated on patient features influencing uptake of prenatal diagnostic procedures in both a priori 'high risk' pregnancies (advanced maternal age) as well as in previously 'low risk' pregnancies which had become 'high risk' by virtue of abnormal maternal alpha-fetoprotein (MSAFP) screening. The second two studies evaluated features influencing abortion decisions after the discovery of either chromosomal anomalies, or non-aneuploid ultrasonographically detected structural abnormalities. Data suggested that (1) older and more highly educated women tended to choose CVS over amniocentesis; (2) perceptions of genetic risk within couples was most influenced by attributes of their partners; (3) anxiety and perception of risk was higher in young women having abnormal screening MSAFP, than in the advanced maternal age group although this difference appeared to be commensurate with actual risks; (4) for fetal aneuploidy, the specific karyotype and, to a lesser extent, coexistent structural anomalies are the major determinants of decisions to abort; (5) for euploid fetal structural abnormalities the prognostic severity and potential for beneficial medical intervention (either antenatally or postnatally) as counselled by the physician were the principal determinants influencing abortion decisions. Further study is needed and important questions still to be addressed are discussed.
This article examines access to reproductive genetics services for low-income women and women of color. It explores implications of the use of reproductive technologies; access and barriers to general prenatal care and its impact on accessing reproductive-genetic services; the implications of obtaining reproductive genetic services through public programs and funding, especially as they relate to equal provision of services. The traditional barriers to reproductive-genetics services; the decision-making process involved in genetic counseling when Caucasians dominate the process of counseling people of color; financial/insurance barriers to care for low- and moderate-income clients are also addressed. Recommendations are made to address the problems and inequities.
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A couple asked for prenatal testing, the husband being a retinoblastoma survivor. Family history suggested that the tumor predisposing mutation came from his paternal side. DNA analysis indicated that the foetus had not inherited that mutation. Detection of a regressed retinoblastoma in the husband's mother changed the interpretation of the haplotypes obtained, and it was concluded that the foetus had inherited the mutation. Ultrasonography on the 3rd day of extra-uterine life showed a retinal mass in the newborn's left eye. Two years later, the couple asked for a new prenatal diagnosis. DNA analysis showed that the foetus had inherited the mutant retinoblastoma haplotype from the father. Fundus examination on the 2nd day of extra-uterine life showed a retinal lesion in the newborn's left eye at the posterior pole. This case indicates the necessity of a thorough check on history and an ophthalmological examination of family members.
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