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Evidence for High Frequency of Chromosomal Mosaicism in Spontaneous Abortions Revealed by Interphase FISH Analysis

Svetlana G. Vorsanova, Alexei D. Kolotii, Ivan Y. Iourov, Viktor V. Monakhov, Elena A. Kirillova, Ilia V. Soloviev and Yuri B. Yurov

Institute of Pediatrics and Children's Surgery, Russian Ministry of Health, Moscow, Russia (SGV,ADK); National Center of Mental Health, Russian Academy of Medical Sciences, Moscow, Russia (IYI,VVM,IVS,YBY); and Moscow Medical I.M. Sechenov's Academy, Moscow, Russia (EAK)

Correspondence to: Y.B. Yurov, National Center of Mental Health, Russian Academy of Medical Sciences, Zagorodnoe sh.2, 119152, Moscow, Russia. E-mail: y_yurov{at}yahoo.com; i_yurov{at}mail.ru

	Summary

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Numerical chromosomal imbalances are a common feature of spontaneous abortions. However, the incidence of mosaic forms of chromosomal abnormalities has not been evaluated. We have applied interphase multicolor fluorescence in situ hybridization using original DNA probes for chromosomes 1, 9, 13, 14, 15, 16, 18, 21, 22, X, and Y to study chromosomal abnormalities in 148 specimens of spontaneous abortions. We have detected chromosomal abnormalities in 89/148 (60.1%) of specimens. Among them, aneuploidy was detected in 74 samples (83.1%). In the remaining samples, polyploidy was detected. The mosaic forms of chromosome abnormality, including autosomal and sex chromosomal aneuploidies and polyploidy (31 and 12 cases, respectively), were observed in 43/89 (48.3%) of specimens. The most frequent mosaic form of aneuploidy was related to chromosome X (19 cases). The frequency of mosaic forms of chromosomal abnormalities in samples with male chromosomal complement was 50% (16/32 chromosomally abnormal), and in samples with female chromosomal complement, it was 47.4% (27/57 chromosomally abnormal). The present study demonstrates that the postzygotic or mitotic errors leading to chromosomal mosaicism in spontaneous abortions are more frequent than previously suspected. Chromosomal mosaicsm may contribute significantly to both pregnancy complications and spontaneous fetal loss. (J Histochem Cytochem 53:375–380, 2005)

Key Words: mFISH • spontaneous abortions • chromosomal abnormality • chromosomal mosaicism

	Introduction

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FLUORESCENCE IN SITU HYBRIDIZATION (FISH) is a powerful technique for the rapid identification of chromosomal abnormalities (aneuploidy and polyploidy) in human uncultured interphase cells. The main advantage of the technique is the rapidity, inasmuch as a multicolor fluorescence in situ hybridization (mFISH) allows detection of several chromosomes in one nucleus. The study of numerical chromosomal imbalances in spontaneous abortion tissues is of great significance for genetic counseling of couples who have experienced recurrent spontaneous abortions as well as for human reproduction investigations. FISH is considered an appropriate technique for rapid and efficient analysis of chromosome abnormalities in spontaneous abortions (Jobanputra et al. 2002).

Approximately 15% of all clinically recognized pregnancies are spontaneously aborted before 20 weeks of gestation. Chromosomal abnormalities are recognized as one of the main causes of spontaneous abortions. Previous studies have estimated the frequency of chromosomal abnormality in spontaneous abortions as 50–70% (Boue et al. 1975; Ohno et al. 1991; Jobanputra et al. 2002; Stephenson et al. 2002). For such studies, one of the most suitable molecular cytogenetic techniques is mFISH. The most common cause of spontaneous abortions is de novo numerical chromosome abnormalities, such as trisomy of autosomes 13, 14, 15, 16, 21, and 22; sex chromosome aneuploidy, and polyploidy (Jobanputra et al. 2002; Stephenson et al. 2002). Regular forms of chromosomal abnormalities in human fetuses are the result of meiotic errors leading to the appearance of chromosomally abnormal gametes. In contrast, mosaic forms are the result of postmeiotic errors. The frequency of chromosome mosaicism in spontaneous abortions during the prenatal period has not been evaluated, probably because of the absence of criteria for defining a sample as a mosaic. It was demonstrated that postmeiotic errors could lead to a high incidence of mosaic forms of chromosomal abnormalities (aneuploidy, haploidy, and polyploidy) in human preimplantation embryos in vitro (Bielanska et al. 2002). Application of FISH with DNA probes to chromosomes X, Y, 2, 7, 13, 16, 18, 21, and 22 have indicated that 50% of human preimplantation embryos are chromosomal mosaics. If chromosomal mosaicism occurring in the preimplantation stage does not affect implantation, embryos with mild aneuploidy will be candidates for fetal or confined placental mosaicism (Bielanska et al. 2002). However, the incidence of chromosomal mosaicism in spontaneous abortions has not previously been investigated by molecular cytogenetic methods (FISH). This problem is further complicated in the case of low-level chromosomal mosaicism occurring in spontaneous abortions. Therefore, it seems to be of great interest to carry out mFISH analysis in interphase nuclei of spontaneous abortions using a set of DNA probes containing the probes for the chromosomes mentioned above. In the present study, we have applied a set of original DNA probes for chromosomes 1, 9, 13/21, 14/22, 15, 16, 18, X, and Y and mFISH to assess the efficiency of the technique for the investigation of the chromosome complement in spontaneous abortions. Special attention was paid to assessment of chromosome mosaicism occurrence.

	Materials and Methods

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Tissue Preparation
Specimens of spontaneous abortions of the pregnancy period from 3 to 17 weeks (mean value 7 weeks) were obtained from 148 females aged 17 to 44 years (mean age: 28.1). All tissues of spontaneous abortions were grossly examined under a dissecting microscope and freed from maternal deciduae, and the villous tissues were separated. To clean the specimens of the rest of the maternal blood, the samples were washed in hypotonic (NaCl) solution three times. Approximately 3–5 mg of tissue was used for FISH analysis. The samples were then rinsed for 30 sec with 60% acetic acid and placed in a solution of 60% acetic acid for 5–10 min at room temperature and periodically mixed by inversion. Dispersed single-cell suspensions were fixed in methanol-acetic acid (3:1) fixative mixture two times for 30 and 50 min. The cells were dropped onto wet slides and air-dried at room temperature. Three slides with two drops each of cell suspensions were prepared for each sample.

mFISH
The set of original chromosome-specific DNA probes from the collection developed at the Cytogenetics Laboratory, National Center of Mental Health, Moscow, Russia was used in mFISH studies. DNA probes specific to chromosomes 1, 9, 13, and 21; 14 and 22; 15, 16, 18, X, and Y were selected for the study. Technical characteristics of DNA probes and their processing for FISH have been described previously in detail (Vorsanova et al. 1986; Yurov et al. 1987,1996,2002; Soloviev et al. 1995,1998).

Labeled DNA probes were combined in the following order: (a) chromosome Y–specific probe (labeled by Cy3), chromosome X–specific probe (labeled by fluorescein-FluorX), chromosome 1–specific probe (labeled by biotin or AMCA); (b) chromosome 9–specific probe (labeled by biotin) and chromosomes 13/21-specific probe (labeled by Cy3); (c) chromosome 16–specific probe (labeled by biotin) and chromosomes 14/22–specific probe (labeled by Cy3); and (d) chromosome 15–specific probe (labeled by biotin) and chromosome 18–specific probe (labeled by Cy3).

FISH studies were performed as described in detail previously (Soloviev et al. 1994,1995; Yurov et al. 1996). For dual- and three-color hybridization, DNA probes were mixed in equal proportions (3.5–5 µl each probe at a concentration of 5 ng/µl for each probe). Hybridization was usually performed at 42C for 4 hr or overnight. The slides were postwashed in 50% formamide, 2 x SSC at 45C three times for 2 min and rinsed in 0.1–2 x SSC for 5 min. Detection of biotin-labeled probes was performed by the use of one layer of fluorescein isothiocyanate (FITC)-avidin or AMCA-avidin (Vector Laboraties; Burlingame, CA). Slides were mounted in antifade solution (0.2% p-phenylenediamine in 80% glycerol, 20 mM TRIS-HCl, pH 8.0), and 50–100 ng/ml DAPI (4',6-diamidino-2-phenylindole-2HCl).

Microscopy
For epifluorescence microscopy, a Leitz Orthoplan microscope equipped with a 100 W lamp was used with the following filter sets (Leica Mikroskopie und Systeme; Wetzlar, Germany): A (No. 513,596) for DAPI fluorescence; I3 (No. 513,719) or GR (No. 513,821) for FITC signals; GR (No. 513,821) for both fluorescein and cyanine signals; N2 (No. 513,609) for Cy3 signals. All images were observed with the Plan-Neofluotar 63x or 100x oil immersion objectives.

Analysis of FISH Signals
From 300 to 600 nuclei were scored for each sample for each probe. Only intact and undamaged nuclei free of cytoplasm were analyzed. Nuclei with low signal intensities, diffuse signals, or absence of signals on both homolog chromosomes were considered to be hybridization failures and were not scored. Two small focal (or paired) signals of the same color and the same intensity, separated by a distance of less than the area of one signal, were considered to be a split signal from one chromosome. Interphase nuclei with one large signal of the same color and increased intensity of fluorescence with the absence of a second hybridization signal in an interphase nucleus were considered to be overlapping (or over-position) of two signals and were not scored.

The samples were considered normal (disomic) if more than 95% of all nuclei demonstrated two signals for autosomes and the XX or XY signal pattern for sex chromosomes. Informative abnormal samples with regular forms of chromosomal imbalances were defined as those in which more than 95% of the nuclei demonstrated definite abnormal patterns of the signals (monosomy, trisomy, tetrasomy, XXY signal pattern, polyploidy). Informative mosaic samples were defined as those in which more than 5% of the nuclei had a reproducible abnormal pattern of signals (no less than 15–30 abnormal cells per sample with scoring of 300–600 nuclei) different from normal (disomic) autosomal or normal sex chromosomal signals (XX and XY).

	Results

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The application of mFISH and the set of DNA probes for chromosomes 1, 9, 13, 14, 15, 16, 18, 21, 22, X, and Y have allowed the detecting of chromosomal abnormalities in 89/148 (60.1%) of specimens. Examples of mFISH application in the study are shown in Figure 1. Aneuploidy was detected in 74/89 abnormal specimens (83.1%), and in the remainder of the samples, polyploidy was detected. The results of the chromosome complement study in spontaneous abortion specimens are shown in the Table 1. The male-to-female ratio was estimated as 0.78 (65 samples with male chromosome complement and 83 samples with female chromosome complement). Among the male samples, abnormal chromosome complement was found in 32 (49.2%) cases, and among female samples, in 57 (68.7%) cases. It is noteworthy that six cases (9%) had multiple chromosome abnormalities. Interestingly, in all of these cases, chromosome X was involved (Table 2). We have detected 43/89 specimens (48.3%) with chromosomal abnormalities: 31 cases with a mosaic form of aneuploidy and 12 cases of polyploidy. The frequencies of cells with abnormal chromosome complement in cases of mosaic forms of aneuploidy or polyploidy were from 5% to 90%. Interestingly, the frequency of mosaic forms of chromosomal abnormalities in samples with male chromosomal complements was 50% (16/32 chromosomally abnormal), and in samples with female chromosomal complements, 47.4% (27/57 chromosomally abnormal). The most frequent mosaic form of aneuploidy (19 cases) was related to chromosome X (monosomy, trisomy, or disomy with the presence of chromosome Y). Monosomy and trisomy involving autosomes 1, 9, 13 or 21, 14 or 22, 16 and 18 were also detected.

View larger version (38K): [in this window] [in a new window]   Figure 1 Examples of interphase mFISH in samples of spontaneous abortions with mosaic cell clones. (A) Mosaic form of trisomy involving chromosomes 13 or 21 after application of alphoid DNA probes common for chromosomes 13 and 21. Cy3-labeled DNA probe for chromosomes 13/21 shows five red signals in one nucleus (left) and four red signals (right) in the second. Biotin-labeled DNA probe for chromosome 1 demonstrates two green signals in both nuclei. (B) Mosaic form of triploidy (two nuclei with triploidy are shown). Cy3-labeled DNA probe for chromosome 18 shows three red signals in both nuclei. Biotin-labeled DNA probe for chromosome 16 also demonstrates three green signals in both nuclei. (C) Mosaic form of trisomy involving chromosome 1 (one nucleus with trisomy 1 is shown). Cy3-labeled DNA probe for chromosome 18 shows two red signals, and biotin-labeled DNA probe for chromosome 1 demonstrates three green signals. (D) Mosaic form of triploidy (one nucleus is shown). Cy3-labeled DNA probe for chromosome Y shows one red signal, FluorX-labeled DNA probe for chromosome X demonstrates two green signals, and AMCA-labeled probe for chromosome 1 demonstrates three blue signals. (E) Nucleus with XXY pattern of hybridization is shown. Cy3-labeled DNA probe for chromosome Y shows one red signal, FluorX-labeled DNA probe for chromosome X demonstrates two green signals, and AMCA-labeled probe for chromosome 1 demonstrates two blue signals. (F) Mosaic form of tetraploidy (one nucleus is shown). Cy3-labeled DNA probe for chromosome Y shows two red signals, FluorX-labeled DNA probe for chromosome X also demonstrates two green signals, and AMCA-labeled probe for chromosome 1 demonstrates four blue signals.

	Discussion

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A significant challenge in studies of chromosomal mosaicism in material of spontaneous abortions using standard cytogenetic and molecular cytogenetic techniques is the possibility of maternal cell contamination. In fetuses with female chromosome complement, the presence of maternal cells cannot be ruled out. This fact probably explains the prevalence of female fetuses over male fetuses seen during karyotype analysis of spontaneous abortion specimens. Careful sampling of villous tissue can help somewhat in solving this problem. For example, in our study of 150 spontaneous abortion specimens, two had both male and female cells, probably indicating the presence of maternal cell contamination. These samples were excluded from analysis. The male-to-female ratio was 0.78 (65 samples with male and 83 with female chromosome complements), indicating the prevalence of fetuses with female chromosomal complement. The female fetus predominance could be explained by both maternal cell contamination and the increased rate of male fetus loss resulting from hemizygocity for lethal X-linked mutations known to have a high frequency. Many clinical laboratories report an excess of normal female over normal male karyotypes, and some studies show that maternal cell overgrow is not uncommon (Griffin et al. 1997; Bell et al. 1999). Therefore, contamination by maternal cells during processing of samples for cytogenetic or molecular cytogenetic (FISH) analysis should not significantly affect the results. However, in cases of suspected maternal cell contamination, a "DNA fingerprinting" assay can avoid inaccuracy of cytogenetic analysis (Bell et al. 1999). Interestingly, in our study, the frequencies of mosaic forms of chromosomal abnormalities in samples with male and female chromosomal complements were practically identical—50% (16/32 chromosomally abnormal) for male fetuses and 47.4% (27/57 chromosomally abnormal) for female fetuses. Therefore, there is no prevalence of mosaic forms in female fetuses, and the high incidence of chromosomal mosaicism detected in our representative study of 148 spontaneous abortions is unlikely to be explained by maternal cell contamination.

To our knowledge, the criteria for defining a sample as mosaic using interphase FISH analysis of spontaneous abortion specimens has not been reported. In recent publications in this field using FISH, informative mosaic samples were defined as those in which more than 20% of nuclei had a variation in signal number from the majority or showed a signal pattern other than the normal disomic autosomal or normal sex chromosomal (XX and XY) signals (Jobanputra et al. 2002). It must be noted that usually 50 nuclei or 20 metaphase spreads scored for each probe after FISH. In our study, samples were considered normal (disomic) if more than 95% of all nuclei demonstrated two signals for autosomes and the XX or XY signal pattern for sex chromosomes. To increase the sensitivity and accuracy of FISH analysis, we scored large cell populations for each spontaneous abortion specimen suspected of having chromosomal mosaicism (more than 15–30 chromosomally abnormal cells per sample with scoring of 300–600 nuclei). The low level (5%) of the starting value for scoring of mosaicism and the scoring of large cell populations as well as application of chromosome-enumerating probes for many chromosomes in mFISH studies probably explain the high incidence of mosaicim in spontaneous abortions. It is clear that classical cytogenetic studies based on analysis of 20–50 metaphase spreads are not very effective for assessing low-level mosaicism. Interphase FISH studies allow scoring of a large cell population with high accuracy. Different criteria for defining samples as mosaic may explain the differences in the frequency of detecting mosaicism in the present study as compared with previously published results. However, it is necessary to note that this problem in relation to frequencies of mosaicism in spontaneous abortion has not yet been investigated.

It will be very useful to perform studies of chromosomal variations, including chromosomal mosaicim, in a control population, for example, in material of induced abortions, such as that performed by Horiuchi et al. (1997). In this work, the authors demonstrated that the number of chromosomally abnormal cells in cases of spontaneous abortions with mosaicism is significantly higher than that in induced or spontaneous abortion specimens without abnormal cell populations. However, the use of "internal" controls in large-scale studies, as performed in our study of 148 spontaneous abortions, seems to be adequate. The highly reproducible and regular appearance of chromosomal aberrations in samples with confirmed chromosomal abnormalities, as well as the presence of chromosomally normal samples (serving as "internal" controls) detected in our study, indicates that the mosaicism seen in spontaneous abortions is not likely to be explained as a FISH artifact.

The origin of chromosomal mosaicism in spontaneous abortion could be explained by meiotic as well as mitotic errors. The meiotic origin of mosaic aneuploidy has been proposed to explain confined placental mosaicism resulting from a correction of a trisomic conception by reduction to disomy. The previously accepted frequency range of both confined and generalized types of mosaicism is estimated at 5–10% and higher (Kalousek et al. 1992; Wolstenholme, 1996). Postfertilization somatic errors occurring in the first trimester of pregnancy are an alternative mechanism. Postzygotic mitotic nondisjunction causing mosaic forms of aneuploidy usually occur in a small proportion (1–2%) of live-born children with chromosomal syndromes. The high incidence of chromosomal mosaicism throughout human preimplantation development in vitro was demonstrated by mFISH with an overall frequency of 50% (Bielanska et al. 2002). It is possible to propose that postzygotic errors leading to chromosomal mosaicism could persist throughout preimplantation development in vivo. In the present study, the frequency of chromosomal mosaicism in spontaneous abortions of 3–17 weeks gestation and abnormal chromosome complement is 44.8%. These data indicate the fetal mosaicism due to postzygotic mitotic errors to be rather frequent. Chromosomal mosaicism and regular forms of aneuploidy involving different human chromosomes may contribute equally to a higher rate of spontaneous fetal loss. Regular and probably mosaic forms of aneuploidy are the result of meiotic errors, leading to the appearance of chromosomally abnormal gametes. Additionally, mosaic forms are known to occur due to postmeiotic errors after fertilization. Therefore, one can propose the existence of genetic, epigenetic, and environmental factors that are currently unknown and that are likely to selectively disturb chromosome segregation during mitotic division in somatic cells during human early fetal development.

	Acknowledgments

 
Supported by Copernicus 2 grant no. ICA2-CT-2000-10012 and INTAS grant no. 03-55-4060.

	Footnotes

 
Presented in part at the 14^th Workshop on Fetal Cells and Fetal DNA: Recent Progress in Molecular Genetic and Cytogenetic Investigations for Early Prenatal and Postnatal Diagnosis, Friedrich Schiller University, Jena, Germany, April 17–18, 2004.

Received for publication May 26, 2004; accepted September 2, 2004

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