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Routine prenatal diagnosis of aneuploidy by FISH studies in high-risk pregnancies

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American Journal of Medical Genetics 90:233–238 (2000)
Routine Prenatal Diagnosis of Aneuploidy by FISH
Studies in High-Risk Pregnancies
Baruch Feldman,1 Salah A.D. Ebrahim,2 Sarah L. Hazan,1 Ko Gyi,2 Mark P. Johnson,1,2
Anthony Johnson,1 and Mark I. Evans1,2,3*
Division of Reproductive Genetics, Department of Obstetrics and Gynecology, Wayne State University,
Detroit, Michigan
Department of Pathology, Wayne State University, Detroit, Michigan
Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan
This study is a prospective clinical trial
with fluorescent in situ hybridization
(FISH) as a “routine” test for prenatal detection of the most common aneuploidies in
high-risk pregnancies. Since April 1996,
FISH studies with multicolor, commercially
available, specific probes for chromosomes
13, 18, 21, X, and Y have been routinely performed in our cytogenetic laboratory on uncultured chorionic villous samplings (CVS),
amniotic fluid samples, or fetal blood obtained by cordocentesis from patients with
major or minor fetal anomalies detected by
ultrasonography. Among the 4,193 prenatal
samples analyzed between April 1996 and
June 1998, routine FISH studies were ordered by the referring physicians on 301
(7.2%) cases. Aneuploidies were detected in
32 (10.6%) samples. Fourteen trisomy-21, 10
trisomy-18, 3 trisomy-13, 4 monosomies of X,
and 1 case of triploidy were diagnosed by
FISH. All 1,505 hybridizations were informative, and all 301 results were available
and reported to the referring physicians in
24–48 hr. All relevant FISH results were confirmed by subsequent cytogenetic analysis.
In 10 (3.8%) cases with normal FISH results,
the final cytogenetic analysis revealed abnormal chromosomal rearrangements that
could not be detected by the routine FISH
studies. We conclude that rapid FISH analysis of interphase, uncultured fetal cells is an
accurate and very sensitive method for routine prenatal diagnosis of the most common
aneuploidies in high-risk pregnancies. Am.
J. Med. Genet. 90:233–238, 2000.
© 2000 Wiley-Liss, Inc.
*Correspondence to: Mark I. Evans, M.D., Department of Ob/
Gyn, Hutzel Hospital, 4707 St. Antoine Boulevard, Detroit, MI
48201. E-mail:
Received 13 July 1999; Accepted 30 September 1999
© 2000 Wiley-Liss, Inc.
KEY WORDS: prenatal diagnosis; aneuploidy; FISH
More than a decade ago, fluorescent in-situ hybridization (FISH) was introduced as a potentially powerful tool in clinical cytogenetics [Cremer et al., 1986;
Julien et al., 1986]. The technique has been found to be
highly effective for rapidly determining the number of
specified chromosomes in interphase cells [Cremer et
al., 1988; Lichter et al., 1988]. FISH thus seemed to be
especially appealing for the prenatal detection of chromosomal aberrations. Aneuploidies of only 5 chromosomes (13, 18, 21, X, and Y) account for about 65% of all
chromosomal abnormalities and 95% of the chromosomal aberrations causing live-born birth defects
[Rhoads et al., 1989; Robinson et al., 1990; Whiteman
and Klinger, 1991]. Speed is also a very significant advantage in prenatal diagnosis. Traditionally, one of the
inherent frustrations of cytogenetic prenatal diagnosis
is the length of time it takes to obtain a karyotype from
fetal tissue. Although the turnaround time for a traditional cytogenetic study has decreased from 4 weeks to
about 10 days, the pressure for rapid results, particularly in the face of fetal anomalies detected by ultrasound, is still tremendous.
During the late 1980s and early 1990s, technical issues were the focus of research. Specific probes, determination of cell types suitable for use with FISH, and
more effective techniques for cell preparation and signal detection were intensively studied [Philip et al.,
1994]. The results of these efforts were technical advances such as commercially available highly specific
and reliable probes, direct labeling, and multicolor,
computerized signal detection systems [Divane et al.,
1994; Jalal et al., 1998]. However, concerns on the sensitivity, specificity and predictive values of the test and
lack of uniform laboratory methods produced profound
skepticism of the genetics community. In 1993, The
American College of Medical Genetics (ACMG) stated
that FISH for clinical cytogenetic studies should be
considered investigational [American College of Medical Genetics, 1993].
Feldman et al.
Several major clinical studies, published in the last 6
years have addressed the accuracy of prenatal detection of the most common aneuploidies by FISH [Bryndorf et al., 1997; Bryndorf et al., 1996; Cacheux et al.,
1994; Cooper et al., 1998; Eiben et al., 1998; Klinger et
al., 1992; Mercier and Bresson, 1995; Jalal et al., 1998;
Verlinsky et al., 1998; Ward et al., 1993]. Most of these
studies were limited to uncultured amniocytes. Although most studies were blinded, very few were true
prospective clinical trials in which FISH analysis was
performed upon the physician’s request, and results
were reported to referring physicians and patients as
soon as they were available [Eiben et al., 1998; Ward et
al., 1993]. A high percentage of samples not suitable for
FISH and many uninformative and problematic results
were the other major limitations of the previously published studies.
The purpose of the current study was to determine
the accuracy of FISH in detection of aneuploidies in
real clinical practice with very high-risk pregnancies,
i.e., those with fetal anomalies detected by ultrasound.
We chose this group of patients for three major reasons: (a) these patients can undoubtedly benefit from
fast results since they suffer from substantial anxieties; (b) artificial blinding is not indicated. This group
of patients allows testing upon the physician’s request
and reporting of FISH results in real time without violating the ACMG guidelines, which dictate that “patient–management decisions should not be based on
results obtained by FISH alone;” and (c) it allows cytogenetic evaluation of a significant number of normal as
well as abnormal cases because the incidence of chromosomal abnormalities was expected to be relatively
high in this group.
We established a protocol based mainly on the published experience of others combined with our extensive 10 years of experience, which has included pilot
studies with a few hundred cases. The study was designed to evaluate the method as a tool in a clinical
prenatal diagnosis program. Routine FISH was performed only upon the referring physician’s request and
results were officially reported on a real time basis. To
avoid the major obstacles of the previous studies, we
based our protocol on the use of multicolor commercially available probes, and defined criteria for interpretation to allow very few “problematic” or “uninformative” cases to be reported.
Clinical Protocol
All routine FISH studies for chromosomes 13, 18, 21,
X, and Y that were performed from April 1996 to June
1998 at the Cytogenetic Laboratory at Wayne State
University were included in the study. Patients with
fetal anomalies detected by ultrasonography having invasive procedures for prenatal karyotyping were counseled about the availability of rapid analysis by FISH
compared to standard karyotyping. The limitations of
routine prenatal FISH analysis were also explained in
detail. Major as well as minor fetal anomalies were
included; however, routine FISH analysis was performed only when specifically requested by the referring physician.
All fetal cell types including amniocytes, chorionic
villous cells, or fetal blood cells obtained by amniocentesis, CVS, or cordocentesis, respectively, were included in the study. The only exclusion criterion was
grossly bloody or a heavy stained brownish amniotic
fluid sample. There was no minimum total sample size,
volume of amniotic fluid, or amount of chorionic villi
required to perform both FISH and cytogenetic analyses.
FISH results were reported to the referring physician as soon as they were available. The written report
included (a) a short description of the technique including the specific probes used; (b) results of the test in
numbers of modal signals for each tested chromosome;
(c) interpretation of the results including the sex of the
fetus based on the sex-chromosomes complement, and
the ploidy status of chromosomes 13, 18, and 21; (d) the
major limitations of routine prenatal FISH analysis,
which are its inability to detect structural chromosomal aberrations, mosaicism, and numerical abnormalities of chromosomes other than on chromosomes 13, 18,
21, X, and Y; (e) the policy statement of the ACMG
regarding the investigational nature of the test and its
recommendation that no irreversible therapeutic action should be initiated on the basis of FISH results
The standard cytogenetic analysis was based on examination of G-banded chromosomes from at least 15
cultured metaphase cells from a minimum of two independent cultures. The results were reported to the referring physician on a separate form, approximately 1
week after the FISH report was issued.
The PloidySTAT set (Oncor, Gaithersburg, MD) was
used for all our routine FISH studies until July 1997. It
was then replaced by the AneuVysion assay kit (Vysis,
Downers Grove, IL). Both assays include two sets of
multicolor probe mixtures, one for chromosomes 18, X,
and Y, and the other for chromosomes 13 and 21. In
each mixture the probes are labeled with different fluorophores, which can be visualized on different color
spectrums. Technical characteristics, as supplied by
the manufacturers of the probes, are listed in Table I.
Preparation of Uncultured Cells
Amniocytes. For each specimen, 2–4 ml of clear amniotic fluid was centrifuged for 10 min at 1,200 rpm.
The pellet was resuspended in 4 ml of trypsin-EDTA,
gently vortexed, and incubated at 37°C for 20 min. Following centrifugation at 1,200 rpm for 10 min, the pellet was resuspended by slowly adding 10 ml of prewarmed (37°C) hypotonic solution (0.8% sodium citrate). The tube was then placed in a 37°C incubator for
20 min followed by centrifugation at 1,200 rpm for 10
min. The supernatant was removed and the pellet was
resuspended by adding 2 ml of fixative (3:1 mixture of
methanol and acetic acid) and gentle mixing. The suspension was kept in refrigerator (2–8°C) for at least 1
hr before preparing slides.
Chorionic villous cells. Chorionic villi were thoroughly cleaned under the microscope and 1–2 pieces of
Prenatal Diagnosis of Aneuploidy by FISH
TABLE I. Probes Used for the Routine FISH Analysis*
PloidySTAT™ (Oncor) until 8/97
Probe Mixture 1
Probe Mixture 2
AneuVysion™ (Vysis) since 8/97
Quint-Essential 18
X ␣-Satellite
Y ␣-Satellite
X cen
Y cen
CEP 18
18 cen
X cen
Y cen
Quint-Essential 13
Quint-Essential 21
LSI 13
LSI 21
*Chromo, Chromosome; ™, Trademark; cen, centromere; CEP, chromosome enumeration probe; LSI, locus specific identifier.
cleaned villi were transferred to a 35-mm petri dish for
FISH. After pipetting off the medium, 2 ml of prewarmed (37°C) hypotonic solution (1% sodium citrate)
were very slowly added and the villi incubated at room
temperature (RT) for 15 min. The hypotonic solution
was removed and 2 ml of fixative (3:1 mixture of
methanol and acetic acid) were added, drop by drop, on
the villi. The dish was placed at −4°C for 20 min and
the fixative was replaced by 2 ml of fresh solution for 5
min at RT. The fixative was removed and the villi were
air-dried for 2 min. The chorionic villi were dissociated
by adding 60% acetic acid. Slides can be prepared starting 2 min after the dissociation solution was added.
Fetal blood cells. Fetal blood (0.5–1.0 ml) obtained
by cordocentesis was mixed with hypotonic solution
(0.56% KCl) for 20 min. The sample was centrifuged at
1,000 rpm for 8 min and the pellet was resuspended
with the fixative (3:1 mixture of methanol and acetic
acid). The suspension was kept in refrigerator (2–8°C)
for about 1 hr before preparing slides.
ation and interpretation of results were almost always
the responsibilities of one very experienced and highly
trained laboratory technician. The most-experienced
physician in the laboratory evaluated all extended
analyses and reported results of all studies performed.
At least 50 interphase amniocytes or lymphocytes, or
100 trophoblasts from CVS, were examined for each
probe. If available, only nicely rounded cells were selected for analysis. Clusters or overlapping cells were
always excluded. Cells with high background or very
low signal intensity were also not scored, if possible.
The following criteria were chosen for interpretation.
Euploidy was diagnosed if at least 85% of the cells were
euploids; aneuploidy was diagnosed if at least 85% of
the cells had the same aneuploid signals; and if more
than 10% of the cells had the same aneuploid signals,
the study was extended and 100–200 cells were analyzed. The final diagnosis by FISH was determined by
the signals detected in the majority of cells. Mosaicism
was suspected in these cases, and the standard cytogenetic analysis was extended as well.
Hybridization and Signal Detection
Hybridization protocols of Oncor and later Vysis prenatal detection kits were generally followed. Slides
were “dropped” according to routine slide-preparation
protocol. At least one extra slide was prepared for each
sample as a backup. The slide was incubated for 30 min
at 37°C in a coplin jar containing prewarmed 40 ml of
2 × SSC (saline sodium citrate). The slide was then
dehydrated in 70%, 80%, and 95% ethanol at RT for 2
min each. For denaturation, the slide was immersed in
denaturation solution (70% formamide in 2 × SSC) at
70°C for 2 min, and then rehydrated in ethanol as previously described. For hybridization, 10 ␮l of each of
the two probe mixtures were applied on marked areas
of the slide. The marked areas were covered by coverslips and sealed by rubber cement. The slide was then
incubated for 4 to 16 hr at 37°C in a humidified chamber. After incubation the coverslips were removed and
the slide was placed in 0.5 × SSC at 72°C for 2–3 min.
The slide was then washed in 2 × SSC/0.1%NP-40 at
RT for 2 min and air-dried in the dark. DAPI-II counterstain was applied and a coverslip was placed. A filter set specific for different spectrums was used with
an Axioscope fluorescence microscope (Zeiss, Oberkochen, Germany) for analysis.
Interpretation of Results
Although cell preparation and sometimes hybridization were performed by others, the microscopic evalu-
A total number of 4,193 prenatal samples (3,379 amniocenteses, 802 CVSs, and 12 cordocenteses) were
analyzed in our cytogenetic laboratory from April 1996
to June 1998. Routine FISH studies were requested
and performed during the time of the study on 301
patients, with 213 minor and 88 major fetal anomalies
detected by ultrasonography. The distribution of cases
by the invasive procedure performed, and the type of
fetal anomalies detected, are summarized in Table II.
All studies were done upon the referring physician’s
request with no exceptions. However, 2 cases were excluded from routine FISH analysis because of bloody
amniotic fluid samples. Utilization of routine FISH
analysis almost tripled between 1996 to 1998 (Table
TABLE II. Distribution of Cases by Types of Procedures and
Fetal Anomalies*
Fetal anomalies
*CVS, Chorionic villous sampling.
Feldman et al.
III). All FISH results were available to the referring
physicians within 24–48 hr from the time of the procedure. For 52 (17%) cases, the referring physicians requested specifically, and the results were available
within 14–18 hr. All 301 cases analyzed by FISH,
which included 1,505 hybridizations with five probes
per case, were informative.
Extended FISH studies were indicated by our interpretation criteria in 7 (2.3%) cases. In 4 cases, 5 to 7
cells of the 50 analyzed had the same aneuploidy signals. In these 4 cases, the aneuploidic cells had three
signals for chromosome 21. The extended study revealed only 1–2 more cells with trisomic signals in each
of the 4 cases. Thus, based on the protocol, we reported
FISH results as euploidy for these cases. The standard
cytogenetic analysis was also extended for these cases
and the final karyotypes were normal without mosaicism in all 4 cases. The three other studies were extended because the intensity of the signals of chromosome 18 in 2 cases, and X in 1 case, was relatively low.
The reported FISH results as well as the final karyotypes were normal in all 3 cases.
In the 301 FISH studies, the correct number of signals was detected for all five probes in more than 85%
of the analyzed cells. The mean proportions of scored
cells that showed the accurate number of signals, in
accordance with the final diagnosis by FISH, are summarized in Table IV.
Standard cytogenetic analyses revealed 42 (14%) abnormal fetal karyotypes in our study group. We detected 32 aneuploidies involving chromosomes 13, 18,
21, X, and Y, 2 balanced rearrangements, 4 unbalanced
rearrangements, and 4 aneuploidies involving chromosomes other than those analyzed by our routine FISH
studies (Table V). The incidence of chromosomal abnormalities among patients with major fetal anomalies
was twice that of patients with minor anomalies detected by ultrasound (21.6% and 10.8%, respectively,
Table V).
Of the 32 aneuploidies involving the analyzed chromosomes (14 cases of trisomy-21, 10 of trisomy-18, 3 of
trisomy-13, 4 of monosomy-X, and 1 case of triploidy),
all were accurately diagnosed by routine FISH studies.
All 301 relevant normal and abnormal FISH results
were confirmed by subsequent cytogenetic analysis
with no false positives or negatives for what the FISH
measures. However, from the clinical perspective, routine FISH analysis for the most common aneuploidies
missed about 25% of all chromosomal abnormalities.
The sensitivity, specificity, and predictive values of the
routine FISH as prospective clinical test in our study
group are summarized in Table VI.
TABLE III. Physicians’ Requests for Routine FISH Analysis
During the Study
Total no. of
No. of FISH
of requests
TABLE IV. Percentage of Cells With Expected Number of
Signals in 50 Representative Normal Cases and
All Aneuploidies
XX or XY
All aneuploidies
Percentage of analyzed cells
with expected number
of signalsa
97.9 ± 1.6%
97.5 ± 1.5%
97.2 ± 3.0%
99.5 ± 1.4%
95.5 ± 3.5%
Euploid number for euploidies; aneuploid number for aneuploidies.
Traditional cytogenetic analysis detects chromosomal aneuploidies with great accuracy. Its primary advantage is the ability to detect other chromosome rearrangements. Standard karyotyping, however, must be
done on metaphase cells following culture time of several days. In certain clinical situations, especially in
prenatal diagnosis, waiting for chromosome analysis
may place a significant emotional stress on the patient
and clinical burden on the referring physician [BerneFromell and Kjessler, 1984; Evans et al., 1988; EversKiebooms et al., 1988]. Apart from being timeconsuming, traditional cytogenetic analysis is also
technically demanding, labor intensive, relatively expensive, and requires highly trained analysts.
The potential ability of FISH to identify specific chromosomes in uncultured interphase nuclei was determined by early studies. The potential application of
FISH technology for rapid routine prenatal diagnosis of
the most common aneuploidies has also been established. However, early attempts at aneuploidy detection in uncultured amniocytes suffered from significant
limitations caused by probe design, sample preparation, and assay conditions. Several recently published
studies demonstrated the applicability of routine FISH
analysis as a clinical test for the prenatal detection of
aneuploidies. Klinger et al. [1992] and Ward et al.
[1993] reported the results of the first major studies
comparing aneuploidy detection by FISH with standard cytogenetic analysis. Their studies formed the basis of the clinical protocols for the application of FISH
to prenatal diagnosis. However, these two and most of
the following studies [Bryndorf et al., 1997; Bryndorf et
al., 1996; Cacheux et al., 1994; Cooper et al., 1998;
Eiben et al., 1998; Jalal et al., 1998; Mercier and Bresson, 1995; Verlinsky et al., 1998] had several obstacles
that delayed wide acceptance of FISH as a highly reliable method for routine prenatal diagnosis. Some authors used probes constructed by their own laboratories [Bryndorf et al., 1997; Bryndorf et al., 1996;
Klinger et al., 1992; Ward et al., 1993]. Most cytogenetic laboratories are not qualified to synthesize DNA
probes and to perform the necessary quality-control
studies. Furthermore, the assay conditions should be
modified for each set of probes because the quality and
characteristics of the probes are the key factors for successful FISH analysis.
All studies were limited to one specific cell type,
which is not the case in many clinical prenatal diagnosis programs.
Prenatal Diagnosis of Aneuploidy by FISH
TABLE V. Chromosomal Abnormalities in the Study Group
Fetal anomalies
Final cytogenetic diagnosis
Aneuploidies of 13, 18, 21, X, Y
Other unbalanced rearrangements
Balanced rearrangements
Total no. of chromosomal abnormalities
Normal karyotype
Total no. of cases
Only two major studies were true prospective clinical
trials [Eiben et al., 1998; Ward et al., 1993]. Most studies were artificially blinded at best, and did not evaluate the test in actual clinical settings.
Significant numbers of samples were excluded prior
to FISH analysis because of blood contamination of amniotic fluid or lack of a sufficient amount of specimen.
The final diagnosis in a significant number of FISH
studies was “unsuccessful due to failed hybridization”
or problematic results due to insufficient number of
nuclei for analysis of one or more chromosomes. Of special concern was the fact that, relative to normal karyotypes, FISH missed a higher percentage of aneuploidies due to problematic or unsatisfactory results. For
example, 9.8% of samples found to be suitable for FISH
in the study of Ward et al. [1993] were reported as
uninformative whereas 7.5% of them were potentially
detectable aneuploidies. The overall detection rate of
the relevant aneuploidies was 73.3% in their study
[Ward et al., 1993]. In more recent studies, Bryndorf et
al. [1997] could not reproduce these results whereas
others [Eiben et al., 1998; Jalal et al., 1998] have demonstrated potential overall detection rates of almost
In most studies, FISH misdiagnosed few false negatives and positives.
The present study was generally designed on the basis of previously published major clinical trials and our
own long-standing experience [Evans et al., 1994;
Evans et al., 1992]. To avoid the obstacles of the recently published studies, we used commercially available multicolor probes. We defined criteria for interpretation of the results to allow very few uninformative
cases. All available fetal cell types were included, and
the only exclusion criterion was bloody amniotic fluid.
Most importantly, however, is the fact that the study
was a true prospective clinical trial in which the test
was performed upon physician’s request and results
were reported as soon as they were available. The present study is the first published clinical trial in which
TABLE VI. Characteristics of Routine FISH Analysis as
Clinical Test for High-Risk Pregnancies
Sensitivity, 76.2%; Specificity, 100%; Positive predictive value, 100%;
Negative predictive value, 96.3%.
18 (8.4%)
4 (1.9%)
1 (0.5%)
23 (10.8%)
190 (89.2%)
14 (15.9%)
4 (4.6%)
1 (1.1%)
19 (21.6%)
69 (78.4%)
32 (10.6%)
8 (2.7%)
2 (0.7%)
42 (14.0%)
259 (86.0%)
the modified routine FISH technology, with a potential
of 100% accuracy, was integrated into a clinical prenatal diagnosis program.
As expected, the incidence of all chromosomal abnormalities in very high risk pregnancies is relatively high
(14%), with aneuploidies of 13, 18, 21, X, and Y being
the most common finding (76%). As demonstrated by
many others, fetal anomaly detected by ultrasound is
the most significant risk factor for chromosomal abnormalities. The risk is doubled from about 10 to above
20% in cases with major as compared to minor anomalies.
We believe that the major problems of most studies
were the result of unsatisfactory criteria for interpretation of results. The different cutoff points for the proportion of cells with identical pattern of signals needed
for diagnosis by FISH were between 50–70% in different studies. This cutoff point could be optimized in our
study to be as high as 85% due to very reliable probes
and optimization of several steps in preparation of
cells, hybridization, and detection. The relatively small
total number of cells needed for diagnosis, practically
100, gave a much better option to be more selective in
cell quality, and was a major factor in the efficiency
and accuracy of the test. Our observation that in the
vast majority of hybridizations more than 95% of cells
showed the accurate number of signals strongly supports our chosen high cutoff point. These modifications
were the basis for the zero uninformative FISH results
in our group.
We cannot comment on the incidence of exclusion
due to bloody amniotic fluids because the referring physicians were aware of the exclusion criterion and might
preexcluded some specimens. The incidence of bloody
fluids referred to our laboratory for standard cytogenetic analysis was less than 1% during the time of the
study, thus the significance of that factor is most likely
negligible. We are currently studying the routine FISH
protocols for bloody specimens, hoping that FISH
analysis will be available for all prenatal cases.
The sensitivity, specificity, and predictive values for
the routine FISH analysis as a method to detect aneuploidies of chromosomes 13, 18, 21, X, and Y in our
study group were all 100%. However, the laboratory is
requested by the referring health providers to detect all
cytogenetically visible chromosomal abnormalities. By
that definition, even with 100% accuracy of the test,
routine FISH analysis will miss about 25–30% of the
detectable cytogenetic abnormalities.
Therefore, the future of routine FISH analysis for the
prenatal detection of aneuploidies is highly dependent
Feldman et al.
on protocols with practically zero false positives, and
educating physicians and patients about the basis of
the unavoidable inherited clinical false negatives. The
best proof for the applicability of the test and its usefulness in day-to-day clinical practice is the fact that
physicians’ requests for routine FISH analysis almost
tripled during the study period.
Like any other test, this method is subjected to pitfalls. Even with the most reliable protocols, some rare
rearrangements and familial variants, as well as technical errors, could cause false results [Hockstein et al.,
1998; Tardy and Toth, 1997; Thangavelu et al., 1998;
Verlinsky et al., 1995; Verlinsky et al., 1998]. However,
like no other test, this technique has a very reliable
backup—traditional cytogenetic analysis.
We believe that FISH should be approved to be used
as a standard clinical test in the prenatal cytogenetic
laboratory. However, we agree with other authors that
FISH should generally be used as an adjunct to the
traditional karyotyping and not as its replacement.
These results were presented at the 48th annual
meeting of the American Society of Human Genetics,
October 27–31, 1998, Denver, CO.
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prenatal, high, pregnancies, fish, risk, studies, routing, aneuploidy, diagnosis
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