College of American Pathologists’ Cytogenetics Committee
Chromosomal abnormalities are thought to be the leading cause of spontaneous
abortions, accounting for approximately 50% of clinically recognized early
pregnancy losses.1 It is estimated that
a minimum of 10-15% of conceptions have a chromosomal abnormality, and
at least 95% of these abnormal conceptions are lost before term.2
Karyotype studies of miscarriages indicate that about 50% of the chromosomal
abnormalities are trisomies, 20% are monosomies and 15% are triploids.
The remainder consists of conceptuses with tetraploid karyotypes and various
structural abnormalities.2 Chromosomal
defects compatible with life but causing significant morbidity occur in
approximately 0.65% of newborns; another 0.2% of newborns carry structural
chromosomal rearrangements that will eventually affect reproduction.
The most common aneuploid condition compatible with survival to term
is trisomy 21, which is seen in approximately 1 out of every 800 to 1000
live births. Less frequently seen aneuploidies include trisomy 18 (Edwards
syndrome) and trisomy 13 (Patau syndrome). These autosomal trisomies are
most commonly caused by meiotic nondisjunction of maternal origin. Sex
chromosome aneuploidies compatible with survival in most cases include:
trisomy X, 47,XYY and Klinefelter syndrome (47,XXY). Monosomy X (Turner
syndrome) is a frequent cause of pregnancy loss with only approximately
1% of 45,X conceptuses surviving to term.
Screening for genetic abnormalities is routinely offered during prenatal
care and includes maternal serum screening and fetal ultrasound examination.
The American College of Obstetrics and Gynecology recommends prenatal
diagnosis for fetal aneuploidy (amniocentesis, chorionic villus sampling
and, in rare cases, percutaneous umbilical blood sampling) be offered
when: the woman is age 35 and older at the time of delivery; there has
been a previous pregnancy complicated by an autosomal trisomy or sex chromosome
aneuploidy; an ultrasound identifies a major structural defect; or either
parent has a known chromosomal abnormality. It is imperative that genetic
counseling be offered prior to testing.
Standard cytogenetic analysis of prenatal specimens detects chromosome
aneuploidies and rearrangements with greater than 99% accuracy.3
Amniocentesis fluid obtained mid-trimester is the most common sample submitted
for cytogenetic analysis. Culture of the amniotic fluid cells is optimal
when they are obtained between 14-16 weeks gestation. The risks of amniocentesis
include leakage of fluid, cramping, bleeding, infection and miscarriage.
Cytogenetic analysis remains the gold standard for determination of fetal
aneuploidy, but requires the isolation of metaphase chromosomes and can
take between 7 to 10 days for the final result. More recently, the use
of fluorescence in situ hybridization (FISH) on uncultured amniotic fluid
samples for enumeration of chromosomes 13, 18, 21, X and Y has become
widespread, as results can be available in as little as 48 hours. In one
study, FISH results have been shown to be 99.8% concordant with standard
cytogenetics.3 Yet significant clinical decisions should not
be made based on only FISH test results.
At this time, the American College of Medical Genetics recommends4
the following for FISH testing:
- For management of the fetus, it is reasonable to report positive
FISH test results. However, clinical decision-making should not be based
solely on FISH; rather, inclusion of confirmatory chromosome analysis
and/or consistent clinical information is imperative.
- For management of reproductive risks in families in which a fetus
tests positive for a chromosomal abnormality by FISH, the results should
be further characterized comparing traditional chromosome analysis with
FISH results to try to determine the mutational mechanism responsible
for the FISH-detected abnormality.
- In disorders in which FISH testing provides results not possible from
standard cytogenetic testing, the testing is stand-alone and should
be accepted as such (i.e., microdeletions and microduplications).
Ultimately, it is up to the patient, with advice from the clinician,
to determine just how much prenatal diagnostic information is desired
in the pregnancy. Then the patient, clinician and diagnostic laboratory
can work together to ensure that the patient’s needs are met.
1. ACOG Practice Bulletin. Clinical Management Guidelines for Obstetrician-Gynecologists.
Prenatal diagnosis of fetal chromosomal abnormalities. Obstet
Gynecol. 2001 May;97(5 Pt 1):suppl 1-12.
2. Jorde L, Carey J, Bamshad M, et al. Clinical cytogenetics: The chromosomal
basis of human disease. In: Medical Genetics. 3rd ed. St. Louis, MO: Mosby.
3. Tepperberg J, Pettenati MJ, Rao PN, et al, Prenatal diagnosis using
interphase fluorescence in situ hybridization (FISH): 2-year multi-center
retrospective study and review of the literature. Prenat
4. Technical and clinical assessment of fluorescence in situ hybridization:
an ACMG/ASHG position statement. Genetics in Medicine.
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NewsPath® Editor: Megan
J. DiFurio, MD, FCAP
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