College of American Pathologists
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   Posted March 1, 2006


The Role of Cytogenetics in Perinatal Medicine

Jean Thomsen, MD
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:

  1. 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.
  2. 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.
  3. 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. 2005:107-135.

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 Diagn. 2001;21(4):293-301.

4. Technical and clinical assessment of fluorescence in situ hybridization: an ACMG/ASHG position statement. Genetics in Medicine. 2000;2(6):356-361.

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NewsPath® Editor: Megan J. DiFurio, MD, FCAP
This newsletter is produced in cooperation with the College of American Pathologists Public Affairs Committee and may be reproduced in whole or in part as a service to the medical community. Copyright © 2006 by the College of American Pathologists.
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