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Analysis  |   Inversions  |   Nondisjunction  |   Translocation

Chromosome Analysis

Case: 25 year old G2 S2 had chromosome studies of the “products of conception” sent at the time of her D+C for the second spontaneous pregnancy loss.

Question: The chromosome studies could not be completed since the cells submitted were degenerate (dead). Why do living cells need to be submitted for chromosome analysis?

Answer: Most cells within the body are not actively dividing. Healthy placental (pregnancy) cells may be actively dividing or they may be stimulated to divide in the laboratory.

Cells become suitable for chromosome analysis when they go through certain stages (metaphase) of cell division (mitosis), at which time the chromosomes become visible under a light microscope. Placental cells that are induced to grow within a laboratory can be arrested (in the metaphase stage of cell division), the (visible) chromosomes can be stained, and then the chromosomes can be studied.

Cells that are degenerate, or dead, are not suitable for this type of chromosome analysis since they cannot be grown (cultured) in the laboratory. Tissue that is passed at home, collected, and brought into the physician’s office is (similarly) often unsuitable for chromosome analysis.

Case: 31 year old G5 S5 undergoes a basic recurrent pregnancy loss evaluation with normal results, including chromosome analyses that are normal (46 XX for her and 46 XY for her husband).

Question: Could there be an unrecognized genetic basis for the recurrent pregnancy losses?

Answer: Research in human genetics is very active. It seems that several major advances occur within the field of human genetics each year, and that as our understanding of this field expands we increasingly become able to identify diseases that have a genetic basis.

Many reproductive endocrinologists believe that most cases of “unexplained” recurrent pregnancy loss have a genetic basis (that has not yet been discovered). Others believe that most cases of “unexplained” recurrent pregnancy loss have an immunologic basis (that has also not yet been identified).

A chromosome analysis basically identifies the (number and type of) chromosomes present and their banding pattern, which can then be used to identify structural abnormalities such as deletions, inversions, and translocations. A normal chromosome analysis is not able to identify specific gene abnormalities. Gene abnormalities constitute the basis for most genetic abnormalities and therefore a normal chromosome analysis is not able to exclude the presence of a genetic abnormality.

Chromosome Inversions

Case: 26 year old G3 S3 has a pericentric inversion of one of her chromosomes on chromosome analysis.

Question: Is this inversion likely to be related to her recurrent losses and should genetic counseling be suggested?

Answer: Pericentric inversions are usually relatively easy to identify on chromosome analysis and may account for (be the primary reason for) 0.1% (1 in 1000) of recurrent pregnancy losses. Pericentric inversions may also be due to the cell culture conditions within the laboratory, where cells grown in a particular lab may have an especially high rate of a particular type of inversion on a specific chromosome, so the laboratory should initially be contacted when they report out an inversion to determine whether this situation (a culture artifact) is likely (given the prior experience of the laboratory with similar inversions).

If the inversion is unlikely to be a culture artifact, then the couple should seek genetic counseling. The theoretical risk (based on the principles of genetic transmission of disease) of a chromosomally abnormal child in couples with a chromosomal inversion is much greater than risk found in actual clinical experience. If the woman carries the inversion the risk of an abnormal offspring is about 8% and if the man carries the inversion the risk of an abnormal offspring is only about 5%.

Chromosome Nondisjunction

Case: 34 year old G4 S4 had a D+C to evacuate her uterus in order to complete her fourth spontaneous pregnancy loss. A chromosome analysis of the “products of conception” revealed trisomy 16.

Question: What is the significance of the finding of trisomy 16?

Answer: A major chromosome abnormality can be identified in over 50% of single spontaneous pregnancy losses. The most common class of chromosomal abnormality that is found in these pregnancy losses is an autosomal trisomy, the most common of which is trisomy 16.

Trisomy 21 (Down’s syndrome) is the only autosomal trisomy that is consistent with (prolonged) life. Trisomy 21 has characteristic physical features that are relatively easy to identify.

Trisomies occur as an accident in chromosomal assortment (separation) during meiosis (sperm or egg division during their maturation), whereby an egg or sperm cell contains an extra chromosome. When (otherwise normal) fertilization occurs with this egg or sperm cell, the resulting embryo has an extra chromosome (a total of 47 rather than a total of 46 chromosomes) and this is called a trimsomy. These sorts of accidents around the time of fertilization do not tend to recur in subsequent pregnancies and therefore are not a recognized cause of recurrent pregnancy losses.

This patient should consider undergoing a basic recurrent pregnancy loss evaluation since she has had several consecutive losses.

Chromosome Translocation

Case: 31 year old G4 P1 S3 with three consecutive spontaneous losses after an uneventful term pregnancy and delivery that resulted in an apparently normal healthy girl. Maternal chromosome analysis reveals a translocation.

Question: How could a normal child be delivered to this woman if she has a translocation and what is her risk of spontaneous loss in the future?

Answer: Chromosome translocations involve the exchange of genetic material between 2 non homologous (different) chromosomes. Since there is a pair of each of the (23) chromosomes in normal humans (for a total of 46 chromosomes), when a chromosomal translocation involves one of a pair of chromosomes the other chromosome in that pair remains normal.

On occasion, both of the normal chromosomes from the two pairs of chromosomes that are involved in the translocation will be passed on to the egg, to give the egg a normal chromosome complement. On other occasions, both of the translocation chromosomes from the two pairs of chromosomes that are involved in the translocation will be passed on to the egg, to give the egg a “balanced translocation” with a complete set of genetic material. On still other occasions, one of the translocation chromosomes and one of the normal chromosomes will be passed on to the egg, which usually resulting in a lethal chromosome abnormality that will result in a spontaneous pregnancy loss.

The relative rates of occurrence for normal chromosomes, balanced translocations and lethal mutations depend partially on the exact nature of the translocation involved. Couples with translocations should therefore seek genetic counseling for a better understanding of the clinical experience (and actual risk of spontaneous loss) with their specific abnormality.

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