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Robertsonian Translocations

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One of our readers left the comments/questions below that were worthy of a post for general consumption by interested readers...

Anonymous has left a new comment on your post "Recurrent Early Pregnancy Loss - 3 - Chromosomal C...": Hi-I am 30 years old and have suffered 3 miscarriages. After my third, my Dr. did a karotype and found that I have a Robertsonian translocation between 13 & 14. From what I've learned researching this topic, is that I have a 50-50 shot of producing an egg with the correct number of chromosomes or with the same translocation as I have. Is that assumption correct?Also, is IVF w/PGD our best bet in having a healthy baby? Is it also true that if I have this translocation that chances are one of my parent's have it and/or my sibling's?Thanks so much!! My anxiety has been sky-high ever since I found this out and I can't see a genetic counselor until November 1st. Gina

Gina, all of these are great questions, and as so much in this world of medicine, not as easily answered as you might like…

Under normal (euploid) circumstances, humans have 46 chromosomes in each of the cells that make up their bodies. The complement of 46 chromosomes is composed of 22 pairs of ‘autosomes’ and 1 pair of sex (either XX = female, or XY = male) chromosomes – half of the total complement being inherited from each parent. Individual chromosomes are quite distinct in their appearance and most have long (= p) and short (= q) ‘arms’ that are connected by a structure called the centromere. When cells replicate to make another cell, they first duplicate their chromosomes and centromeres. The centromeres then connect to the structures in the cell that help separate these duplicated chromosomes from each other so that each new cell which results gets exactly the same chromosomal complement that was present in the ‘mother’ cell. This event is called mitosis.

To produce gametes (ova and sperm), a slightly different process is involved. Following duplication of the chromosomes, the overall complement of chromosomes delivered to each gamete must be reduced to half (23) that found in other cells in the body. This is two-step process called meiosis in which the centromeres also play a key role. During meiosis, the individual chromosomes (that were inherited from each of your parents) segregate more or less randomly into the resulting gametes, providing the great variability seen in our offspring.

Five of our chromosomes (13, 14, 15, 21 and 22) have ‘short arms’ that are very small and which contain no essential genetic material. These 5 chromosomes are called acrocentric chromosomes, or ‘acrosomes.’ Acrosomes have a tendency to fuse at the centromeres with other acrosomes, thus producing a ‘single’ larger chromosome made up of the ‘long arms’ of the chromosomes of origin, connected by a single centromere. When this occurs it is known as a ‘Robertsonian translocation.’ If no essential genetic material is lost (or gained) in the process, the individual with such a chromosome is said to have a ‘balanced’ translocation and appears ‘normal’ although they now have only 45, rather than 46, chromosomes in each cell.

Robertsonian translocations can occur between any of the acrosomes although this is not entirely random and the most common forms of these occur between chromosomes 13 and 14 (75%), 14 and 21 (10%), and 21 and 22. Individuals with Robertsonian translocations can have these as the result of a spontaneous event occurring during the meiosis (in either parent) that produced the egg or sperm from which they were made, shortly after conception, or from the inheritance of the same from one of their parents.

Robertsonian translocations are present in approximately 1/1,000 newborns. Individuals with balanced translocations are usually healthy and often unaware of their condition, especially if there is no prior family history that has led to the diagnosis, and often their chromosomal ‘abnormality’ will not be discovered until they have difficulty having children. The problem arises when individuals with Robertsonian translocations try to make gametes. In the case of our reader, who apparently has a balanced 13;14 translocation, the possible gametes she will produce (don’t ask me to explain why at this point) during meiosis may contain:
  • 1) One free copy of chromosome (chr) 13 and one free copy of chr 14.
  • 2) The translocation (chr 13;14) chromosome alone (which contains one copy of chr 13 fused with one copy of chr 14).
  • 3) Chr 13;14 + one free copy of chr 13 (essentially, a gamete with TWO copies of chr 13 rather than just one).
  • 4) One free copy of chr 13 (and NO copy of chr 14).
  • 5) Chr 13;14 + one free copy of chr 14 (TWO copies of chr 14 rather than just one).
  • 6) One free copy of chr 14 (and NO copy of chr 13).

Obviously, 3 through 6 are gametes that have the incorrect number of chromosomes (either too little or too much genetic material). When these gametes get together with the, presumably, ‘normal’ gametes from her partner (which contain one free copy of chromosome 13 and 14), the following possibilities result (in the same order as above):

  • 1) Two free copies of chr 13 + two free copies of chr 14 = NORMAL
  • 2) Chr 13;14 + one free copy of chr 13 + one free copy of chr 14 = translocation ‘carrier’ (just like Mom) with NORMAL TOTAL amount of genetic material
  • 3) Chr 13:14 + TWO free copies (one EXTRA from Mom and one from Dad) of chr 13 + one free copy (from Dad) chr 14 = TRISOMY 13
  • 4) Two free copies chr 13 (one from Mom and one from Dad) + ONE free copy of chr 14 (NONE from Mom and one from Dad) = MONOSOMY 14
  • 5) Chr 13:14 + one free copy of chr 13 (from Dad) + TWO free copies (one EXTRA from Mom and one from Dad) chr 14 = TRISOMY 14
  • 6) ONE free copy chr 13 (NONE from Mom and one from Dad) + two free copies of chr 14 (one from Mom and one from Dad) = MONOSOMY 13.

Therefore, to answer one of our reader’s questions, mathematically, she has only a 2 in 6 (33.3%) chance of having a baby that has the right TOTAL amount of genetic material; one of these will be entirely chromosomally normal and the other will be a translocation ‘carrier’ just like herself. Two-thirds of her babies are at risk for being chromosomally ABNORMAL.

But, as I mentioned at the outset, things are not quite that simple. Indeed, her actual risk for having a baby with a chromosomal abnormality is much lower than this. The monosomy 13 and 14 embryos will not be successful at all and the trisomy 14 embryos also have very little chance of surviving much of the first trimester. Most trisomy 13 embryos will also be lost early in first trimester and the few that survive will have only a small chance of surviving the pregnancy and even a smaller chance of living more than a few hours or days after birth. These babies all have severe congenital malformations and if they manage to survive birth and the neonatal period, profound metabolic disturbances, and mental retardation. Indeed, the ‘selective forces’ are so strong against these chromosomally abnormal conceptuses that at least two-thirds of her pregnancies in which a pregnancy is actually confirmed will be chromosomally normal and the chances of actually DELIVERING a chromosomally abnormal baby are probably only about 1%! The overall risk of miscarriage is about 25%.

With regard to the question of IVF (in vitro fertilization) and PGD (prenatal genetic diagnosis), I have a significant amount of ambivalence. If you have the money to burn, these are certainly options, but they are very expensive procedures. And, if you have no difficulty conceiving and are willing to trust nature to do the right thing, as pointed out above, the risk for actually having a baby with an unbalanced karyotype is so small, that it is often simply waiting until the dice roll correctly to have a normal baby. I know that can be difficult psychologically and at times physically. However, because there is nothing that can be done to correct a translocation, if one can accept the fact there is an increased risk for miscarriages, and that when these occur, it is probably the result of an aneuploid fetus, dealing with the pain of pregnancy loss may be a little bit easier.

There is a lot we have not discussed about Robertsonian translocations in this post, but I would like to make a few recommendations in closing (and we can always use these other issues as an excuse to write another post). First, I would suggest that any couple with a known Robertsonian translocation, consider having combined first trimester screening for aneuploidy performed and seriously consider a chorionic villus sampling if this is 'abnormal'. Secondly, even if this is reassuring, consider having a fetal karyotype done by amniocentesis. Thirdly, once an individual with a Roberstonian translocation has been identified, I think it is important to let other family members (male or female) of reproductive age know so that they can be screened as well. It may save a lot of anguish down the line.

Anyway, Gina, thanks again for your questions. I am wagering right now that your pregnancy quest will be rewarded in the end. Best of luck to you and your husband and thanks for reading!
Dr T

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