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A Case of Robertsonian Translocation and Turner Mosaicism

The reader below recently lost a pregnancy early in gestation. During the course of her work-up afterwards, she was found to have not only a balanced Robertsonian translocation of chromosomes 13;15, but a low level of mosaicism for Turner syndrome (cells that contained only one X chromosome) as well. All the cells, including the ones containing only one X chromosome also contained the balanced 13:15 Robertsonian translocation. Her questions regarding her prospects for having a “normal baby” are excellent and I have tried to interject my answers into the flow of her comments/questions. For the sake of readers not familiar with Roberstonian translocations, I would refer you to my previous post on this subject, but I will include pertinent information from that previous post to clarify my comments. Before we start, let me review what a Roberstonian translocation is.

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...

Fanny has left a new comment on your post "Robertsonian Translocations" Sun Jan 06, 06:08:00 AM 2008

Hi Dr Trofatter,

I am very grateful to have found your website since I live in Singapore and the statistics/study on chromosomal translocation are scarce and I am feeling helpless. My gynecologist is still locating for genetic counseling for me. I am 32 and got pregnant after trying to conceive for two months. I eventually suffered a missed abortion at 10 weeks. My baby had a heartbeat at 7 weeks and the heartbeat stopped at 7 weeks 3 days. I requested to do a chromosomal analysis and test result was as follow: “Chromosome analysis on this peripheral blood specimen demonstrated the presence of Robertsonian translocation between chromosomes 13 and 15 and an apparent low level mosaicism for Turner syndrome (2 out of 50 cells)”. From my visual layman explanation, one chromosome 15 has gone over to attach one chromosome 13.

Karotype: 45,XX,der(13:15)(q10;q10)[48]/44,X,der(13;15)(q10;q10)[2]. I was given the hardcopies of two test specimens, one with only one X chromosome and the other with two X chromosomes. Both the two specimens contained the (13;15) abnormality.

My first set of question is: Are my chances of conceiving a baby with the right total amount of genetic materials similar to the more common (13;14) translocation in Gina’s case? Can I assume that the gametes analysis you did for Gina is similar to mine and my success rate is 33% with about 15% chance of my baby being a carrier? Or is my (13:15) translocation a very rare case and I have a very low chance of giving birth to a healthy baby? My husband has a normal karyotype.

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. Robertsonian translocations of chromosomes 13 and 15 are less common, but the math plays out the same way as I detailed for our reader in our previous post. I will substitute Fanny’s 13;15 translocation into the scheme so that our other readers can follow the explanation:

Because of the two chromosomes that are connected to each other, when individuals with Robertsonian translocations produce eggs (which normally involves halving the total chromosomal complement from 46 down to 23 in preparation for fertilization with Dad’s 23 chromosomes), some of these will not contain a ‘balanced complement’ of chromosomal material. In the case of our reader, who apparently has a balanced 13;15 translocation, the possible eggs she will produce during meiosis may contain:

• 1) One free copy of chromosome (chr) 13 and one free copy of chr 15.
• 2) The translocation (chr 13;15) chromosome alone (which contains one copy of chr 13 fused with one copy of chr 15).
• 3) Chr 13;15 + one free copy of chr 13 (essentially, an egg with TWO copies of chr 13 rather than just one).
• 4) One free copy of chr 13 (and NO copy of chr 15).
• 5) Chr 13;15 + one free copy of chr 15 (TWO copies of chr 15 rather than just one).
• 6) One free copy of chr 15 (and NO copy of chr 13).

Obviously, 3 through 6 are eggs that have the incorrect number of chromosomes (either too little or too much genetic material) rather than the normal number or equivalent complement of 23 different chromosomes. When these eggs get together with the ‘normal’ sperm from her partner (which contain 23 chromosomes, that include one free copy of chromosome 13 and one of 15), the following possibilities result (in the same order as above):

• 1) Two free copies of chr 13 + two free copies of chr 15 = NORMAL
• 2) Chr 13;15 + one free copy of chr 13 + one free copy of chr 15 = translocation ‘carrier’ (just like Mom) with NORMAL TOTAL amount of genetic material
• 3) Chr 13:15 + TWO free copies (one EXTRA from Mom and one from Dad) of chr 13 + one free copy (from Dad) chr 15 = TRISOMY 13
• 4) Two free copies chr 13 (one from Mom and one from Dad) + ONE free copy of chr 15 (NONE from Mom and one from Dad) = MONOSOMY 15
• 5) Chr 13:15 + one free copy of chr 13 (from Dad) + TWO free copies (one EXTRA from Mom and one from Dad) chr 15 = TRISOMY 15
• 6) ONE free copy chr 13 (NONE from Mom and one from Dad) + two free copies of chr 15 (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 correct 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, her actual risk for delivering a baby with a chromosomal abnormality is much lower than this. The monosomy 13 and 15 embryos will not be successful at all and the trisomy 15 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 as well 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. Indeed, the ‘selective forces’ are so strong against these chromosomally abnormal babies 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%.

Now, I should mention this because it has also been a source of confusion (and some anguish) for some readers in the past. All that I have said to this point only pertains to balanced Robertsonian translocations in which the two chromsomes that are joined together are DIFFERENT. If the balanced translocation involves two of the same chromosomes, such as 21;21 or 14;14 or 13;13, etc, then no normal babies are possible. They will all have either three copies or only one copy of that particular chromosome.

My second question is: Is my “apparent low level mosaicism for Turner syndrome (2 out of 50 cells)” a great cause for concern?

This is a harder question to answer. I do not think it is a “great cause of concern” but it may or may not slightly increase your risk for having a baby who survives with a chromosomal abnormality. The reason I am hedging is that in circumstances with low levels of mosaicism (two populations of cells with different chromosomal complements in a single individual) not all bodily tissues may be affected equally by the mosaicism. In other words, your ovaries (and eggs) may contain an equal, a higher, or even a lower percentage of cells that contain the Turner syndrome (single female X chromosome) genetic make up.

My third question is: Given my (13:15) translocation and mosaicism for Turner syndrome, what are the specific tests that I should opt for if I undertake 1) amniocentesis or 2) CVS? And if CVS is done very early, is there a chance the baby will develop an abnormality in the growth of the baby’s limbs?

This is your choice and depends on how urgently you need to know early in the pregnancy and your level of risk tolerance. Remember, even in experienced hands, the risk of losing a baby as the result of chorionic villus sampling (CVS) is probably about 1%, whereas the risk of an amniocentesis at 16 weeks is only about 0.1% (1 in 1000). The risk of limb reduction abnormalities following CVS has been minized by performing the procedure later in first trimester.

Some women with balanced translocations will simply let nature take its course in first trimester rather than risk losing a normal baby as the result of a CVS. In other words, if the baby is lost, it was probably chromosomally unbalanced. The tougher decision occurs when the baby appears ‘normal’ and has survived first trimester – should you proceed with an amniocentesis or not because the baby has at that point a higher likelihood of having a balanced chromosomal complement (either completely normal or as a balanced translocation carrier). Again, that’s a personal decision. Most geneticist will tell you that because of the chromosomal rearrangements, the baby is at a slightly higher risk for having a subtle chromosomal abnormality as well, and would recommend the amniocentesis at that point. You also might consider that more seriously because of your Turner’s mosaicism.

My fourth question is: Will amniocentesis be able to diagnosis if my baby has is a translocation carrier or it is only possible to know after she/he is born and a chromosomal test is carried out?

Yes, the amniocentesis should be able to tell you that before the baby is born. It may not be able to tell you, however, if the baby has a mosaicism or, even if a mosaicism is detected, how extensive that may be.

My last question is: My hubby and I really love to form a complete family and is determination (keep trying) the best solution? I understand that IVF with PGD does increase my chance of having a healthy embryo but it also subjects me to the risks of failure under IVF although I have no problem with my progesterone levels. Thank you very much. Best Regards Fanny

Quoting myself from my previous post, 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 delivering a baby with an unbalanced amount of chromosomal material 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 a chromsomally unbalanced fetus, dealing with the pain of pregnancy loss may be a little bit easier.
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