Balanced Translocations: 101

This is still bothering me, so excuse me while I declare a few moments of silent scientific concentration here at the Hippo. Now this is what chromosomes one and four look like in a genetically normal person, provided they are made of playdough. The red ones are an exquisite squishy rendering of the first chromosomes, while the more diminutive fourth chromosomes are in blue.

And this is what Playdough Steve looks like. Can you see how he has both copies of one and both copies of four but one part of one copy of each chromosome has switched places? Excellent! THAT is a balanced translocation.

All cells in the genetically normal human body have two copies of each chromosome except sperm (I originally wrote that both the egg and the sperm have only one copy but it turns out I was wrong- how embarrassing for me BUT please for the love of god always point it out when I make an error like that.) Those cells are created by randomly grabbing one of each of a person's twenty-three pairs of chromosomes, so this what the first and fourth chromosomes look like in a normal sperm cell.

Only one of each.

While it is possible for a person with a balanced translocation to create normal sperm cells (exhibit A: Patrick) they frequently get this instead. Chromosome one is all there plus an extra, partial copy of the one. The extra is bad, by the way. Also, only half of the fourth chromosome is present. All of the genes located on that half of the fourth chromosome are gone. That absence is bad too, in case you were wondering.

When this unbalanced sperm cell hooks up with a lovely normal egg and creates the first cell in a new embryo it looks like this. Two and a half copies of the first chromosome and only one and a half copies of the fourth. THIS is the starter cell. THIS is the only genetic information that this embryo will have to work with from these two chromosomes. So, again, I ask, how could a mosaic situation exist?

This last miscarriage was caused by an unbalanced translocation. It was inherited  [unless you want to imagine a new and yet identical de novo (spontaneous) situation of such mind-blowingly coincidental proportions even typing it makes me laugh out loud, Ho ho ho] so we know that the sperm that created it was unbalanced. Therefore that very first cell was unbalanced as well. If that embryo carried normal cells as my IVF clinic would have me believe, well, I ask you, WHERE DID THE MISSING PIECES OF THE FOURTH CHROMOSOME MATERIALIZE FROM? The Piggly-Wiggly? That half of the fourth chromosome was GONE. It DID NOT EXIST.

The Playdough doesn't lie, people.

Do you want to know what I think? I think they transferred the wrong embryo, that's what I think.

And do you know what else? It does not matter one iota. It just... happened. But I did feel a need to explain why I do not think an inherited unbalanced translocation can display patterns of mosaicism.

I expect you will be seeing me and my playdough in Sweden for my Nobel prize quite soon.....

(Aw damn it. This looked much prettier in my browser window. I keep trying to move the little images so it is all slick and informative but I do not know how. I DO know this is boring, however, and I am sorry. But it is also good for you, like spinach, so buck it up campers. I did just get permission from Steve to write about his adoption and finding his birthmother so if you like more human interest and less genetics stick around.)   

Edited for clarification (I hope): Whoa, the human egg carries 46 chromosomes?? Really? Is that true? So much for Sweden...

Mosaicism is when an embryo has both chromosomally normal and chromosomally abnormal cells. Patrick won't let me have the playdough back so we are just going to have to squinch our eyes and try some Imagination Time to visualize this. It is sort of easy to see how this can happen with trisomies (trisomies occur when there are three copies of the same chromosome; Down's Syndrome is an example of this.) You could start with a trisomy and during cell division the extra chromosome could be shed and voila you have a normal cell replicating itself right along with the abnormal ones. Or, conversely, you start with a normal cell and during cell division an extra chromosome gets tacked in and voila you have an abnormal cell replicating itself right along with the normal ones. That makes sense, doesn't it? The reason I do not think that mosaicism is a reasonable explanation in our case is that the embryo must have started with missing genetic information that could not be replaced (See Playdough, above.)

If this last miscarriage had carried any other abnormality than the one it did I would say ah, yes, well, such is the mystery of meiosis (or maybe mitosis; if I got the egg thing wrong I am clearly not to be trusted too much with the biology, although my logic is flawless, thank you) but it carried Steve's very very specific translocation. Not just the same chromosomes but the q break at 33.1. Like I said, specific. 

It is easier for me to imagine a mis-labeled embryo than it is for me to imagine strange coincidences at the cellular level. I am simple like that. But but BUT I do not know. They do not know. Collectively we will never know, which absolutely kills the mystery reader in me, but other than that I can live with it.

Believe it or not, I think the clinic did a great job, over all. I am even impressed by the way they researched the cause of the miscarriage, down to bringing Steve's original karyotyping slide to DC via courier. And while I appreciate your righteous vehemence on my behalf, I still think it was decent of them to offer us anything at all towards another cycle. I know, I know, you guys believe they should cover the whole thing AND send me orchids every day but I am satisfied with less. I would certainly use them again if they were not so far away and if IVF had added one damn thing to my life. I still might, I suppose, who knows. IF the wrong embryo was transferred then I believe such an occurrence falls under the banner of easily understood human error. Frequently someone has to bear the burden of living with imperfect individuals in an imperfect world. When I was 17 I was a hostess in a nice DC restaurant. One night a couple came in to wait for a table and I completely forgot about them. Eventually I started seating people as they walked in the door and the guy who had been waiting for over an hour lost it and told me that I had ruined dinner for them, not just for that night but FOREVER. See, in that situation, he was the victim of my imperfection. Maybe it just was my turn with the PGD.

Personally, I like Ms Sisyphus' excellent theory that I was Caligula in a past life and I am paying for it now.             

Comments

[anja]

Very impressed by the creative playdough. All genetics should be displayed in playdough, I think. Not boring! :)

[lizardek]

Sweden?? Did you say Sweden? We have a guest bedsofa!

[Kinneret]

I think you should show the folks at the Grove of Shadiness your playdough presentation. Because it sounds like they screwed up. I'm sorry.

[Brooke]

Yeah, I don't buy the mosaic explanation at all. And I just got an MS in molecular biology (well, I think I did. It hasn't actually shown up in the mail yet), so I know playdough. Uh, I mean genetics.

I hadn't thought about transfering the wrong embryo. I just assumed they screwed up on the karyotyping.

I don't know if it's worth confronting them about their crack-pot explanation, but I'm amazed the think you know so little about what a balanced translocation is.

Although, thinking about it, I guess a mosaic situation could show up if they transferred a normal and an unbalanced embryo and they fused. But that is unlikely and they still would have had to transfer an unbalanced embryo. Or they could have fused in the lab, but I think they would have noticed that.

wow. this is a long comment.

[Karen]

I'm sorry, they did WHAT??

This is Karen, your lawyer friend, speaking. I think you definitely need to show them your presentation. And tell them about Karen, your lawyer friend. And ask them to re-word their offer of "another cycle at cost," wherein they replace the phrase "at cost" with the word "free."

Hmph.

[Mollie]

I feel like someone just pushed me off a tall building.

[MsSisyphus]

I thought it was pretty darn interesting, actually. A real credit to your writing that you could make it so. (of course, the playdoh helped. How can you not love playdoh?) I agree that the proof is in the playdoh, and I commend you for seeming so sanguine about it. I you believed in reincarnation, you'd have to be asking yourself which one of you was Caligula in a past life, because man, the universe seems determined to make you pay for something. Hopefully your reward will far surpass the price you had to pay to get there.

[Lisa C.]

I tested out of two years of college biology about 8 years ago, but I still remember enough about meiosis and mitosis to know that you are exactly right.

It sounds like "mosaic cell presentation" is a fancy medical way of saying "we don't know what we're doing."

I think the Grove of Shade needs to take a deep breath and offer you a free cycle. 100% free. Transplant genetically abnormal embryo, do not collect $20,000.

[S]

I'm working on a PhD in cancer research, and it doesn't make any sense to me, either. I will ponder some more, though. Did you ask them about it?

[S]

http://www.carolguze.com/text/442-4-chromosome_abnormalities.shtml

Goes over all types of translocations toward the bottom.

Could the embryo have had a de novo crossover (just like Steve's) as it was dividing? That way, every cell after the one that crossed over would be crossed over and the regulars would produce more normal cells, giving you two types in one embryo. I don't know a lot about in vitro fertilization, I'm assuming they wait for at least a clump of 8 before trying to implant.

[KatBT]

Man, Julia, you are bad ass! I seriously think you should push the Shady folks there at the Grove about what the fuck really happened. I hate those stupid little disclaimers on everything genetic about the miniscule possibility of unforseen mosaicism. Just covering their asses.

By the way, I'm PG again (at least today). If this on last a few weeks and I get the luxury of actually thinking about my translocation, I'll be coming to you for a play-doh presentation.

Seriously, though, if you have any good links to info about Robertsonian Translocations, let me know. It seems like almost every google search I go to sends me to a website about PGD rather than the translocation. I need info on the condition, not the latest "cure."

Thanks,
kat

[Cat, Galloping]

*Boiling mad over here.*

I truly hope that whatever you decide about the next round, you have THIS EXACT conversation with the folks over at Shy Grve. Bet you the reason they're offering you a little gift certificate is exactly what you said-- they transferred the wrong embryo and they know it and they're hoping you're too dumb or too grief-stricken to figure it out and sue their asses. In which case, they owe you 100% back on the last round PLUS another totally free cycle (or, frankly, however many you need/want to get another actual healthy baby).

[Lisa S (et al, aka Stolidoli)]

I totally understood you for the first time, until you started talking about mosaicism. I used to think I was bright.

Guess I'll try the website given above.

Anyway, regardless of MY being able to understand you, I believe you when you say you're right. Go Julia!

[Jenn]

I really hope you confront them with this and let us know what they say. What you are saying makes perfect sense to me.

[Kristine]

Um, I didn't take biology. So... your baby's father was Mr. Bill? I'm confused.

Just kidding. (well, a little) I think you and Karen should get your asses over there and get you a do-over at no charge.

[Ollie]

You explained that FAR better than my crappy Biology teacher did. And I think your theory is pretty sound. I distrust IVF professionals these days anyhow.

[Diatryma]

Your theory is sound-- but I've heard of mosaic Downs syndrome, too, and-- okay, after looking it up, it isn't exactly the same, but you can sometimes end up with weird results.
I would ask for free, or maybe they could pay you. Silly people.

[victoria]

The playdoh helped me, too. I agree with Karen, your lawyer friend: even if the contract did not guarantee you a healthy pregnancy, they breached the contract by their gross negligence. While the contract may shift to you the risk of ordinary negligence, their transferring the wrong frickin' blast is grossly negligent.

In other words, what happened is the same thing as if you'd paid & performed your promises under the contract, and they just basically sat there & did nothing.

They still owe you specific performance. They still owe you what they promised.

And you owe them nothing.

You would have to get a lawyer to make them comply, however, which would take you time & add even more stress & misery to this whole process. I'm not sure you would want to be treated by health care providers whom you were suing.

[Laura K.]

I think I'll just send people this link when trying to explain my balanced translocation to them - I'll bet I'd get a lot less head-nodding with the blank stares...

Do they make a 'genetics' playdough kit? You know, one with special cutters and presses just for making chromosomes?

[Danielle]

Normal sperm has 23 chromosomes but a normal egg has 46 chromosomes right up until it is fertilized.

[Crystal]

I'm with Lisa. You had me until unbalanced, and mosaic... But I'm probably missing important pieces here.

Hey, liking the Ph.D cancer researcher person.... Want a subject? I'm available...

Julia, care to elaborate on whatever my feeble mind is missing? I'd like to understand, but I'm afraid I don't. Perhaps that's telling in and of itself...

[KatBT]

Hey Julia,
I've just gone back and reread your post so it's even clearer in my mind. And now I REALLY REALLY agree with you that they may have put the wrong one in there. If I'm understanding mosaicism as it's been described to me by my GC, mosaicism is where there might be an unknown percentage of cells IN THE BODY that can't be determined by testing a handful of cells. BUT... in an few-celled embryo, if that one cell is unbalanced, it's ALL unbalanced. The mosaicism excuse is just bullshit. (Of course, I'm not a scientist. It just doesn't jive.)

One thing's for certain, you're certainly in a fairly public position to vouch (or not vouch) for those shady grovesters through this blog. I'm not suggesting that you threaten them, but I will say that I think your continued honesty about this is a really good thing for others considering using SGrv.

And then again, I really do hope you nail their asses to a wall until they make up for this with a better offer than what they have already given. They probably didn't know what they were getting into working with you... you show them that playdoh girl!!!!

~kat

[Shamhat]

I think the most likely explanation is that the PGD results were incorrect--they transferred an embryo that they had identified as not having the translocation, but they were wrong. PGD isn't straightforward and reliable yet. I don't suppose the fee is refundable...

[Sarah]

Juila,
Thanks for the demo--I finally get it!

Sarah

[LauraN]

Julia,
I am really picking my brain to retrieve all I learned in the olden days of my college life (Biology degree and 8 years of graduate studies, including more Genetics). The one thing that I can think about is that the embryo started normal and then an imbalanced translocation happened during the first few cell divisions. What are the chances of that happeing? Probably rare, but that's how it may have happened for Steve, his bio-parents may not have carried the translocation, his could be a new one.

If I were you I would get a copy of all the karyotypes, the medical records etc. I would then try to find a geneticists not connected with the hospital/clinic where you had your IVF to discuss your case.

If the missing piece of chromosome was prominent they should have seen it during the PGD analysis, so my thought is that they really tested a normal cell. On the other hand there is the chance that they transferred the wrong embryo but I am afraid they will try to cover it up. BUT, if indeed they had detected a new unbalanced translocation in one of the embryos, before the transfer, my guess is that they would have informed you, right? That's major information in my opinion and there should be some indication on the medical records, embryo reports. Is the unbalanced translocation in one of the chromosomes where Steve has his?

Good luck trying to get through all of this,

Laura

[LauraN]

Julia,
I am really picking my brain to retrieve all I learned in the olden days of my college life (Biology degree and 8 years of graduate studies, including more Genetics). The one thing that I can think about is that the embryo started normal and then an imbalanced translocation happened during the first few cell divisions. What are the chances of that happeing? Probably rare, but that's how it may have happened for Steve, his bio-parents may not have carried the translocation, his could be a new one.

If I were you I would get a copy of all the karyotypes, the medical records etc. I would then try to find a geneticists not connected with the hospital/clinic where you had your IVF to discuss your case.

If the missing piece of chromosome was prominent they should have seen it during the PGD analysis, so my thought is that they really tested a normal cell. On the other hand there is the chance that they transferred the wrong embryo but I am afraid they will try to cover it up. BUT, if indeed they had detected a new unbalanced translocation in one of the embryos, before the transfer, my guess is that they would have informed you, right? That's major information in my opinion and there should be some indication on the medical records, embryo reports. Is the unbalanced translocation in one of the chromosomes where Steve has his?

Good luck trying to get through all of this,

Laura

[LauraN]

Julia,
I realized I accidently posted the same message again. I apologize.

Anyhow, I read again your last entry and the embryo had a missing piece on the fourth chromosome, the same as Steve's. What are the chances that there is a inherited weak area in that part of the DNA so there is a higher chance of breakage there? I know, far fetched, but something a Geneticist would be able to address. I am also remembering that all the chromosomal re-arrangements (sp?) happen in the gametes as they form (therefore creating diversity), so in theory the sperm should have had that translocation, therefore all the embryonic cells should have been the same, so the lab should have detected the translocation. Again, something a Geneticist should explain.

I hope all this makes sense,

Laura

[KatBT]

OK, another thought I had about this last night. Do they know the sex of the embryos they tested? I mean, were there little x's or y's detectable then, or did they only test for the translocation? A clincher for me would be if the one that they tested as OK was a boy. Though they're probably not going to be eager to give you those results now if this is, indeed, what happened. I'm soo soo sorry.

[Karen, Your Lawyer Friend Again]

Hey, babe, if you're happy, I'm happy. You know us lawyers. We get a little jumpy sometimes.

Sincerely,

Someone Who Wants To Grow Up To Be You

[JuliaKB]

Hi Julia,

I think I have figured out a way this could have happened, but it would then require a three-way mosaisism.
I wish I had playdoh to show you what I mean, but let me try in words.

Let's suppose you start with a balanced translocation sperm (blue/red 1 and red/blue 4). Which fuses with normal egg (yes, it has 46 chrmosomes, or rather 23 duplicated chromosomes, but it undergoes Meiosis II division upon fertilization [and creates a polar body with the 23 chromosomes that will not be used in procreation] so only 23 chromosomes are present at the introduction party with the sperm-delivered friends).

Now you have the picture of the first cell just like Steve. Now suppose in one of the MITOTIC divisions, after all DNA is replicated, and copies are held at the centromeres (so you have one double red 1, one double blue/red 1, one double red/blue 4, and one double blue 4), one of the blue/red chromatids recombines with one of the red/blue chromatids. That would give you one double red 1, one blue/red-red 1, one blue-red/blue 4, and one double blue 4. Ok, now these chromatids get pulled to one or the other daughter cell. The double red and blue ones are easy-- each daughter cell gets one of the solid colored ones. Now, suppose the other ones get pulled assymetrically. i.e. solid red goes with red/blue and blue/red goes with solid blue. That would give you two different types of unballanced cells. Depending on what was the fate of the cell where this crazy dance originally happened, one of these types may not have made very many daughter cells.

Of course, all of this is only possible if in some other cell, the balanced translocation fixed itself, so that they could even detect normal cells. And what are the chances?

Occam's raisor says that your explanation is probably right, but I just wanted to throw this crazy possibility out there. But it's so crazy I would never give it as a problem to my students. Way too hard.

[Judy]

If you decide on another demonstration I think you should use either marzipan or colored pasta dough (in place of play dough), so that the demonstration can double as dinner or dessert.

Then for your final slide you can use a photo of Patrick munching on the problem chromosomes. I guess that with Patricks diet you'd be better off using something healthy like sticks of celery and carrot.

[Thalia]

Julia,

I am also a geneticist, and it looks like they messed up. I've played around with some chromosomes tonight and any other explanation is incredibly unlikely. I'm with karen - you should go for a free cycle, not to mention I bet you could sue them for pain and distress (you're american, after all - isn't that what you guys always do??)

[Cathy]

Hi Julia,

I did a quick search on mosaics in the scientific literature. This first paper that I looked at (ref below) studied the embryos of a couple that carried a translocation. Of ten of the embryos, 2 were strange. One could be explained by a non-disjunction event (they called it a mosiac), but the other had a combination that didn't make any sense. I think that this is a very new area of research and there is a lot that is not understood about how a cell deals with new chromosomal combinations, particularly ones that are deleterious to its survival. I think it's worth trying again. You probably were simply unlucky (either b/c of the mosaic or b/c SG made a mistake) and next time it should work.

By the way, an egg does have 23 chromosomes, unless you count the useless leftovers of meiosis (called the polar bodies).

"Preimplantation genetic diagnosis for an insertional translocation carrier"
Human Reproduction 2004 19(12):2777-2783

[ManhattanAnne]

Ouf.

[S]

Unless you have some kind of university pass you're not going to be able to download the article mentioned. Let me know if you want me to e-mail it to you. Beats going to the library.

[Anita]

We just joined a church last week in a feeble attempt to integrate our new family into a socially active (as in feed the poor and comfort the discomforted) community. Our lesson today was on forgiveness. I agree with you that it's highly unlikely that anything random happened and highly likely that they transferred the wrong embryo. yay for you for forgiving this error. This is a good example we could have used in our discussion.

I'm so pulling that the next IVF works out well.

[Kim]

Forget the forgiveness - make them, A, admit they screwed up, and, B, give you at least one free pass, maybe two for pain and distress. You understand this so completely - I am quite impressed with the Playdough demonstration.

You go, girl!!!!!!!!!

[Mollie]

Oh, dear God, please tell me you wouldn't have need of two free passes.

[Toni]

I love playdoh - you can use it for EVERYTHING (perhaps a top ten list similar to the baking soda is in order??).

As for the genetics stuff...loved it in college - have no clue after 6 years out. Going to agree with those that commented that discounted should be changed to free.

I wish you luck on this one....it's tough.

[Sara]

Two other thoughts:

Is Steve actually mosaic for his translocation, himself? Has he been tested with a variety of cell types? ALthough that shouldn't make a difference, because his sperm would still be either good or bad, depending on whether it came from a good cell or a translocated cell.

And: I"ve read that its possible for two blasts to crash into each other before implanting. Sometimes they fuse (the opposite of identical twinning) and sometimes they separate again, and sometimes they exchange bits of information when they do that. Interesting stuff, embryology.

[Stephanie]

Well, I can actually come up with a few exlanations of how the mosaicism could occur, not easily described in comments though. Some of the explanations of how they could have gotten the results they did on the testing depends on how they would have set up the testing. Failure of the test to detect the unbalanced form and transfer of the wrong embryo would be possibilities that would exist too. The reality is that it will be very difficult if not impossible to know for sure and there are explanations that do not involve human error. If you want a better explanation from the clinic, you are absolutely entitled to one and they should provide one, with as many playdough demonstrations as necessary for you to understand.

PS I have a PhD in genetics and have worked exclusively in human genetics including prenatal testing, karyotyping, and FISH.

[Brad]

Does anyone else think the fact that Shdy Grve voluntarily offered a discount is a screaming mea culpa? Why would they offer a "settlement" before you even started asking questions? I think you should push for a little more information on the whole thing and "settle" for a freebie, too.

[KatBT]

I think it's noble to be fogriving. But I agree with the previous commenter and others, that their "offer" of voluntarily giving you something seems a bit pre-emptive. Something doesn't smell quite right with this. And the fact that the breakpoint is the same is very suspicious.

It's also interesting that you have geneticists commenting on here, one saying that it was probably a mistake. Another saying that it probably wasn't.

Can you talk to a geneticist about this, show them your playdoh diagram and ask your questions? Someone unbiased... definitely not Dr. K since he's too connected to the SGers.

In spite of it all, does this mean you're going to do PGD again?

~kat

[S]

I think it boils down to the following - it could be a mistake, but sure, weirder things have happened and it's possible that it looked like the right combination after their testing. Are you going to take the freebie?

[Rebekah]

THANK YOU for explaining all of this so well! I am totally a visual learner, and this was perfect for my addled brain.

[Elizabeth]

I'm totally *not* a geneticist, but if the sperm in question had both the red-blue and the blue-red chromosome, couldn't you get a mosaic if they switched back to where they belonged in some of the cell? You only have the "case of the missing DNA" if the sperm had a plain red chromosome and a red-blue one (or other combination of regular and mixed up). Right? Maybe?

Love the visuals.

[Tonya]

I've not been online for a week or so, mostly because I've been freaking out about the amnio that I got last Tuesday and awaiting the results. (FISH came back as no trisomies- specifically no trisomy 21, which was the basket that held all of my worried eggs. The fetus showed 2 soft markers for downs.) Now I am awaiting the full genetic work up, and although I know the chances of downs are very, VERY slim, I can't help the worry machine from humming about a translocation.

Your post was very timely- thanks for the refresher course.

[hans]

actually... is it abnormal translocations can cause miscarriages...? i mean is it most cause by this process or others process such as mosaicism or uniparental disomy...