Balanced translocation and chromosome inversion, explained

If you’re reading this because you’ve recently been diagnosed with a balanced translocation or chromosome inversion, I’m sorry you’re here.

I was diagnosed with a chromosome inversion right as COVID-19 began to make its way to the U.S. It felt like I was faced with two raging pandemics, both of which would upend my life. I want to help you navigate this diagnosis with the information I wish I had when I was first diagnosed.

What is a balanced translocation or chromosome inversion?

If you found out you have a balanced translocation or chromosome inversion, it’s because you’ve had a karyotype, or map of your chromosomes, created. Likely, this was done after recurrent pregnancy loss.

Balanced translocations and chromosome inversions fall under the umbrella of “structural chromosome rearrangements.” These refer to when a chromosome breaks off and reinserts itself 180 degrees (inversion) or breaks off and re-joins with another chromosome (translocation).

Let’s take a step back for a biology refresher in case you, like me, were much more interested in baking cookies and watching “Friends” than in doing biology homework. Genetically typical (I prefer this phrasing to “normal”) people have 23 pairs of chromosomes. Chromosomes 1-22 carry hundreds of thousands of genes that can determine your physical and mental traits, propensity for diseases and more. Your 23rd chromosomes determine your sex. I should note that “determine” is a complicated term and we could argue how much of genes are deterministic—and when it comes to sex, how our definitions are cultural, not scientific—but let’s put a pin in that for now.

Each chromosome is akin to a construction truck transporting thousands of workers, or genes, that all play a role in executing the blueprint that makes you. Each construction worker is tasked with a function, which may be to create your eyeballs or to ensure your blood clots properly.

In “balanced” chromosome rearrangements, it means no genetic information was lost or gained in the rearrangement. The construction-truck-chromosomes swapped rows of workers or have the workers upside down, but everyone can still do their job. “Unbalanced” chromosome rearrangements mean genetic information was lost or gained (or both) in the rearrangement. It’s as if one or more of the construction-truck-chromosomes lost some workers or gained workers who mess up the blueprint. It’s an imperfect analogy but I hope it helps you conceptualize this abstract topic.

How does a balanced translocation or inversion impact me and my fertility?

I’ll start with a caveat—genetic research on structural chromosome rearrangements is still relatively new. Honestly, it’s such a bummer. If the billionaires of the world could pause their space fantasies and invest in simple genetic research (and let’s face it, anything that benefits birthing people), we’d all be better off. Alas, I digress.

If you have a balanced chromosome rearrangement, you have all the genetic information you need to be healthy. Your blueprint was executed just fine. When you try to have children, however, that’s when the problems occur.

First, your pregnancy outcomes are the same whether you have the rearrangement, or your partner does. It doesn’t matter who is birthing the child. Because these rearrangements affect the sexes equally, I’d hope it’d be a rallying cry for more research in this arena.

And frankly, even reproductive experts don’t quite understand these phenomena. When listening to a recent episode of “The Egg Whisperer” podcast, I was shocked to hear Dr. Aimee give a flippant response to a caller who was concerned about her chromosome inversion affecting her pregnancy outcomes. It was a major ‘ouch!’ for me. I’ve been at it over three years with six naturally conceived pregnancies that were all genetically atypical. This is to say, even your IVF doctors and other medical experts likely don’t quite know what’s in store for you.

For people who have, or are attempting to reproduce with someone who has, a balanced structural chromosome rearrangement, every pregnancy is like rolling a genetic dice. There are four possible outcomes:

1. Your embryo is genetically typical. It has all its chromosomes and all the genetic information it needs, in all the typical places. Thus, this pregnancy is not a carrier, and your rearrangement ends with you.
2. Your embryo carries the same balanced structural chromosome rearrangement as you or your partner. In other words, they have all the genes they need to be healthy, with some being rearranged. They may have trouble trying to have genetically typical children.
3. Your embryo is unbalanced. In the process of your and your partner’s chromosomes matching up and crossing over to create an embryo, some of the genetic information got deleted or duplicated. Enough genetic information is negatively affected (deleted and/or duplicated) that you miscarry.
4. Your embryo is unbalanced. In the process of your and your partner’s chromosomes matching up and crossing over to create an embryo, some of the genetic information got deleted or duplicated. Not enough genetic information is negatively affected for you to miscarry, but your pregnancy will either live only shortly after birth or survive and have developmental issues. The range of development issues varies significantly. Some elect to terminate these pregnancies.

I’ll add that miscarriage and stillbirth unfortunately can occur at any stage, including embryo demise before implantation or before HCG is detectable.

I know these different scenarios are overwhelming. How do we go from #1-#4 in the same person, right?! If I weren’t the one affected by this, I’d find it fascinating. As a person suffering from it, I find it cruel and terrifying.

Now, #3 and #4—unbalanced embryos—are what keep us up at night. Some of us may have one or two miscarriages before getting to a genetically typical child. For others, it takes tens of miscarriages. For others, it’s a mix of miscarriages and pregnancy terminations. For some of us, a pregnancy or genetically typical pregnancy never happens.

What determines your pregnancy outcomes are luck, how much genetic information is affected by your rearrangement (or your partner’s), and whether you have the financial resources to dedicate to IVF and/or donor eggs/sperm.

One of the notes on a karyotype report is where your breaks are. “Breaks” refer to where your chromosome broke off and either reinserted itself 180 degrees (inversion) or connected with another chromosome (translocation). Typically, the larger your breaks, the more genetic information is affected, meaning a miscarriage is more likely than a pregnancy that goes to term.

How did I get a balanced translocation or chromosome inversion?

You didn’t do anything wrong. If you have a balanced structural chromosome rearrangement, you either inherited it from one of your parents (whomever had it would be called the “carrier”), or it developed “de novo,” which is Latin for ‘fuckin’ bad luck.’ Just kidding; de novo is Latin for a form of a genetic mutation that occurs for the first time.

I know that neither option is necessarily more comforting than the other. For those who’ve inherited it, you may feel resentment toward your parent carrier. I’m sure your parent wishes they could take back this terrible family heirloom. For those who’ve spontaneously developed it, you may feel your luck is terrible. All your feelings are valid and I’m sorry.

I inherited my inversion from my mother who didn’t know she had it until my twin brother and I, after recurrent pregnancy losses, got tested and found the cause. I asked my mom to get tested to see if she was the carrier and she was. While the diagnosis explains her miscarriages and stillbirth before having me and my brothers, it offers no comfort. My older brother appears to have been spared. He’d be #1 in the scenarios above. My twin and I would be #2.

How frequently do structural chromosome rearrangements appear?

Here we go again with the caveats. There’s just not enough research on each type of balanced structural chromosome rearrangement to know for sure how frequently each occurs, but we know that balanced translocations, which are more common than inversions, occur in up to 1/500 people.

Where do I go from here?

There is some hope for people with chromosome rearrangements to have a genetically typical pregnancy.

With IVF, we can test embryos to see if they’ve been affected or not before we transfer them. Those with structural chromosome rearrangements will want to opt for both PGT-A and PGT-SR testing. You will want to speak with a genetic counselor to best decide which tests can catch unbalanced embryos. I’ve known some people to have rearrangements that required a special “probe” be designed to test their embryos.

If you go the IVF route, make sure your reproductive endocrinologist has experience with balanced translocations and that the genetic lab they use is similarly well versed. I say experience with “balanced translocations” as opposed to “structural chromosome rearrangements” or “inversions” because “balanced translocations” are the most common and thus most known.

Keep in mind, as I’m sure you intuitively know if you live in the U.S., infertility coverage is sparse, especially when it comes to IVF. Even in the most progressive state, California, IVF is considered an elective procedure and employers are not required to cover it. To add insult to injury, in the rare cases your employer offers IVF coverage, your insurer may define “infertility” as “inability to conceive,” which precludes many people like us. These injustices fill me with the rage-fuel needed to actively advocate for changes to healthcare law.

Resources

If you’ve been diagnosed with a balanced translocation or inversion or your partner has, there is a fantastic Facebook support group here. I don’t know how I would have survived this diagnosis without it.

Want further reading? This article is helpful, but it may take some time to understand. I also recommend the book, Not Broken: An Approachable Guide to Miscarriage and Recurrent Pregnancy Loss (I’ll note that the author only dedicates a few pages to balanced translocations and none to the other rearrangements).

Again, I’m sorry you’re here. I hope you found this helpful.