Variant of Unknown Significance
The Ins, the Outs, and the Unknowns of Genetic Testing
I have Marfan syndrome. Everyone and their moms know it. I am tall and lanky. My fingers are spindly and my lenses are dislocated. I was diagnosed at 8. My mother died from an aortic dissection. I am pretty much the textbook case of Marfan syndrome. Trust me, I have a lot of textbooks — I majored in genetics and taught genetics in graduate school. That was also when I finally came to see a geneticist. I opted for genetic testing mostly for the sake of curiosity. I was certain what the result would be: a mutation in the FBN1 gene. According to all the sources — Wikipedia, my various textbooks, the NIH’s Genetics Home Reference — “mutations in the FBN1 gene cause Marfan syndrome.” I’m stuck with this syndrome anyway, so it would be cool to know what kind of mutant I am.
The results came: I was a “variant of unknown significance.” My FBN1 gene didn’t have any mutations, but they found a change in my COL5A1. Did I lose you already? Come back, I’ll explain all the acronyms and jargons.
Marfan syndrome is a connective tissue disorder. Connective tissue is the glue that hold your body together — it’s in your skin, your bones, your eyes, your lungs, your blood vessels, so pretty much everywhere. It is made from assorted proteins that weave themselves into very tight and neat braids. You know Jenga, the game in which you try to remove building blocks from a tower without making it fall apart? It gets harder and harder, because when you pull out a bunch of blocks, the tower becomes really wobbly. Normal connective tissue is like the starting Jenga tower: organized and stable. Marfan connective tissue is somewhere between a mid-game and a game-over tower: fragile and topsy-turvy.
Now that you have all that under your belt, I’ll tell you about two kinds of “blocks”: fibrillin and collagen. Sounds like the stuff Olay puts in their lotion? Yep, they claim it helps your skin because it is in your skin. FBN1 is one of the genes that tell your body how to make fibrillin, and COL5A1 one of those that tell it how to make collagen. In Marfan syndrome, the instruction gene has mistakes. When genes have mistakes, they are called mutations or variants. Their products — the protein blocks — are misshapen. The whole structure of connective tissue becomes weak. This leads to all sort of symptoms: dislocated lenses, funny joints, long bones, wimpy lungs, and flimsy blood vessels.
When genes have mistakes, they are called mutations or variants. Their products — the protein blocks — are misshapen.
Fibrillin and collagen are huge proteins, which means the instructions to make them are super long. Just like putting together an IKEA dresser: the longer the instructions are, the more chances there are to make mistakes. So when fibrillin and collagen are made, mistakes happen pretty often. Sometimes they just happen out of nowhere (the fancy term is de novo, in case you want to impress/confuse someone). This is why many Marfan people have their own unique variants with no family history, even though Marfan is a genetic condition. Besides, not all mistakes are equal. It’s one thing if you paint your IKEA dresser a bad color, but if you skip some screws where they should be, that’s another thing. The problem is, a lot of the time, we don’t know what kind of mistake it is. Is it a bad paint job kind that doesn’t affect function much, or is it a missing-screws kind that will make the whole thing fall apart? And that, my friend, is what they call “variants of unknown significance.”
But I have all the symptoms. My lenses have dislocated. My lungs suck at being lungs. My mother has died. What on earth is unknown about this significance?
While the Marfan patient in me is upset, the geneticist in me knows the answer to that question. The mutation I have in my gene is not well understood, and how it leads to symptoms is not known. It creates these problems in me, but nothing guarantees that it will create the same problems in other people. Even my mother and I didn’t have the exact same problems, assuming I got the mutation from her, so we carry the same variant. She didn’t have dislocated lenses, and her lungs were fine. I have not and might never have an aortic dissection like she did. There is a reason Marfan is called a “syndrome”: symptoms are different patient to patient, and so is the underlying genetics. The path from genes to symptoms are long and chaotic, and there is not yet a way to predict what a mutation or variant will turn out with absolute certainty. My result didn’t say “no significance,” it said “unknown significance.” That’s the way science shrugs, “I don’t know.”
Research is trying to untangle that mystery, but it takes time. As a rare disease, Marfan syndrome is not easy to figure out. To study a genetic variant, first, they have to get enough patients who have that same variant. Since Marfan is both rare and caused by huge genes whose mutations are random, the chance of recruiting these ideal patients is very, very small. Priority will be given to variants that pop up frequently across patients, and others will remain “of unknown significance” for a while. That’s not because science is heartless. Quite the contrary, it’s trying to be as useful and efficient as possible. It ought to help the most number of people while running on limited resources (funding, trained experts, time, etc), which means it can’t look into all the unique variants at once.
The path from genes to symptoms are long and chaotic, and there is not yet a way to predict what a mutation or variant will turn out with absolute certainty. My result didn’t say “no significance,” it said “unknown significance.” That’s the way science shrugs, “I don’t know.”
If you have a common variant that is already somewhat understood, genetic testing is useful, since lifestyle has huge impacts on the progress on Marfan syndrome. If the test comes back as an absolute yes, that sucks and I’m sorry you have this condition, but at least you know to not run triathlons. You know you should have an echocardiogram every so often. And you know to watch out for chest pain. You can suggest your family members to get tested, and then they could take all the precaution to protect themselves from the worst thing Marfan can cause: sudden death. When the test comes back negative or unknown, it’s not yet time to celebrate, especially if you have family history with Marfan-related symptoms. You might have a rare variant that isn’t detected in the test. It might be on a gene that isn’t known to cause Marfan syndrome. The test might have been wrong because of some technical mistakes — that does happen. Genetic testing is nowhere near 100% absolute, it should be prescribed with a grain of salt.
Doctors often don’t explain all of the ins and outs of genetic testing to their patients. Maybe it doesn’t occur to them, maybe they don’t know how to explain it well, or maybe they don’t understand what it means themselves. If the confused patient is lucky, they will be referred to a genetic counselor. Right now in the U.S., there are about 4000 genetic counselors and about 50,000 to 200,000 people who have Marfan syndrome, depending on your source. That is not counting the 25 million people who are affected by the other 6000 rare diseases. How many people are not getting the counseling they need? Too many.
Genetic testing is nowhere near 100% absolute, it should be prescribed with a grain of salt.
People tend to think about genetic testing as the end of a story. The word “test” gives us a feeling that it is something we take at the end, like a final exam: we either pass or fail. But genetic testing is not a final exam. It is only the beginning.
Once the test comes back, who gets to read it? The patient and their medical professional team? Sure. Their family? Okay. How about their insurance? Their employer? The government? The public? I hid Marfan syndrome from other people for a long time, for I didn’t want to be treated differently. In college, I once tried to tell my PE teacher that I needed an exemption from practicing basketball. I showed him a doctor’s note. He didn’t look at it. He told me “If you are not well enough to play basketball, you shouldn’t be in college.” In Vietnam, my home country, employers still ask for “health status” on job application. This is not for equal opportunity purpose, but the opposite: so that they don’t hire people who would have to take medical leave all the time.
But genetic testing is not a final exam. It is only the beginning.
Or imagine you are a young pregnant woman living in Missouri. Someone in your family has Huntington’s disease — a neurological disorder with late onset and no cure. You want to be tested. The test comes back positive. Your health insurance just expired, and no one will take you because you will have this costly disease some day. It will start breaking down your nerve cells, making it hard for you to move, to talk, and to think. You can’t get car insurance either, because Huntington’s comes with jerking movements and loss of balance. You might not be able to get a job. As Huntington’s progresses, even brushing your teeth will become absurdly difficult. In the last stage, it takes away the ability to walk, to speak, and eventually to live. You also realize that your baby will have 50% chance of having this disease. I wish this was just an imaginary story I made up to scare you. When I first heard it, I cried.
What would someone do during the months or years they wait for their test results? They might proceed with life normally and happily. They might pause everything and hold their breath. Either way, it is a decision to be made.
There are a lot of decisions to be made with genetic testing. Getting tested at the first place is itself a decision. I won’t talk about the blessing of knowing versus ignorance bliss; let us go into mundane things: money and time. In the U.S., testing service of high quality is expensive without insurance. There are cheaper ones that you can order on the Internet, but they are even less conclusive — remember “variants of unknown significance”? You will be left swimming in an ocean of information without knowing 1) Is it accurate?, and 2) What does it really mean? The test takes months, sometimes years, to come back. What do you do in the meantime? I take Marfan into account when I make many decisions: getting married, having kids, choosing jobs, picking a place to live. My partner has to be ready and willing to go through this with me. I have to think about the risks on me and on my children if and when I want to have them. Strenuous jobs aren’t for me. Before I move anywhere, I need to know the medical system there like the back of my hand. What would someone do during the months or years they wait for their test results? They might proceed with life normally and happily. They might pause everything and hold their breath. Either way, it is a decision to be made. And there are more decisions down the road when the test comes back. It is only the beginning.
Science says the first word on everything, and the last word on nothing.
— Victor Hugo