Genetic Testing- Coping with Uncertainty

Its been a while. I’ve been up and down and all over the place in the past few months. Such is the nature of chronic illness. I still feel better than a year ago, on the whole. But I find myself wishing I felt better. Especially as the summer winds down and I find myself facing the upcoming academic year. So much uncertainty about what it will hold, both professionally and physically.

I want to talk through some thoughts about genetic testing. When I was first diagnosed with hEDS, my geneticist recommended Trio Whole Exome Sequencing. This is a kind of test that looks not just for specific genes, but at everything that is on the outside of the DNA–the exome–and matches any significant mutations against your parents to show where the variant came from or if it us unique to you– “de novo”. In particular, the geneticist wanted to rule out vascular EDS (there is a history of intestinal rupture on my dad’s side of the family) and any of the known breast cancer genes (runs on my mom’s side). I decided to wait for several reasons. First, my mother lives abroad, and getting a sample from her would be tricky. I also wanted to wait because I knew it would be expensive and I wanted to let the science mature a bit, allowing the cost to come down and more to be discovered about the genetic basis of hEDS. And, I wasn’t entirely sure I wanted to know about the breast cancer genes.

Well, my mom had a health crisis several months later and was going to be around for a while, so I decided to get the test done anyway. After a three month wait the results came in with (drum-roll, please) ABSOLUTELY NOTHING. Good news really. There is no sign of vEDS, and none of the scary cancer genes were detected either. Phew.

But also … ugh. I mean, it’s pretty silly. I never had a genetic test to “prove” I had asthma or allergies or migraines. Those were all clinical diagnoses too, but I think lots of people with hEDS would love it if we could point to a mutation and say “Aha! There it is!” In reality hEDS is likely caused by more than a single mutation (probably why they haven’t nailed it down). And some folks think hEDS may be caused by MCAS or other environmental factors. Frankly, I’m dubious of that theory simply because I see so many EDS traits throughout my family and not everyone deals with MCAS. But the point is, we just don’t know yet what causes hEDS and smart, educated people disagree about it. But still, there is something that feels reassuring about having an answer that is more than clinical (just based on symptoms). After years of being told it is all in our heads, or that if we just lost weight we’d feel better, the certainty of molecular diagnosis sounds pretty good.

But the problem is genes aren’t the concrete, black and white thing we think they. They interact with our environment, they expresses themselves variably, or they don’t express at all. Genes are not destiny. Yet we imbue them with a kind of determinism–the idea that they not only hold answers for us, but that they determine our path in life. Of course, as someone with a heritable disease, I would never go so far as to say genes don’t matter. But we, myself included, have to be careful about how much weight we give to our genetic code. And, in particular, those of us suspected to have a genetic disease need to be cautious about placing all our hopes on finding a clear singular cause of all our troubles. It is a common way of coping. However, becoming comfortable with ambiguity and uncertainty is what will really help us cope with our illnesses better.

That’s what I tell myself when I’m trying to be a functional adult.

But, the science nerd in me just wasn’t satisfied with the blank official report the genetics lab sent me. I mean, I wanted to see the data. Not that I really know what it means. But, still, I wanted to see it. I learned that there are several companies out there that will read your raw data files and give you unofficial reports that tell you what genetic variants you have that might not be considered clinically relevant (yet). So, I made a records request and last week I got my files and uploaded them to Promethease.

WARNING-my genetics is self-taught! I have a BA in chemistry and workplace training in immuno-chemistry, but that’s it. I may have some of the science wrong here. I’m doing my best, but please don’t take anything here as gospel.

It turns out, I DO have one of the oft-discussed homozygous mutations (homozygous means two identical copies or alleles, which often, but not always, means you are more likely to experience problems due to the mutation) in the MTHFR gene (folate processing) as well as variants in CYP2D6 (drug metabolism), CYP21A2 (of RCCX theory fame), TNXB (hEDS???). And, I have multiple mutations in several of the collagen genes (COL1A1, COL1A2, 1COL3A1, COL5A1, COL12A1) though none of my specific mutations are considered pathogenic or diagnostic for any known type EDS, which is why the genetics laboratory didn’t report them. But, is that because they aren’t important. Maybe? All of them are currently considered or “presumed” to be non-pathogenic. On the other hand, the Promethease report takes me to an opensource genetics database that shows my specific mutations have the lowest research significance rating (meaning there is very little research), and are listed as benign with respect to other conditions that are not EDS. So, what that tells me is that we just don’t know. That’s why my official report was blank. I’m just going to have to wait for the scientists to do their jobs. It takes time and I know they are working at it diligently! It may be that some time in the future this data will help give me molecular confirmation of my diagnosis. Or maybe I just have a unique to me/my family type of EDS.

It is kind of fun to poke around in my data, but it is ultimately unsatisfying. It didn’t tell me anything I didn’t already know. For example, I have 20 mutations associated with asthma and another 20 associated with migraine. Shocker. But, there were other things that showed up in there that were also not surprising, but a little daunting. Lots of gene variants associated with cancer, autoimmune disease, diabetes, and dementia. Looking around my family, yep, I believe it. But it is a bit scary to see those things there. I reminded myself again, the lab didn’t report them because none of them are the BIG BAD SCARY ones. Most of them have very small impacts on risk. And most of them are fairly common variants. The vast majority of humans live with those types of risks. So, I reminded myself that genetics is not destiny–those genes may never express themselves. The best thing I can do is not stress and keep doing what I’m doing to take care of myself … And, get my mammograms. If I believed in Jesus, I’d let him take the wheel.

As a fat zebra, there was another element that was interesting and thought provoking. I have homozygous mutations (again that means two copies, so more likely to express) in the FTO, INSIG2, and a several other genes associated with both childhood and adult “ob*sity.” Again, shocker. I was a fat kid and I am a fat adult–didn’t need whole exome sequencing to tell me that! But there was something strangely cathartic about seeing those mutations. It is the concreteness I so desire with hEDS. My fatness is a genetic trait just like my eye color or hair color. And yes, it comes with some risks. But so does hair color (red heads are at risk for anesthesia resistance and have increased risk of skin cancer). There is no reason genetic variations should be stigmatized. Not red hair, not fatness.

But fatness is stigmatized. And, I strongly suspect that if it weren’t, I wouldn’t be as fat as I am. Remember that whole genes/environment thing? I was genetically predisposed to be fat from the start, but living in a toxic environment (culturally and chemically) has had a tremendous impact on the expression of those genes. We know that endocrine disrupting compounds contribute to fatness. We also know (though we can barely admit it to ourselves) that dieting contributes to fatness. If I hadn’t worked so hard trying to manipulate my body size through food restriction, I would not have triggered my natural set point to move up and up and up. I might have stayed plump rather than becoming superfat. OR, maybe with the combo of homozygous FTO and INSIG2 mutations, I would have been superfat in any case. Regardless, I know I would have been healthier, in a holistic sense, had I never dieted.

But there is no going back. This superfat body is here now and it deserves love and nourishment and healthcare … and non-dairy Hagen Daz. Trying to manipulate my body size is as futile as trying to manipulate my height or any other genetic trait. No, actually it’s worse than “futile”, because trying to shrink my body is actively harmful. Knowing I have fat genes makes me feel even more resolute that I will not engage in restrictive dieting. Instead, I will nourish and move my body to keep it as healthy as it can be given the mess of mutations I’m carrying around.

This has been an exercise in grappling with the social and emotional meaning we bestow upon those millions of A’s C’s T’s and G’s–the particular arrangements of amino acids shape, but don’t make us who we are. Our genes interact with our environment (social and natural) and express in a multitude of ways. They are both supremely important and also not that meaningful (yet?) from a medical perspective. And yet many of us look to them for answers about who we are, where we came from, and where we are going.

What’s amazing to me about our genes is that they aren’t actually all that unique. After all, we share 50% of our genes with a banana and 96% with Chimpanzees and Bonobos. Among humans, we share 99% with each other. More mind boggling still is the fact that genes make up only about 2% of our DNA … the rest is “junk” (or so the scientists think!). It is amazing that all these variants that cause the myriad human traits we can see (and many more that we cannot) happen in just 1% of our genes and just 0.02% of our DNA! Many of us, whether we are ill or not, put a bit more faith in the state of the science than it perhaps merits. Though we know more than ever before, we still know very little about what it all does and how specifically our genes interact with the complex world in which we live. For now, those of us with hEDS seeking answers among the base pairs of adenine, cytosine, thymine, and guanine will just have wait for the science to catch up to our expectations. Getting comfortable with ambiguity and uncertainty is the best bet to coping with the emotional toll chronic illness takes.

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