What Genes Can’t Tell Us Living in the “Yet”: When Genetic Tests Don’t Reveal the Answers You Seek
As a mother, I’ve had to ask myself: What would never getting an answer, or even no longer expecting an answer, look like?
This is What Genes Can’t Tell Us , a monthly column by Taylor Harris on parenting, genetics, and the quest for answers to medical riddles.
The answer, you should know, is no.
Genetic testing did not help me see my son, Tophs, more clearly. Whole exome sequencing, the most advanced test available to us, the one whose results took four months to process, did not help me find the boy behind those deep and wide umber eyes.
I had been searching, with the help of his pediatrician (and Google, if I’m honest), to find the source of my three-year-old’s frightening hypoglycemia, short stature, carnitine deficiency, and developmental delays. What I wanted more than any diagnosis, though, was to understand what made him tick. As parents, we may never fully know our children, but as Tophs entered preschool, I could no longer ignore my gut: Too much of him seemed unreachable to me.
Maybe I hadn’t paid close enough attention to how the test worked. I had talked to Shelley, our genetic counselor, signed consent forms, and taken home a copy of the lab’s Whole Exome Sequencing Patient Guide. It contained paragraphs of text, along with figures and drawings—an electric turquoise X for a chromosome, a glowing orange cell and nucleus, a blue double helix winding its way down and across white space. It read:
Our body is made up of cells that contain our chromosomes. Chromosomes are made of DNA, which carries the genetic information in units called genes which are passed down from one generation to the next (Figure 1).
I thought the scientists, whose faces I would never see but whose brains I trusted, would superimpose my boy over maps of these normal cells and nuclei discussed in the pamphlet, and he would either line up exactly or not. I assumed it would work like one-to-one correspondence.
Approximately 2% of our DNA provides instructions for proteins, and that 2% is called the exome. When mistakes in our DNA lead to disease, they occur most often in the exome. Once we receive the sample, the lab isolates the DNA from the blood and compares the sequence of the affected individual’s exome with the sequence of the exome from healthy people.
The results did tell us something. It’s not like the lab over-promised or falsely advertised. Shelley hadn’t misled us. But my expectations hadn’t left room for the unknown. It was as though I hadn’t learned my lesson after a year of leaving specialists’ offices without answers—as though my soul refused to release its hope for absolute clarity.
This comparison looks for misspellings, or mutations, that could leave a gene unable to do its job correctly and could be the cause of the individual’s disease.
The results, in fact, told us exactly where the mutation was, I mean down to the exact location on the gene. Down to which variant letter replaced the expected one—as in, Tophs has an “A” where a “G” should be.
Then, even with all of this specificity and insight into the unseen parts of my son’s body, it was as if Science herself took me aside, put her hand on my shoulder, and meekly admitted: But I don’t know if any of this actually matters.
A numbing, then crushing, then perplexing confession.
What caught me off guard, even though I had signed papers acknowledging I’d been counseled on how complex the test results could be, was how complex the results could be. How they could leave me numb. And then wanting.
“We found some changes in his genes,” Shelley told me, “but none that really explain what we’re seeing in him.” As she talked me through the results over the phone, I wrote down names of genes, disorders sometimes caused by mutations in those genes, and then the phrase “not clinically relevant.”
My son’s genes do contain misspellings. His exome doesn’t completely match up with a typical one. But this, in itself, isn’t rare. If everyone you passed on the street underwent whole exome sequencing, we’d see a lot of mutations. Some would be benign, familial quirks; others would be potentially harmful or disease-causing. Still others would fall into a third category of misspellings, called variants of uncertain (or unknown) significance. This is where most of Tophs’s changes fall.
A variant of uncertain significance means there’s a change in a genetic sequence, but it hasn’t been determined whether that change is harmful or benign. It could carry a risk of disease, or not. It could be related to my son’s short stature or hypoglycemia, or not. This glitch might be the ticket to understanding his developmental delays, but so far, there’s no evidence to support that. As far as we know, there’s no other Tophs running around, say, Minnesota with similar health challenges and mutations. But maybe Minnesota Tophs just hasn’t been tested yet. Maybe he lives miles and miles from a research hospital, or maybe his parents decided against further testing, or maybe they didn’t have health insurance.
Or maybe our Tophs is just our Tophs, and there’s no need to wait for another.
Genetics has this way, I’ve learned, of being completely specific and still not locating you in time and space and significance. I know information about my son that most parents will never know about their children, but I still don’t know what to expect at his next IEP meeting. I know which mutation could possibly, someday, be linked to a glycogen storage issue, but I still have no answers to why he woke up Thanksgiving weekend with a blood glucose level of 60. At some point, it feels a little like we’re chasing ghosts.
Whose job is it to locate our son, anyway? Maybe we are meant to find him for ourselves. Perhaps, as people of faith, this is where we look to God. Where we pray harder and ask Him, “Do you see us? Are you with us? And what do you expect from these imperfect bodies you’ve always known would be?”
Even though prayer looks different than an appointment with Shelley, I actually don’t see faith as a departure from science. Geneticists and genetic counselors are some of the most faith-filled people I know. The key word in their field is yet. We don’t know yet. But they believe the day is coming.
The field is moving so fast, who knows what we will know in ten years, Science says as she hugs me and turns to go. The next day, she’ll return to her lab. She’ll run a secondary analysis. She’ll call another mother. She may help to find another boy.
For now, my family and I live in the yet. As the developmental pediatrician had said to us before the whole exome testing, “He’s got something; we’re just not smart enough to figure out what it is yet. ” You can find us here in the in-between, somewhere between Knowing Nothing and Understanding Cause. We stand in a space defined by what it is not, formed by what we don’t know.
The first time I heard the term liminal, I was sitting in an African American Studies 101 class at the University of Virginia. A tall and slender Professor Penningroth had written the words “Middle Passage” in the center of a black chalkboard. He walked us through not just the number of black bodies taken or the number of years over which they were stolen, but what it might have been like to be yanked into a void. To live (or die) between what was and what would be.
The concept instinctively made sense. It felt close and easy, like something I’d always known. But also distant enough that I could roll it between my fingers like academic Play-doh. I could see how far it would stretch before breaking or leave it sitting balled up on my desk when class ended.
The idea of a space without bounds that held within its hull the power to harm or to free or to form—that idea has never completely left me. Would I have thought as an undergraduate student that liminality might one day describe my experience as a Black woman in America? Yes. Would I have guessed it might describe my future experience as a mother, wading through waters of science and faith, in search of the truest way to know her son? Not at all.
As a child, one of my greatest fears was being trapped in an elevator. The idea of being trapped in a tight, stuffy space between floors was too much; I grabbed my mother’s arm and cried so many times in department stores and libraries that eventually she only looked for escalators or stairs. As a mother, I’ve had to ask myself if I’m fearful of being stuck in a forever-liminal space with my son: What would never getting an answer, or even no longer expecting an answer, look like? Would that be stifling and unbearable?
One of my favorite theologians, Christena Cleveland, wrote: “We are formed, fortified and even reborn in the liminal spaces and during the shadowy times.” She may have been referring to the disheartening social and political landscape of our nation, but I also hear her words as a personal offering to me. I see them as an invitation to sit with my son in that stale elevator, to feel the weight of his head on my chest, to accept that I can’t get us out or save us from this.
And to follow the lead of Tophs, who, whenever he sees anyone sick or hurt in the family, prays without ceremony. He doesn’t even worry about the ask. He just says what he knows. It’s “Lord, Jesus, Daddy hurt his head. Lord, Jesus. Amen.” Or “Lord, Jesus, Eliot’s tummy hurts. Lord, Jesus. Amen.” So I will hold him tight in this space, and he will curl his head around to softly kiss my elbow as he does some nights, and I will whisper, “Lord, Jesus. We don’t know. Lord, Jesus. Amen.”