When COVID struck Rebecca Saltzman’s family, the virus unmasked a life-changing discovery: her husband and two of their kids had genetic heart disease. The kind where people drop dead. As their healthy wife and mother, Saltzman had a new role too—guiding her family through what Susan Sontag called the Kingdom of the Sick. In this column, she’ll explore the anthropological strangeness of this new place, the mysteries of the body, and how facing death distills life into its purest form: funny, terrifying, and sublime.
On my computer, a stream of colored letters filled the screen: ATCG—the base pairs of DNA, the code that makes up all living things. But the code on my screen wasn’t just some generic code: it was the one that made up my own child. In the next window, I toggled to my husband’s. The color-coded sequencing looked like modern art. I scrolled through, genes and chromosomes speeding by, until I arrived at a specific gene on chromosome 11. Among all the thousands of As and Ts and Cs and Gs, a single letter here was flagged:
The mutation.
A few weeks earlier, we had gotten the genetic testing results back for my husband, Josh, and our two older children, Iris and Gus. Dr. C, our pediatric cardiologist, had ordered the comprehensive cardiac genetic panel after Josh, Iris, and Gus all had long QTs on their EKGs (in Sickland, the alphabet is heavy with meaning). Now, he met with us on Zoom to discuss the results.
First, the good news: Iris had completely normal results. She had no pathogenic or unknown mutations in the genes the panel tested.
And then, of course, the bad: Josh and Gus had both tested positive for a mutation. Not, however, for long QT syndrome (LQTS), the disease we were looking for. But another one: hypertrophic cardiomyopathy (HCM), a condition that causes the wall of the heart to grow dangerously thick, impeding normal blood flow and electrical function. Like LQTS, HCM puts a person at risk for sudden death.
Many disease-causing mutations are recessive, which means that even if you inherit a defective copy of a gene, your normal backup copy will keep you healthy. In fact, we all likely have deleterious recessive mutations that will never harm us for this reason. But the mutation that Josh and Gus tested positive for is a dominant mutation. It overrides the healthy copy. Just by testing positive, Dr. C explained, they were considered to have the disease.
In other words, Josh and Gus would both need lifelong cardiology care.
We had already veered from long COVID to long QT. Now we were swerving yet again on the Kingdom of the Sick’s hairpin road.
The specific mutation that puts my husband and son at risk for sudden death arose sometime around a thousand years ago, in what is now Eastern France. It is called a founder mutation—that is, the mutation can be traced back, using fancy science and math stuff, to a single ancestor in whom it first appeared.
A millennium ago, a boy or girl was born in medieval Europe with a brand new mutation in their MYBPC3 gene, which helps keep the muscle cells in the heart neatly organized. MYBPC3 is 21,000 base pairs long—21,000 of those As and Ts and Cs and Gs. But in this long-ago French person, an error occurred in the MYBPC3 code, an A that changed to a G. A single typo out of 21,000 letters.
That one change unravels the entire gene. The heart cells become disorganized. The heart wall thickens, obstructing blood flow and disrupting the current of ions through the heart’s electrical system.
Usually, a lethal dominant mutation does not become a founder mutation—people with lethal dominant genes often die before they can pass it on to their descendants. But this HCM mutation doesn’t start to cause symptoms until middle age, which means its carriers can have children and pass on their dangerous genes before they ever know they are sick. This is what happened with our mystery French person, who passed it on to their children, who then passed it to theirs, and so on, for forty-seven generations.
As history unfolded, and people moved around the globe, one of these descendants crossed the Atlantic Ocean to the New World. They brought their MYBPC3 mutation with them. In 1930s Argentina, my husband’s grandmother was born with the mutation and passed it on to several of her children, including a daughter. When the military overthrew the Argentine government in 1976 and disappeared 30,000 people, that daughter fled, first to Venezuela and then to the oil fields of West Texas, where she married a man with cowboy boots and a southern twang and gave birth to a son: Josh. And the mutated MYBPC3 came with her, carried on the winds of history.
I sometimes wonder about that person in France so long ago. Were they a midwife, or a monk, or a serf? Did they paint weird medieval cats? When their heart muscle began to thicken, did they feel the strange flutterings inside their chest, their heart straining to pump blood? Or did they simply die, a sudden collapse as they harvested rye or baked it into bread? Here and then gone, the first in a long chain, stretching into endless tomorrows.
So, where did this leave us? (Besides getting to tease my Argentine-Texan husband that he was secretly French.)
Although Gregor Mendel first hypothesized inheritance in the 1860s, and Rosalind Franklin (and two other guys) discovered the structure of DNA in the 1950s, humanity didn’t really enter the Genetic Age until 2003, when the Human Genome Project was completed. Our genetic code was unlocked, and with it, the promise of new information, treatment, and cures.
Genetic testing is often marketed as a way to get clear, easy answers. The direct-to-consumer testing company 23andMe sells its services with the tagline “Know your genes. Own your health.” Medical testing companies tend to be more measured in their promises, but still use a similar approach: Invitae, the service we used, offers to give patients a “more complete story.”
It’s true that clinical genetic testing, offered in certain scenarios with appropriate counseling, can reveal important information. In our case, learning that Josh and Gus had the HCM gene was potentially life-saving. HCM, as Dr. C pointed out, is most dangerous in people who don’t know they have it—and, therefore, aren’t getting appropriate monitoring and treatment to reduce the risk of death.
But for us, genetic testing also opened up new questions, and left existing ones unanswered. This is the part the brochures don’t brag about.
What would a positive gene test mean for Josh and Gus? Although HCM is a dominant mutation, and although this means they will need care for the rest of their lives, we still don’t know everything. The mutation does not have, in Sickland parlance, 100 percent penetrance (cue Beavis and Butthead snicker). This means that some people who have the gene will nonetheless never develop the disease, but we don’t have a way to know which people those are. And if they do develop HCM, we don’t know how severe it will be.
And what about the long QT? Despite Josh, Iris, and Gus all testing negative for known LQTS genes, we could not rule out the disease. In 20 to 25 percent of confirmed LQTS cases, genetic testing is negative. That’s still one in five to one in four people—not an insignificant amount. So it was possible that they carried an undiscovered mutation—medical genetic testing uses up-to-date and highly accurate methods, but it still only scans certain regions of certain genes.
Another possible factor: Could the HCM gene be causing Josh’s and Gus’s prolonged QTs? It was impossible to rule that out.
But Iris was negative for HCM. (A bit of joy here! She was free of it!) And yet, she, too, had a prolonged QT. Still in that gray zone, but prolonged nonetheless. Genetic testing hadn’t answered the mystery—in a way, it had only deepened it.
And all of this still meant that Josh and I would have to bring our third child, Gabriel (plot twist—we have another kid!), in for testing, too. Because HCM is a dominant mutation, we now knew that Gabriel had a 50 percent chance of having it too.
A million questions turned through my head. A million new anxieties. Only months earlier, Josh and I were a healthy couple with three healthy kids. Now he and all of our kids were at risk for serious heart disease. Worry painted dark circles under my eyes. Xanax became my new BFF.
A gene is not always destiny. The future is a locked box. But the future, we would soon learn, still had more in store for us.