Why Some People Are Born With Devastating Gene Mutations—And Never Get Sick

As soon as her daughter was born, Stephanie DeRosa-Marrazzo knew the child had inherited her husband’s rare eye disease. Instead of a blue or brown iris, Pandorraa’s eyes only had pools of black pupil—the signature of a condition known as aniridia that causes cataracts, glaucoma, and other forms of vision loss. When Stephanie’s second child was born six years later, the couple held their breath. Aayden, however, was born with seemingly healthy vision.

“The eye doctor told us he looked fine,” Stephanie says. The only difference doctors could find was a small red mark outside a brilliantly blue iris.

Which is why Stephanie was so shocked when she learned years later that her son, now 11, likely carried the same mutation of the PAX6 gene on chromosome 11 that had stolen the vision of his sister and father.

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Not all that long ago, scientists like Eric Pierce and Elizabeth Rossin would have told you that disease-causing genetic variants were extremely rare, and that anyone carrying one would almost certainly develop the associated disease—whether it was cystic fibrosis, spinal muscular atrophy, amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease), or the inherited retinal disorders they study in their labs at Mass General Brigham hospital. But when Rossin and Pierce looked, they found that in fact the majority of people with mutations linked to rare, inherited eye diseases were just fine—only a small number actually developed eye disease.

"Some variants really are deterministic," Rossin says, meaning that if you carry them, you will almost certainly develop disease. Others, however, are inherited with less certainty—or degrees of a characteristic scientists call penetrance. This phenomenon, Rossin says, “means we need to change the paradigm we use to think about rare inherited disease."

Their study, published earlier this year in the American Journal of Human Genetics, is part of a sea change in genetics research showing that the landscape of so-called single-gene disorders is far more complex than anyone realized. Time and again, when researchers examined the DNA of wide swaths of people, they found that only a small handful of individuals carrying genetic variants linked to disease actually got sick. This reality has started to turn the field of genetics on its head. Instead of asking what gene is making someone ill, geneticists have begun to investigate the biological reasons why someone stays healthy. This, says Leigh Jackson, a geneticist at the University of Exeter in the U.K., may help reshape our fundamental understanding of biology and inheritance, as well as develop new treatments for some of our deadliest diseases.

"This whole paradigm that we had, of variant A causes disease B almost all the time, is actually not the norm," Jackson says. “We've started from disease and found the genetic variants people have got. Now we can start from the genetic variants and see if they ended up getting disease.”

What the family’s doctors couldn’t tell Stephanie, what no one could, was why Aayden had been spared—and whether his luck was permanent or only temporary.

A Model With a Baked-In Bias

When geneticists first began searching for the genes responsible for various inherited diseases in the 1970s and 80s, they worked backwards, starting with large families impacted by often devastating conditions. After recruiting these families to specialized clinics, geneticists began combing through their genes to find out which sequences traveled with the disease from one generation to the next. The strategy was slow and painstaking, but undoubtedly successful as geneticists identified the cause of everything from cystic fibrosis to Huntington’s disease to retinitis pigmentosa (a group of eye diseases that cause the light-sensing cells in the retina to die off).

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"Up until the late 2000s, almost everything we knew about severe disease-causing variants came from sequencing families where someone was already affected," says Daniel MacArthur, a geneticist at the University of New South Wales in Australia. In those families, nearly everyone who inherited a disease variant also developed the disease—making their fate appear almost inescapable.

But the model had a baked-in bias. Because it was so laborious and expensive, scientists only sequenced the DNA of “the sickest of the sick," says Kelly East, vice president for educational outreach at the HudsonAlpha Institute for Biotechnology. "It led to inflated statistics of what it meant to have these genetic changes."

This began to change in the wake of the Human Genome Project, a landmark global effort to sequence the entire human genome. Besides being a massive scientific milestone, the project, which ran from 1990 to 2003, fueled a dramatic advance in genomic technologies. Over the next two decades, the cost of sequencing plummeted. For the first time, geneticists could not only study sick individuals but also large numbers of healthy ones. What they found was that the fate of people with genetic mutations wasn’t so inescapable after all. In 2014, for example, a large study analyzing 60,000 genomes found that each person carried a large number of genetic changes previously linked to severe disease despite not showing any signs of that condition. It suggested the penetrance of many genetic diseases might be lower than previously thought.

Rossin and Pierce were curious whether this might also be the case for the inherited retinal disorders they specialized in treating. Instead of searching for a genetic variant among individuals with a disease, the pair instead asked how many healthy individuals carried genetic variants linked to disease. It was a small shift, “but it flips the question on its head,” Rossin says. With this flip, Rossin and Pierce joined a small number of other labs asking this type of question.

The pair turned to two of the world’s largest biobanks, the All of Us biobank and the UK Biobank, each of which contain full genetic sequences of hundreds of thousands of participants as well as their medical histories. The researchers identified a cohort of individuals with genetic variants linked to inherited retinal disorders, then reviewed detailed eye measurements also stored in the biobanks to independently determine whether a person had retinal abnormalities. By focusing their attention on adults over 40, the team could also be far surer that participants would have almost certainly already started showing signs of disease, as Pierce notes the average age of legal blindness among those with inherited retinal disorders is 40.

“We thought there's probably a few people walking around,” Rossin says. “Like maybe 90 percent of people who have the mutation have disease, and maybe there's 10 percent of people walking around who don't have disease.”

Nothing prepared them for the true numbers. In their analysis, only 9 percent of the people with potentially disease-causing genetic variants for retinal disorders actually had any kind of eye disease. That meant 9 out of 10 people who had inherited this DNA all appeared to be perfectly fine.

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“It's becoming increasingly clear that the data is what the data is—it's real,” Pierce says. “It's becoming apparent that there's a similar pattern in other diseases too.”

Indeed, in May 2026, a team of U.K. scientists found that only 20 to 40 percent of individuals carrying the genetic variants linked to the bone disease osteogenesis imperfecta showed clinical signs and symptoms such as easily broken bones and deformities. And a March 2026 study in the Annals of Neurology found only 6.6 percent of the people who had inherited a disease-causing gene variant known for causing ALS developed disease.

For the first several years of Aayden’s life, it seemed he would be among this group of individuals whose disease-causing genetic variant was DNA background noise for their lives. Stephanie imagined him doing things that Pandorraa never would, such as getting a driver’s license. But she still couldn’t shake her anxiety. “There was always that fear that one day he's going to say, Oh, I can't see this, and it's like, Oh, it's starting all over again,” Stephanie says.

Finding the Genes That Mitigate Disease Risk

How people like Aayden can remain disease-free isn’t just a question of scientific curiosity. The answer might help scientists learn more about what causes disease and how to target it with therapeutics.

Of course, some scientists argue that it’s possible we’ve had it all wrong from the beginning: It’s not that people with a specific genetic variant miraculously remain disease-free but perhaps that genetic variant was never actually the cause of disease. MacArthur says this is why he and Heidi Rehm, a human geneticist at the Broad Institute, have devoted so much time to going back through some of the older sequencing data to reassess disease-causing variants.

“We're now pulling genes off lists because they're much lower penetrance than we anticipated," Rehm says.

Stanford University cardiologist and geneticist Euan Ashley also questions whether the so-called healthy individuals really are completely free from disease. In one study, for example, researchers found that people carrying pathogenic variants linked to inherited cardiomyopathies often had no diagnosis of heart disease but were more likely to be taking medications for high blood pressure or heart failure and showed subtle abnormalities on cardiac imaging. Other carriers had mild structural changes in their hearts that would never have been detected without careful screening. Rather than representing an all-or-nothing distinction between healthy and sick, Ashley says, these findings suggest a continuum of disease.

“Health isn’t binary,” Ashley says. "These aren't necessarily completely unaffected people. They're people who may have much milder manifestations than we previously appreciated."

But scientists are also looking to the tens of thousands of other genes in the genome that can may alter a person’s risk of developing disease.

One reason the body is so resilient is that billions of years of evolution have engineered backup systems and backups of backups. Think of it, says Harvard geneticist Isaac Kohane says, like assembling flat-pack furniture. If you wind up with an extra bolt or screw, that doesn’t mean your bookcase will automatically collapse as soon as you use it. The package may have contained some extra hardware, or perhaps the bookcase was designed such that certain missing parts wouldn’t cause massive problems. Your body is much the same way. Your body might have another gene—or several working together—that might compensate for the effects of a disease-causing gene.

Finding those genes is admittedly tricky, requiring a deep genetic dive on individuals who are healthy carriers of a variant. But the strategy has paid off in other fields of medicine: In July, the U.S. Food and Drug Administration approved a new cholesterol drug inspired by a cohort of people whose mutations in the PCSK9 gene resulted in “impossibly low” cholesterol levels. The new drug edits the gene in people with high cholesterol to mimic that mutation.

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Knowing what genes are protective of eye disease—or cystic fibrosis or ALS—could allow researchers to create a drug that simulates their effect on other people. Somewhere in our genome, then, may hide a clue to therapies preventing blindness, neurodegeneration, metabolic disease, and more.

For Rossin and Pierce, their next task is to begin sifting through the genomes of their patients and families to identify more healthy individuals with inherited disease-causing genetic variants and scour their DNA to identify what other variants might be keeping them healthy.

In a world where genetic testing is at our fingertips, it’s relatively easy to find out if you carry these variants, says Jackson. What’s far harder is understanding what this means and if you should be worried.

And then there are families, trying to use this information to make decisions about whether their children might inherit gene variants for diseases like cystic fibrosis, sickle cell disease, and spinal muscular atrophy. When answers are no longer yes or no but maybe, a decision’s complexity expands dramatically.

"We've got to get over this idea that genetics is as deterministic as we kind of all think it is," Jackson says.

While Aayden’s vision remains better than his sister’s or father’s, Stephanie says his visual acuity has dropped dramatically in the last year or two. Even if he still has aniridia, understanding how Aayden’s genome and environment have allowed him to have a milder form of the condition could lead to an extraordinary advancement for other people with the disease. It’s an everyday wonder, hidden in his DNA.