Their Mutated Genes Were Supposed to Be Harmless

Back when he was 17 and in high school, Eric Sid fainted. In the emergency room, he was diagnosed with anemia, which can cause fainting spells, and for years he thought that was the end of the story. About a decade later, in the early 2010s, he came down with pneumonia and had blood work done. He took a peek at the results and saw markers of anemia, as he expected. But the report also mentioned that his red blood cells were smaller than normal.

Sid was in medical school at the time, and he immediately thought of a few genetic conditions that could explain this result. One was thalassemia, which causes low levels of hemoglobin, leading to anemia and other related problems. A laboratory test showed that he had this inherited illness. And this meant that he had a gene mutation. Finally, he thought, he had an explanation for symptoms he had been experiencing for years.

Except there was a catch. In the most common forms of thalassemia, people who show symptoms have mutations in both copies of the related genes. Those born with the most severe forms of thalassemia require transfusions for life to get enough healthy red blood cells, and if the condition is not diagnosed soon enough it can be fatal in early childhood. But Sid’s lab results suggested that only one copy was affected, so he was considered a carrier of the illness, who could pass it on to his children but didn’t have it himself. According to conventional wisdom at the time, carriers were asymptomatic, and compared with someone suffering from the disease’s worst manifestations, he seemed fine.  

Sid now works on a rare-disease program within the National Institutes of Health. Since he first found out that he was a carrier for thalassemia, he told me, research has shown that people like him can experience health consequences. These include lethargy and fainting—symptoms that hardly capture the disease’s classic presentation but still have real consequences. And thalassemia is not unique. There are hundreds upon hundreds of known disorders for which carriers were thought to be safe; for a growing number of those diseases, doctors and scientists now believe that being a carrier can come with health problems. Plenty of patients have guessed all along that being a carrier could explain mysteries about their health, Sid said. “It took a while for the science to basically catch up to that suspicion.”

In these types of “recessive” conditions, the people who show the classical manifestation of the disease have a pair of mutated genes. Our 23 chromosomes come in pairs that are essentially near duplicates of each other (with the exception of XY pairs). A person with just one nonworking version of a gene was supposed to be protected by the functioning second copy on the matching chromosome, which would provide cover against any disease. Inheriting two mutated copies of a gene is statistically rare, so many families with carriers may not include members with the full-blown version of a disease. As a result, the mutation can be unknowingly passed down from generation to generation, without carriers being aware of the real consequences.

In October, researchers in Louisiana reported on a case involving a college football player who had heart palpitations during practice. The athlete was a carrier for the blood disorder sickle-cell disease—one of the most common genetic disorders in America. Up to 10 percent of Black Americans are carriers for sickle cell. As far back as the 1970s, scientists noted blood and heart complications in carriers following physical exercise, and a lawsuit following the sudden death of a college football player two decades ago led to widespread screening for the sickle-cell trait in university athletics. However, experts are still trying to understand the risks to carriers.

The Louisiana man survived, but researchers noted that he had a dangerously irregular heartbeat during training and would need cardiac surgery. The authors of the October paper stress that coaches and players need more education about the possible hazards for carriers of the sick-cell trait.

Experts who study cystic fibrosis, which is caused by mutations in the CFTR gene, also want more attention on the health complications that carriers can experience. As many as one in 25 Americans of European descent is a carrier for cystic fibrosis, but many are not aware of their status. For this disease, reports of symptoms in carriers go back at least several decades. Take, for example, infertility. Almost all men who have two mutated copies of the CFTR gene lack vas deferens, and without these tubes, sperm have no path out of the testes. In the mid-’90s, scientists found a handful of cystic-fibrosis carriers who lacked vas deferens, despite only one of their CFTR copies being mutated.

Carriers of cystic fibrosis can face other real health issues—dramatic sinus problems requiring multiple surgeries, pancreatitis, and possibly pancreatic cancer, which researchers have documented in papers over the past several years. “We’ve always said being a carrier of a single cystic-fibrosis mutation doesn’t usually lead to health issues. And usually it doesn’t,” Michael Boyle, the president and CEO of the Cystic Fibrosis Foundation, told me. “However, we do know, and probably have a greater appreciation than ever, that being a carrier can lead to health issues for some.” There are about 10 million cystic-fibrosis carriers in the United States alone, so if even a fraction of them have some degree of symptoms, that amounts to many people with manifestations of the disease.

Questions about carriers’ health problems go beyond well-known diseases such as sickle cell and cystic fibrosis. Consider xeroderma pigmentosum: People with two mutated gene copies are up to 2,000 times more likely to develop melanoma than the average person; a 2023 analysis found strong evidence that some carriers of the disease were also more likely to develop skin cancer. Up to 3 percent of carriers of hereditary hemochromatosis show symptoms such as iron overload in their organs. Carriers of Gaucher disease Type 1 are at increased risk of Parkinson’s. Carriers of LIG4 syndrome experience a version of the immunodeficiency that, in the fully expressed syndrome, causes life-threatening illness.

For many of these diseases, having two mutated copies of the related gene generally means that the disease will come for you. Having one copy can still mean nothing: Plenty of carriers of recessive genetic diseases seem none the worse for it. An estimated one in 20 people is, like Sid, a carrier for thalassemia, but not all people with a copy of the mutation experience anemia and fainting like he did. Why some carriers of genetic illnesses might be affected and others remain free from symptoms is not clear. But “people who are thought to be just carriers but show some symptoms of that disease may sometimes have a second hard-to-discover mutation,” Edward Neilan, the chief medical and scientific officer of the National Organization for Rare Disorders, told me. “They may actually have two mutations.”

Being a carrier can have benefits. One theory of why genetic diseases spread widely is that having one copy of a mutated gene has some advantage. It’s well understood, for example, that being a carrier for sickle-cell disease offers some protection against malaria. And some have theorized that being a carrier for cystic fibrosis can defend against severe cholera, although the evidence for this theory is more scant. A 2023 analysis discovered that although two variant copies of the SCN5A gene elevates a person’s risk of severe heart-rhythm problems, just one copy actually might lower a person’s risk of heart-rhythm irregularities compared with the general population.

Even when being a carrier of a particular disease isn’t itself beneficial, knowing that you are a carrier can be. Carriers of certain variants of xeroderma pigmentosum, for example, might want to go to extra lengths to avoid excessive sun exposure; some carriers of Alpha-1 antitrypsin deficiency, who appear to have a heightened risk of lung issues, might decide not to smoke. And people with the sickle-cell trait might be well-advised to acclimatize before doing sports at high altitudes.

Knowing you’re a carrier for cystic fibrosis might help guide your family-planning decisions, for instance. (Even without vas deferens, a person could still become a father using sperm extraction and in vitro fertilization—which some carriers of cystic fibrosis opt for anyway, to avoid passing on the disease.) But there are limits: The science is still out on whether Trikafta, a relatively new medication that has transformed the disease for many people, would help with sinus or pancreatic issues in carriers. The medication isn’t approved for carriers, either.   

For Sid, knowing that he had a thalassemia mutation—which can cause dizziness—has made him feel less bad about his difficulty with intensive physical training, for example. And he is comforted to know what likely caused his high-school fainting episode. Finding out about the mutation in his genome gave him a fuller picture of his health. “Personally,” he said, “that’s kind of how I saw it—this kind of gave me some more understanding.”