Sometime in the early 1800s, a young woman who lived in a village along the shore of Lake Maracaibo in Venezuela gave birth to several children and, in doing so, indelibly entered the records of human genetics. Unbeknownst to her, she harbored a stretch of excess DNA on her fourth chromosome, which she passed down to many of her children. By the time they reached late middle age, many of her descendents would develop jerky, uncontrollable movements, dementia, and depression: the hallmarks of Huntington’s disease.

In 1993, almost 200 years after the woman lived, scientists managed to pinpoint the single gene responsible for the disease by sampling DNA from hundreds of members of the Venezuelan family. These days, though, no one is discovering new diseases by looking for symptoms that run in families—those low-hanging fruit have all been picked. The ever-expanding field of medical genetics now looks quite different: Researchers strive to tether conditions as different as depression and diabetes to scores of different genes, and doctors decide how to treat cancers based on the combinations of genetic mutations they carry. Science has left behind the era of the lone wolf mutations.

Or so it seemed until, in 2020, researchers showed that a single mutation in a gene called UBA1 could cause a previously unknown inflammatory disease, which they named Vexas (an abbreviation of some of its key characteristics: vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic). Scientifically speaking, the disease was big news—the first Vexas study was published in the The New England Journal of Medicine, the most prestigious medical journal in the United States—but that wasn’t necessarily enough to make clinicians care. “Most people think, ‘Oh, this is another disease from the NIH that I’ll never see in my life,’” says Peter Grayson, an investigator at the US National Institutes of Health and one of the discoverers of Vexas. 

But late last month, a study published in the Journal of the American Medical Association revealed that Vexas might not be all that rare after all. Sifting through a genetic database, researchers found 11 people with the condition, equating to a rate of about 1 in 4,000 in men over 50. That’s just a preliminary estimate of Vexas’ prevalence—the data all came from a rural Pennsylvania health care system, so it will be important to replicate the results in more diverse populations—but it’s still a far more dramatic result than the researchers anticipated. If the estimate is correct, Vexas is more common than ALS, the disease that successfully captured the world’s attention when the Ice Bucket Challenge went viral in 2014. 

For decades, Vexas has hidden in plain sight. It shares symptoms with many other diseases—frequent fevers, widespread inflammation, intense fatigue—so patients were siloed off into different diagnostic categories, isolated from the many others who had the same mutation. That’s because in rheumatology—the medical field that specializes in inflammation and the immune system—the underlying cause of most conditions remains a mystery, so diseases are often defined by appearances alone. The end result is that Vexas patients will have previously been classified as having conditions like vasculitis, psoriasis, and even leukemia—if they got any diagnosis at all.

But sometimes, peeling away the layers of symptoms and laboratory tests to look at the genetics beneath can bear fruit. “Vexas shows us that we can create entirely different taxonomies of disease,” Grayson says. “It really does radically transform how we may think about adult onset inflammation diseases.”