The Stars Align: The Incredible Discovery Story of VEXAS

Dr. David Beck arrived at the National Institutes of Health (NIH) in 2016 to begin his training in clinical genetics with one goal in mind: to use genetic analysis to help unravel some of the mysteries that still dog internal medicine. When Beck started seeing patients in the clinic, he was soon involved in the care of a family with a severe, undiagnosed disease that had tragically resulted in 3 children dying in the first year of life. It seemed likely that the children had inherited a fatal condition from their parents, but the nature of this disease, to that point, had not been understood.

Beck analyzed every piece of the family’s genetic sequences and what he ultimately found was a damaging variant in a gene that affected ubiquitylation, a process in which proteins are tagged in order to indicate if they should be turned on or off. For this family, each child had inherited a gene that turned on too much ubiquitylation, leading to waves of uncontrolled inflammation that hastened their demise.

The experience had a big impact on Beck, and he sought out a meeting with Dr. Daniel Kastner, his research mentor at the NIH. For decades, Kastner has evaluated and cared for patients at the NIH with confirmed or suspected autoinflammatory diseases. With their permission, he has kept clinical notes and thousands of laboratory samples from these patients and formed what is called the Periodic Fever Database. In parallel to Kastner, the NIH Undiagnosed Diseases Program, under the leadership of Dr. William Gahl, has similarly maintained a database of patients that have been evaluated through the years. Although Kastner, Gahl, and their colleagues have helped to identify the cause of disease in a fair number of their patients, many remain without answers.

Beck believed that the databases of patients from the Periodic Fever Database and Undiagnosed Diseases Program were fertile ground for exploration. He told Kastner that he had a big idea: he wanted to look at the hundreds of genes known to have something to do with ubiquitylation and see if any variants in these genes could be causing the symptoms seen in some of these patients. Instead of focusing on a single gene, Beck wanted to study a whole class of genes simultaneously. This large group of genes would be selected based on their relationship to the process of ubiquitylation rather than their being known to cause any one specific disease. Taking this approach, Beck hoped to uncover common genetic threads that could connect patients in ways that had not been possible simply by looking at their clinical symptoms.

Beck compiled a list of the 841 genes thought to be involved in ubiquitylation and set to work examining the genetic sequences of thousands of patients in the databases. After pouring through the data, Beck found 3 patients—all middle-aged men—who had the same misspelling at the same location in a particular gene called UBA1. This finding was curious for several reasons. The UBA1 gene encodes the protein that starts the entire process of ubiquitylation. Because of this, UBA1 gene mutations would have a high chance of killing a person before they make it to adulthood, yet these patients had all lived for several decades before their symptoms began.

The second puzzling finding was that these men appeared to have 2 different copies of the UBA1 gene: one normal and one abnormal. Yet, the UBA1 gene is located on the X chromosome, which men only have one of. Looking into this further, Beck discovered that only some of the cells in these patients’ blood contained the mutation, whereas other cells did not. This made it appear as though the men had inherited 2 different versions of the gene from the same parent, which was not the case. A more likely explanation was that a somatic mutation had occurred later in life and was affecting only certain cells, leading to mosaicism, a state in which 2 or more groups of cells in a person’s body possess different genetic compositions.

Since the mutations were seen in cells found in the bone marrow, Beck and Kastner went to speak with Dr. Katherine Calvo, a pathologist at the NIH with expertise in marrow-related disorders. Calvo noted that certain cells in the bone marrow of these patients had vacuoles, a finding that is highly unusual and caused only by a few conditions, none of which these patients had. Calvo remembered having had a handful of patients in the past with this same unexplained finding. She delved into her records and was able to find 2 patients—also middle-aged men like the patients Beck had identified—that Kastner had evaluated 8 years before but for whom he had no answer by which to explain their symptoms. Calvo speculated that both men may have the same mutation in the UBA1 gene as the 3 men identified by Beck. Genetic testing was pursued, and Calvo was proven right: both men had the identical mutation as seen in Beck’s 3 patients.

Beck next went to speak with Dr. Peter Grayson, a rheumatologist at the NIH who had cared for 2 of the 3 patients initially identified by Beck. Grayson immediately recalled the intimate details of the medical histories of these patients, who had seemed linked in his mind for some unexplainable reason. Now, with Beck’s new finding of the UBA1 gene mutation in both men, there appeared to be a possible answer.

Grayson started to speak with colleagues about what he had learned and was soon in contact with Dr. Marcela Ferrada, one of his research collaborators whose work has focused on relapsing polychondritis (RP). Grayson described the symptoms and signs witnessed in the patients that Beck had identified, which included the type of chondritis that is classically seen in RP. He also noted that all the patients had the unusual findings of macrocytic anemia and vacuoles in some of the blood cells in their bone marrow. Ferrada immediately thought of 2 patients in her RP cohort—both male—who had these exact same strange findings. She had spoken with many colleagues to understand what may be happening in these patients, but no one could provide an answer. She wondered if these patients might also share the same genetic mutation, and she and Grayson agreed that it would be worth sending for genetic testing.

Less than 2 weeks later, Grayson was on a beach with his wife and children when he got a call on his phone from Dr. Keith Sikora, one of his collaborators. Standing barefoot in the sand with the sounds of the ocean in the background, he received the news: these men, too, had the UBA1 gene mutation.

Over the ensuing year, Beck and his fellow researchers were able to identify a total of 25 patients with the UBA1 gene mutation and collect sufficient evidence to show that the mutation was rare, novel, and clinically important. After Beck and his collaborators published their description of VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) in December 2020,¹ the NIH was flooded with referrals of patients thought to possibly have the disease. Clinicians around the world also started looking for the condition. It is now estimated that about 1 in every 4000 men aged > 50 years in the United States may have VEXAS,² a total far larger than anyone at the NIH would have ever suspected when the story began. What started as a curious research project by a new clinical genetics fellow has turned into a monumental discovery that has changed the field of rheumatology for all time.

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