Using a genotype-first strategy for disease discovery, a multidisciplinary team of NIH researchers has identified a new inflammatory disorder, called vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic syndrome (VEXAS), which is caused by mutations in the UBA1 gene. The disorder, which appears to result in high mortality among those male patients diagnosed to date, connects what have been seemingly unrelated adult-onset inflammatory syndromes, and causes symptoms that included blood clots in veins, recurrent fevers, pulmonary abnormalities, and vacuoles (unusual cavity-like structures) in myeloid cells.

“We had many patients with undiagnosed inflammatory conditions who were coming to the NIH Clinical Center, and we were just unable to diagnose them,” said David B. Beck, MD, PhD, clinical fellow at the National Human Genome Research Institute, who is first author of the team’s published paper in the New England Journal of Medicine. “That’s when we had the idea of doing it the opposite way. Instead of starting with symptoms, start with a list of genes. Then, study the genomes of undiagnosed individuals and see where it takes us.” The scientists’ results are described in a paper titled, “Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease.”

Nearly 125 million people in the U.S. live with some form of a chronic inflammatory disease. However, many of these diseases exhibit overlapping symptoms, which often makes it difficult for researchers to diagnose the specific inflammatory disease in a given patient, the researchers noted. “Identifying the causes of systemic inflammatory diseases, particularly in adult populations, remains a challenge that limits our understanding of the pathophysiology, prognosis, and treatment.”

Usually, researchers discover a previously unknown disease by studying several patients with similar symptoms, then searching for a gene or multiple genes that may play a role in causing that disease. However, the widespread availability of genomic DNA sequencing means that researchers can now take genotype-driven approaches to understanding human diseases. Rather than start with a set of symptoms, a genotype-first approach typically involves bringing together individuals who have undergone genomic sequencing but who do not, necessarily, present with similar phenotypes.

Researchers at the National Human Genome Research Institute have discovered a new inflammatory disorder called vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic syndrome (VEXAS), which is caused by mutations in the UBA1 gene. VEXAS causes symptoms that included blood clots in veins, recurrent fevers, pulmonary abnormalities and vacuoles (unusual cavity-like structures) in myeloid cells. [Harry Wedel, NHGRI]

“The objective is to find damaging variants in a common gene that underlie a previously unrecognized grouping of patients with particular clinical characteristics,” the investigators continued. “These studies take advantage of shared genetic commonalities, rather than clinical similarities, to overcome the limitations of recognizing discrete phenotypes. Rheumatologic diseases may be well suited to this approach because of their complex and highly variable clinical presentations.”

For their newly reported studies, the NHGRI researchers, together with colleagues from other NIH Institutes, studied the genome sequences of 2,560 individuals with undiagnosed inflammatory diseases, more than 1,000 of who had undiagnosed recurrent fevers and body-wide inflammation. The rest of the participants, part of the NIH Undiagnosed Diseases Network, had unusual and unclassified disorders. The team’s study focused on a set of over 800 genes related to the process of ubiquitylation, which helps to regulate various protein functions inside a cell and the immune system overall. “Our objective was to see if any of the 2,560 patients shared variations in the same gene,” said Daniel Kastner, MD, PhD, scientific director of the Intramural Research Program at NHGRI, and a senior author of the NEJM paper. “Instead of looking at clinical similarities, we were instead taking advantage of shared genomic similarities that could help us discover a completely new disease.”

Out of the 800 genes, one stood out. Three middle-aged males had rare and potentially damaging genomic variants in the UBA1 gene, but each of the three males appeared to have two copies of the UBA1 gene, with only one copy harboring the mutation. This might not, at first sight, be unexpected, because humans usually have two copies of every gene. However, the UBA1 gene resides in the X chromosome, and males have only one X chromosome (the other is a Y chromosome). “We were amazed to see this and wondered what it could mean. And that’s when it clicked—this was only possible if there was mosaicism in these men,” said Beck. Mosaicism occurs when some people have groups of cells with mutations that are different from the rest of the body.

The team predicted that there were specific cells in the patients’ bodies that carried the UBA1 gene in its normal form, while other cells carried the gene in its mutated form. Using DNA-sequencing methodologies, the researchers found that the mosaicism was indeed present in the patients’ myeloid cells, which are responsible for systemic inflammation and act as the first line of defense against infections.

They then analyzed the genome sequences of additional individuals from various NIH cohorts and databases, which led to the discovery of an additional 22 adult males with the UBA1 gene mutations. Most of the individuals had symptoms that included blood clots in veins, recurrent fevers, pulmonary abnormalities and vacuoles in the myeloid cells. “The fact that we identified this mutation only in men, all of whom were clinically affected, suggests that the additional allele in women protects against effects of the mutant allele, although it is possible that, owing to skewed X-inactivation, the disease is milder in women,” the scientists commented.

Out of the combined 25 male individuals identified, the researchers were able to find a link between the various clinical rheumatologic and blood-related diagnoses made for the patients. “By using this genome-first approach, we have managed to find a thread that ties together patients carrying all of these seemingly unrelated, disparate diagnoses,” Kastner said. And because these conditions exist in people with UBA1 mutations, the team grouped the various conditions into a new, life-threatening disease, designated VEXAS, which so far, has resulted in the deaths of more than a third of patients diagnosed with the condition. “Of the 25 participants, 10 (40%) died from disease-related causes (respiratory failure or progressive anemia) or complications related to treatment,” the authors wrote. “Given the increased mortality among patients with the VEXAS syndrome, efforts to identify effective treatment strategies that target the clonal somatic process, such as bone marrow transplantation or gene-editing therapies, should be considered.”

The researchers hope that this new genome-first strategy will help healthcare professionals improve disease assessments and provide appropriate treatments for thousands of patients who have various inflammation-related conditions. The study may also pave the way for a new and more appropriate classification of inflammatory diseases. “Using a genotype-driven approach, we identified a disorder that connects seemingly unrelated adult-onset inflammatory syndromes,” they concluded. “More generally, our findings suggest that X-linked mosaic mutations may cause other diseases.”

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