Scientists Use Clues in Human Genome to Discover New Inflammatory Syndrome

Researchers from NIH 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. The scientists reported their findings in the New England Journal of Medicine.

Nearly 125 million people in the U.S. live with some form of a chronic inflammatory disease. Many of these diseases have overlapping symptoms, which often make it difficult for researchers to diagnose the specific inflammatory disease in a given patient.

Researchers at NHGRI and collaborators from other NIH institutes took a unique approach to address this challenge. They studied the genome sequences from more than 2,500 individuals with undiagnosed inflammatory diseases, paying particular attention to a set of more than 800 genes related to the process of ubiquitylation, which helps regulate both various protein functions inside a cell and the immune system overall. By doing so, they found a gene that is intricately linked to VEXAS, a disease which can be life-threatening. So far, 40 percent of VEXAS patients who the team studied have died, revealing the devastating consequences of the severe condition.

“We had many patients with undiagnosed inflammatory conditions who were coming to the Clinical Center, and we were just unable to diagnose them,” said Dr. David B. Beck, clinical fellow at NHGRI and lead author of the paper. “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.”