The current, clinically based taxonomy of rheumatic disease is inadequate, but genetic contributions to rheumatic disease pathophysiology varies widely across diseases. While germline mutations have been identified as the cause of some rheumatic diseases, no germline mutations have been identified for other complex diseases.
But emerging research suggests that somatic mutations may underlie both monogenic and genetically complex immune-mediated rheumatic diseases, according to Dan Kastner, MD, PhD, Head of the Inflammatory Disease Section at the National Human Genome Research Institute at the National Institutes of Health.
Dr. Kastner discussed recent research advances during the session Reimagining the Genetics of Complex Rheumatic Diseases on Tuesday, Nov. 9. The session can be viewed on demand by registered meeting participants through March 11, 2022.
Dr. Kastner highlighted recent work led by David Beck, MD, PhD, Assistant Professor of Medicine at NYU Langone Health. As a fellow in Kastner’s lab, Dr. Beck and a few of his colleagues were eager to explore the two-thirds of patients seen at their autoinflammatory clinic that did not have a genetic diagnosis.
“Rather than using a conventional approach of grouping patients together by their phenotype — the same form of arthritis or the same pattern of fever — instead [Dr. Beck] would take things from a genotype-first approach,” Dr. Kastner said. “He made a list of genes he was interested in and tested against all patients hoping that would define a common phenotype.”
The researchers started with 841 genes related in some way to protein ubiquitylation. They then made a list of 1,477 patients from the clinic who did not have a diagnosis and another list of 1,083 patients from the undiagnosed disease program. They were looking for genes that were pLI >0.9.
Dr. Beck found three middle-aged men heterozygous for the p.Met41 variant in the UBA1 gene. Interestingly, the UBA1 gene is encoded on the X chromosome. Men only have one X chromosome, but these men had two variants. To explain this, the researchers hypothesized that the men had two populations of cells, one of which had the mutation and another that did not.
To test this hypothesis, Dr. Beck and his colleagues looked at fractionated cells of different types. The three patients were found to have these mutations in their bone marrow. When samples were examined in the hematopathology suite, vacuoles were seen. The pathologist remembered seeing similar vacuoles years earlier, Dr. Kastner explained. When those previous patient samples were tested, they were also found to have UBA1 mutations. One of these patients had been diagnosed with relapsing polychondritis.
Dr. Beck and the research team then identified other patients with relapsing polychondritis and tested for UBA1 mutations. Eventually a cohort of 25 patients with UBA1 mutations was identified. All were middle-aged men, and all experienced disease onset after the age of about 40. All had unexplained fevers as well as other common symptoms like ear/nose chondritis, skin lesions, alveolitis, and thromboembolic disease. The patients had been diagnosed with a number of conditions, but relapsing polychondritis was the most common, Dr. Kastner said.
The researchers named the newly identified condition VEXAS syndrome — vacuoles, E1 ubiquitin-activating enzyme, X-linked, autoinflammatory, somatic.
“Using a genotype-first strategy, one can define new illnesses based on genetic variants shared among patients carrying distinct clinical diagnoses,” Dr. Kastner said. “This may give rise to a new molecular taxonomy of rheumatic disease.”