Researchers attached to the National Institutes of Health (NIH) have found a new inflammatory disorder called vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic syndrome (VEXAS) that is caused by mutations in the UBA1 gene by using clues in Human Genome.
VEXAS causes symptoms like blood clots in veins, recurrent fevers, pulmonary abnormalities and unusual cavity-like structures (vacuoles) in myeloid cells.
The scientists have published their discoveries in the New England Journal of Medicine.
Around 125 million people in the United States live with some form of a chronic inflammatory disease. Many of these diseases have overlapping symptoms that often make it difficult for researchers to diagnose the specific inflammatory disease in a given patient.
Researchers at the National Human Genome Research Institute (NHGRI), a division of the NIH, and collaborators from other NIH Institutes taken measures to address this challenge.
Human genome sequences
They researchers analysed the human genome sequences from more than 2,500 individuals with undiagnosed inflammatory diseases. They paid attention to a set of more than 800 genes related to the process of ubiquitylation that helps regulate both various protein functions inside a cell and the immune system overall.
With this process, they discovered a gene that is intricately linked to VEXAS, a disease which can be life-threatening.
Dr David B. Beck, clinical fellow at NHGRI and lead author of the paper, said, “We had many patients with undiagnosed inflammatory conditions who were coming to the NIH Clinical Center, and we were just unable to diagnose them,”
“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.”
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Out of the human genome sequences of 2,560 patients with undiagnosed inflammatory conditions, Beck said more than 1,000 patients had undiagnosed recurrent fevers and body-wide inflammation.
According to Dr Daniel Kastner, scientific director of the Intramural Research Program at NHGRI and a senior author of the paper, said, “Our objective was to see if any of the 2,560 patients shared variations in the same gene,”
Instead of looking at clinical similarities, Kastner said, “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 one copy harboring the mutation, which was not 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 (and one Y chromosome).
The researchers 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.
Out of the combined 25 individuals, researchers were able to find a link between the various clinical rheumatologic and blood-related diagnoses made for the patients. Because these conditions exist in people with UBA1 mutations, the team grouped the various conditions into a new disease: VEXAS.
The researchers believe this new genome-first strategy will help healthcare professionals to improve assessing diseases and provide necessary treatments for thousands of patients who are suffering from various inflammation-related conditions.
(With inputs from The OnLook Research Team)
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