Researchers from the National Institutes of Health (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 the National Human Genome Research Institute (NHGRI), part of the NIH, 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
over 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 that
can be life-threatening. So far, 40% of VEXAS patients who the team studied
have died, revealing the devastating consequences of the severe condition.
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 the disease. However, this was not a viable option for
the NIH research team.
“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, M.D., Ph.D., 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.”
Out
of the genome sequences of 2,560 patients with undiagnosed inflammatory
conditions, over 1,000 patients had undiagnosed recurrent fevers and body-wide
inflammation. The rest, part of the NIH Undiagnosed Diseases Network, had
unusual and unclassified disorders.
“Our
objective was to see if any of the 2,560 patients shared variations in the same
gene,” said Daniel Kastner, M.D., Ph.D., scientific director of the Intramural
Research Program at NHGRI and a senior author of the 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 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).
“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 Dr.
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.
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. Most of the individuals had
symptoms that included blood clots in veins, recurrent fevers, pulmonary
abnormalities and vacuoles (unusual cavity-like structures) in the myeloid
cells.
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.
“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,” Dr. Kastner said.
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.
Journal
article: https://www.nejm.org/doi/10.1056/NEJMoa2026834
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