A team of NIH researchers have identified a new inflammatory disorder in men using a genotype-first strategy for disease discovery. The disorder, termed ‘vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic syndrome’ (VEXAS), causes a wide range of different symptoms such as recurrent fevers, blood clots in veins, vacuoles in myeloid cells, and pulmonary abnormalities. The diverse and seemingly unrelated symptoms have led to VEXAS going undiagnosed.
Inflammatory diseases are common. Approximately 125 million people in the United States are living with a chronic inflammatory disease. Since many inflammatory diseases have similar symptoms, determining which specific disease a patient has is problematic, as is identifying the specific causes.
New inflammatory diseases are usually discovered by studying a cohort of patients with similar symptoms and identifying a shared gene, mutation, or multiple genes which are common among the patients that could be contributing to the inflammation. This is now much easier thanks to the wide availability of genomic DNA sequencing.
Rather that studying patients with a similar set of symptoms – which is problematic with inflammatory diseases – researchers can take a genotype-first approach and identify groups of patients with the same phenotype, but who may be displaying very different symptoms, as was the case with patients with VEXAS. This approach can make disease discovery much easier, especially for diseases that cause a wide range of seemingly unrelated symptoms.
“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 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.” This approach is likely to be well suited to rheumatic diseases as they often have complex, highly variable clinical presentations.
The researchers studied the genome sequences of 2,560 individuals with an undiagnosed or unusual inflammatory disorder to identify whether any of the patients shared similar variations in the same gene. The symptoms experienced by these patients were diverse, although around 1,000 individuals had unexplained recurrent fevers and body-wide inflammation.
The researchers looked at around 800 genes and identified one that showed promise – the UBA1 gene. Three middle-aged men in the group were found to have rare and potentially harmful variants of the UBA1 gene, with two of the men having two copies of the gene. While this is not unusual, it was unusual in this case as both copies of the gene were on the X chromosome, of which there is only one in males. The researchers attributed this to mosaicism, which is where individuals have groups of cells with mutations that are different from the rest of the body.
The researchers hypothesized that these patients had groups of cells which contained the normal, fully functional copy of the UAB1 gene and groups of cells with the defective copy of the UAB1 gene. The researchers used DNA sequencing techniques and found there was mosaicism, and a mutated copy of the gene was present in the myeloid cells. Myeloid cells trigger inflammation in response to infection as a first line of defense.
After identifying the genes responsible, the researchers analyzed genome sequences from other individuals in NIH databases and identified a further 22 males that had UBA1 mutations, although different symptoms such as vein blood clots, vacuoles in the myeloid cells, and pulmonary abnormalities.
The researchers suggest that since the disorder was only found in men, the additional allele in women had a protective effect against the mutant allele, and prevented development of the disease or made it far less severe in women due to skewed X-inactivation.
To date, patients diagnosed with VEXAS have had poor outcomes, with the disorder having a high mortality rate. 10 of the 25 patients diagnosed with VEXAS have since died from disease-related causes or complications from treatment.
“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,” suggest the researchers in the paper.
You can read more about the study in the paper – Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease – which was recently published in the New England Journal of Medicine. DOI: 10.1056/NEJMoa2026834