Throughout the history of medicine, technological progress has enabled physicians to understand and diagnose previously enigmatic syndromes. Although Hippocrates described many of the features of tuberculosis, it was not until the invention of the microscope that physicians understood the cause to be Mycobacterium tuberculosis. In a similar way, the technology and application of genome sequencing (genomics) is now revolutionizing the understanding of many diseases and syndromes. (1)
In 2001, the first effort to sequence the human whole genome took more than 5 years; it is now possible to generate clinically actionable results from whole genome sequencing in as little as 5 days. (2) The wealth of data generated by these techniques has shown that many undiagnosed syndromes have specific genetic causes.
We illustrate the power of genomics to affect clinical diagnostics and practice with the newly discovered vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome, which has provided a unifying genetic diagnosis for a group of patients with a previously undiagnosed autoinflammatory syndrome. This syndrome is relevant to many physicians as it can present with a wide variety of symptoms involving many organ systems and it has an adult age of onset, which shows that genetically driven disorders can affect almost any patient. At present, many patients with VEXAS are placed within existing diagnostic categories and will benefit from accurate diagnosis based on the genomic driver of their disease.
What are autoinflammatory syndromes and how can they present?
Autoinflammatory syndromes (also known as systemic autoinflammatory diseases) are defined by the presence of pathogenic hyperactivation of immune pathways in an antigen-independent manner. More than 40 distinct monogenic conditions that can lead to an autoinflammatory syndrome have been described.3 The exact features depend on the specific disease, but a common presentation is fever of unknown origin, defined as a persistent fever (> 38.3[degrees]C for > 3 wk) without an obvious cause after appropriate initial investigations. In a recent prospective study from the Netherlands of 73 patients with fever of unknown origin, an autoinflammatory syndrome was identified in 22% of patients. (4) Autoinflammatory syndromes should be considered for patients with fever of unknown origin for whom extensive investigation for infection, malignant disease, hemophagocytic syndrome and other causes of fever and systemic inflammation have been excluded.
What is VEXAS syndrome and when should it be considered as a diagnosis?
Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome was first described in December 2020 after whole genome sequencing was performed for a cohort of patients as part of the Undiagnosed Diseases Program at the National Institutes of Health (NIH). (5) By integrating large-scale gene mutation data with information on patients' symptoms, the NIH identified 25 individuals with similar syndromic features who all had mutations in the X-linked UBA1 gene, which produces an enzyme that is important in recycling proteins within cells. (5) This mutation was confirmed to be somatic (i.e., acquired and not inherited), and was shown to reproduce some features of VEXAS when inserted into an animal model. (5) Shortly after this landmark publication, the...