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Tuesday’s Opening of ASHG 2020 Virtual Annual Meeting (October 27-30) Features Report of Research That Is Described in NEJM Article Published Today--“Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease”

The American Society of Human Genetics (ASHG) 2020 Virtual Annual Meeting (October 27-30) opened today (Tuesday) and one of the highlights of many stimulating presentations was a talk entitled “Somatic Mutations in a Single Residue of UBA1 Are Associated with a Severe Adult-Onset Autoinflammatory Disease” (Abstract #1052). The ASHG meeting presentation was delivered by David B. Beck, MD, PhD, Clinical Fellow, Inflammatory Disease Section, National Human Genome Research Institute, NIH. At the end of his presentation, Dr. Beck noted that the work he just described was published online today (October27, 2020) in the New England Journal of Medicine (https://www.nejm.org/doi/full/10.1056/NEJMoa2026834). Dr. Beck is the first author on the NEJM article. In the abstract for today’s ASHG talk, Dr. Beck and colleagues noted that identifying the causes of adult-onset diseases remains a challenge in clinical genomics, and limits targeted diagnosis, prognosis, and treatment. The researchers hypothesized that mutations in genes regulating the post-translational modification of ubiquitin, previously implicated in inflammatory diseases, may define new rheumatologic disorders. Using a genotype-first approach, agnostic to inheritance or phenotype, the group analyzed peripheral blood exome sequence data from 2,560 individuals with inflammation-related diagnoses for deleterious mutations in highly-constrained genes. After discovering three patients with novel, somatic, UBA1 mutations at the same residue, the researchers identified and characterized additional cases based on clinical similarities. [Editor’s Note: UBA1 is the gene coding for ubiquitin-like modifier-activating enzyme 1.] Twenty-five males were identified with somatic mutations at methionine 41 (p.met41) in UBA1, an X-linked gene, encoding the major E1 enzyme required to initiate all cellular ubiquitylation. Mutations were present in more than half of hematopoietic stem cells, exclusively in peripheral blood myeloid cells, but not in lymphocytes or fibroblasts. Patients developed an often-fatal, treatment-refractory inflammatory syndrome in late adulthood, with fevers, cytopenias, characteristic vacuoles in myeloid and erythroid precursors cells, dysplastic bone marrow, neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis.
Patients fulfilled clinical criteria for inflammatory (polyarteritis nodosa, relapsing polychondritis) and hematologic (myelodysplastic syndrome) conditions. Mutant peripheral blood cells exhibited activated innate immune pathways.

Mutations at p.Met41 resulted in loss of the cytoplasmic isoform of UBA1 and decreased ubiquitylation and, unexpectedly, the expression of a novel, catalytically inactive, toxic isoform, in mutant, but not wildtype, lineages.

The researchers reported that knockout of the zebrafish Uba1 cytoplasmic isoform phenocopied systemic inflammation found in patients.

This genotype-first analysis defined a novel disorder, termed “VEXAS” (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, that connects seemingly unrelated adult-onset inflammatory syndromes and establishes a precedent for a new molecular taxonomy of rheumatologic diseases.

Dr. Beck and colleagues concluded that their work indicates that somatic mutations can be an underrecognized cause of inflammatory diseases.

[NEJM abstract] [ASHG 2020 Virtual Annual Meeting]