May 2021—Autoinflammatory and rheumatologic disorders in adults often present with overlapping clinical features and are challenging to treat. A genotype-first approach has been helpful to guide proper clinical management in other analogous disease settings. The authors conducted a study in which they analyzed the exome/genome sequencing data of peripheral blood cells from two large cohorts: 1,477 people who had undiagnosed recurrent fevers or systemic inflammation, or both, and 1,083 people affected by atypical, unclassified disorders who were identified through the National Institutes of Health Undiagnosed Diseases Program. Recurrent novel missense mutations affecting the methionine-41 codon of the X-linked gene UBA1, which codes for a major E1 enzyme that initiates ubiquitylation, were identified in three men. These UBA1 mutations were confirmed as somatic because they were not found in the matched fibroblasts of the affected individuals and their family members.