Homozygous OTULIN Variant Linked to OTULIN-Related Autoinflammatory Syndrome with Abscess Formation

Homozygous OTU deubiquitinase with linear linkage specificity (OTULIN) variants cause OTULIN-Related Autoinflammatory Syndrome (ORAS). This disease is characterized by early-onset autoinflammation, fever, panniculitis, diarrhea, and arthritis. In contrast, heterozygous and compound-heterozygous OTULIN variants have been associated with a phenotype defined by abscess development in different organs. Whether homozygous OTULIN variants can cause abscessing in affected patients is currently unknown. Here, we report a juvenile female patient harboring a novel homozygous OTULIN variant (Chr5:14687605G>T, p.V185F; referred to as OTULIN ^V185F ), presenting with autoinflammation and sterile abscesses in lung and skin. Through in silico analysis and functional assays, we show that OTULIN ^V185F impairs OTULIN function, leading to compromised degradation of linear ubiquitin linkages. Notably, the patient clinically improved on anti-TNF therapy. Our findings underscore the diverse clinical manifestations of OTULIN dysfunction and call for a new classification of the disease that includes abscess formation as potential ORAS symptom.