Novel genotypes, phenotypes, and triggers in humans with OTULIN haploinsufficiency

Abstract

Human OTULIN haploinsufficiency predisposes to life-threatening necrosis of the skin and lungs. Disease is triggered by infectious agents, typically Staphylococcus aureus, as well as unknown etiologies. We describe and characterize six unrelated patients who carry rare, predicted deleterious variants of OTULIN in heterozygosity. In addition to staphylococcal infections, the disease in the patients is elicited by previously underappreciated triggers, including mechanical or iatrogenic traumas and pseudomonal or clostridial infections. Severe necrosis of the lungs and/or skin are clinical hallmarks of their disease. By combining in vitro allele characterizations and functional studies in patients' cells, we demonstrate that the patients suffer from OTULIN haploinsufficiency. We provide guidance for assessing heterozygous OTULIN variants in diagnostic settings by evaluating in silico measures of predicted deleteriousness. The clinical course of the patients expands the genotypic and phenotypic spectrum of OTULIN haploinsufficiency and provides, in the light of a broadening of triggers, leads for therapeutic interventions.