A novel homozygous ISG15 missense variant leads to severe inflammatory skin lesions, interstitial pneumonia, and basal ganglia calcifications in a Chinese infant with ISG15 deficiency.

Type I interferonopathies are a group of rare inherited autoinflammatory disorders characterized by dysregulation of type I interferon (IFN-I) signaling pathways. ISG15, a unique ubiquitin-like (Ubl) modifier in the interferon-stimulated genes (ISGs) family, plays a critical role in innate immune responses induced by IFN-I. When ISG15 function is impaired, it results in a disorder known as ISG15 deficiency, which is classified as an autosomal recessive systemic type I interferonopathy. Here, we report a 4-month-old Chinese patient presenting with inflammatory skin lesions, interstitial pneumonia, and basal ganglia calcifications. Whole-exome sequencing (WES) identified a novel homozygous missense variant (NM_005101.4: exon2: c.392 T > C, p.Leu131Pro) of ISG15. Functional analysis revealed that this variant impaired ISGylation and disrupted the stabilization of USP18, leading to defective negative regulation of IFN-I signaling and consequent excessive IFN-I production. Consistent with this, the patient exhibited elevated expression of ISGs in both peripheral blood and peripheral blood mononuclear cells (PBMCs). Treatment with the Janus kinase (JAK) inhibitor baricitinib rapidly resolved the patient's clinical symptoms. In conclusion, our findings expand the pathogenic spectrum of ISG15 deficiency and highlight the therapeutic efficacy of baricitinib in this disease. Notably, this case represents the first reported instance of a homozygous ISG15 missense variant in the Chinese population and the third such variant reported worldwide, further enriching our understanding of this rare autoinflammatory disease.