Lu Jiang¹, Chan Huang¹, Xiaohan Hu¹, Xiaozhong Li¹, Aiqing Zhang¹
1- Children’s Hospital of Soochow University, China
Abstract Body
Zinc finger NFX1-type containing 1 (ZNFX1) is a double-stranded RNA sensor; its deficiency is a recently described inborn error of immunity characterised by susceptibility to viral infections systemic inflammation, and type I interferon (IFN-I) activation. However, its full phenotypic spectrum remains incompletely defined. We report a 1-year-old girl presenting with uncorrectable anemia, growth delay , digital clubbing, and interstitial lung disease (ILD) characterized by markedly elevated KL-6 levels and patchy pulmonary opacities. Trio exome sequencing identified novel compound heterozygous ZNFX1 variants, including a paternally inherited frameshift variant (c.981dup) and two maternally inherited variants(c.1605_1630delinsGGGAATATCGTGGA and c.2893G>A). Transcriptome analysis confirmed reduced ZNFX1 expression, while structural modeling suggested impaired protein stability . Functional studies in peripheral blood mononuclear cells revealed significant upregulation of interferon-stimulated genes, including OASL, L Y6E, and DDX58, confirming aberrant IFN-I activation. The patient showed clinical improvement following immunomodulatory therapy with glucocorticoids and tocilizumab. These findings expand the phenotypic spectrum of ZNFX1 deficiency to include ILD and emphasize the role of dysregulated IFN-I signaling in itspathogenesis, suggesting that ZNFX1 should be considered in the differential diagnosis of childhood interstitial lung disease (chILD).