DNAJC17 deficiency: A novel inborn error of immunity with TNF-driven autoinflammation.

Background: Inborn Errors of Immunity (IEI) encompass a broad spectrum of monogenic disorders with variable clinical presentations, including recurrent infections, autoimmunity, and systemic inflammation. Loss-of-function mutations in Methods: We conducted a comprehensive clinical, molecular, and immunological investigation of three affected individuals from two unrelated consanguineous families. Our evaluation included whole genome sequencing with systematic exclusion of alternative genetic etiologies, quantitative analysis of DNAJC17 mRNA expression, and assessment of intracellular DNAJC17 protein levels. In addition, we performed in-depth immunophenotyping of adaptive and innate immune cell subsets, cytokine profiling, and interferon-stimulated gene expression analysis, alongside longitudinal evaluation of responses to therapeutic interventions. Results: All three patients presented with early-onset retinitis pigmentosa, recurrent fever, lymphadenitis, and hypogammaglobulinemia. Sanger sequencing confirmed a homozygous variant (c.681G>A; p.Ala227=) in Conclusion: Our findings establish DNAJC17 deficiency as a novel monogenic inborn error of immunity characterized by retinopathy, combined immunodeficiency, and TNF-driven autoinflammation responsive to targeted TNF blockade. The underlying immune abnormalities underscore the essential role of DNAJC17 in maintaining immune homeostasis and mitochondrial function. This work provides mechanistic insights into disease pathogenesis and establishes a rational, precision medicine therapeutic approach for this newly defined syndrome.