Type I Interferon–Associated Glomerulonephritis as a Novel Renal Phenotype in LIG4 Syndrome

LIG4 syndrome is a rare autosomal recessive inborn error of immunity caused by loss-of-function mutations in the LIG4 gene, encoding DNA ligase IV, a key enzyme in double-strand DNA break repair and V(D)J recombination. The phenotype includes combined T–B immunodeficiency, bone marrow failure, cancer predisposition, hypersensitivity to ionizing radiation, and microcephaly. We report the first case of immune-mediated glomerulonephritis with renal thrombotic microangiopathy (TMA) in a LIG4-deficient patient, demonstrating directly and indirectly type I interferon (IFN-1)–driven kidney injury.

Case Presentation: We report a 36-year-old woman with a homozygous LIG4 mutation (p.Arg278His). At age 12, she underwent successful allogeneic hematopoietic stem cell transplantation for bone marrow aplasia. At 32, she developed metaplastic breast adenocarcinoma, treated with surgery and chemotherapy, which caused severe gastrointestinal toxicity. After eight months, she presented with nephrotic syndrome and renal impairment, with normal complementemia and negative autoimmune serology. Kidney biopsy showed immune complex–mediated lupus-like glomerulonephritis (full-house immunofluorescence) with renal-limited TMA. Myxovirus resistance protein A (MXA) immunostaining and RNAscope for IFN-α mRNA demonstrated indirect and direct intrarenal IFN-I pathway activation, confirmed systemically by IFN-stimulated gene signature. Steroids and ruxolitinib improved systemic symptoms but not renal function. A second renal biopsy revealed evolution to pauci-immune chronic TMA. Given ongoing kidney deterioration, complement inhibition (eculizumab) was initiated, resulting in partial stabilization of renal function. At 25-month follow-up, she has chronic kidney disease stage 5 Kidney Disease Outcomes Quality Initiative (KDOQI) (eGFR 12 ml/min/1.73 m2; proteinuria 1 g/day).

Key Messages for Clinical Practice: This case underscores the clinical heterogeneity and severity of LIG4 syndrome and reveals a previously unrecognized pathogenic pathway leading to organ-specific autoimmunity. Screening of LIG4 should be considered in suspected monogenic lupus or interferonopathies, and inclusion of LIG4 in genetic testing panels may be warranted. Targeted modulation of IFN-I and complement pathways may represent a therapeutic strategy to improve the poor prognosis of this condition.