Novel DNASE2 Variants Linked With Neonatal Acute Liver Failure and Monogenic Systemic Lupus Erythematosus

To the Editor:

Systemic lupus erythematosus (SLE) is a complex autoimmune disease. Although typically polygenic, rare monogenic forms involving over 50 genes have been reported. Among these, DNASE2 variants disrupt DNA degradation and trigger aberrant immune activation.¹ We describe a boy with neonatal liver failure who, by age 7, developed lupus nephritis and SLE. Genetic testing identified 2 novel heterozygous missense variants in DNASE2. Our findings may guide earlier diagnosis and management in patients with similar genetic profiles.

The male patient was born at 38 weeks to nonconsanguineous parents after an uncomplicated pregnancy. Upon delivery, he had neonatal acute liver failure (NALF) with vitamin K–refractory coagulopathy, requiring prolonged care at the neonatal intensive care unit, exchange transfusion for hyperbilirubinemia, and intravenous vitamin K. At 2 weeks of age, a liver biopsy showed hepatocyte necrosis, pericellular fibrosis, cholestasis, giant cell transformation, extramedullary hematopoiesis, and no evidence of infection, supporting a provisional NALF diagnosis. Post procedure, he developed Escherichia coli sepsis, necessitating a 3-month hospital stay.

At age 2 years, endoscopy for upper gastrointestinal bleeding revealed grade II esophageal and gastric varices secondary to liver cirrhosis, which were treated with sclerotherapy.

By 7 years of age, his cirrhosis decompensated with splenomegaly, refractory ascites, cytopenias, hypocomplementemia, proteinuria, and hematuria. Kidney biopsy revealed class IV/V lupus nephritis, and serology showed high-titer antinuclear antibodies (1:640) and anti-dsDNA antibodies (> 300 U/mL), confirming SLE. He was treated with prednisone, mycophenolate mofetil (MMF), and hydroxychloroquine, achieving clinical remission after 2.5 years. He continues on MMF and hydroxychloroquine, with persistent cirrhosis, portal hypertension, and hypersplenism. Additional comorbidities include short stature (for which he receives growth hormone), a learning disability, and inattentive attention-deficit hyperactivity disorder.

Whole exome sequencing (WES) was performed on peripheral blood from the patient and his parents using Illumina HiSeq 2500. DNase2 activity was assessed in lymphoblastoid cell lines by incubating plasmid DNA with serial dilutions of cell lysates. Protein expression was analyzed by Western blotting using primary and horseradish peroxidase (HRP)-conjugated secondary antibodies. Interferon (IFN)-regulated gene expression was quantified from whole-blood RNA, with scores calculated as the geometric mean of 28 target genes where g1-g28 represent the counts for each gene (Supplementary Table S1, available with the online version of this article).

Proband WES identified 2 predicted deleterious missense variants in DNASE2: c.217G>A (p.Gly73Arg), exon 2 (CADDv1.7 = 20.8) and c.897C>G (p.Cys299Trp), exon 6 (CADDv1.7 = 20.6).² Trio Sanger sequencing confirmed each variant was inherited from 1 parent (Figure 1A; Supplementary Figure S1, available with the online version of this article).

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Figure 1.

Genetic and functional analyses of compound heterozygous DNASE2 variants resulting in reduced enzymatic activity. (A) Family pedigree of the proband, where circles denote female family members and squares denote male family members. Shaded symbols denote affected family members, and symbols with a central dot indicate carriers. (B) Western blot showing DNase2 protein levels in lymphoblastoid cell lines from the proband and parents. Whole cell extracts were separated by SDS-PAGE and probed with antibodies against DNase2 and GAPDH as a loading control. (C) DNase2 activity assay where cell lysates were diluted at a ratio of 1:4 into plasma DNA solution in each well. Samples were then run on a 1% agarose gel to visualize DNA degradation. SDS-PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis.

Both variants were absent from gnomAD and have not been reported in functional assays.³ P.Gly73Arg and Cys299Trp are located within the N-terminal and C-terminal catalytic domains, respectively, of the DNase2 protein, forming a single active site. These residues are not highly conserved and computational tools do not universally predict a deleterious effect. However, both substitutions are predicted to destabilize local protein structure or electrostatic interactions, potentially reducing catalytic efficiency. Both substitutions are classified as variants of uncertain significance (Supplementary Table S2, available with the online version of this article).

DNASE2 transcript and protein levels were similar between the proband and his parents (Figure 1B). However, the patient showed markedly reduced DNase2 activity, requiring higher lysate concentrations for plasmid DNA degradation, suggesting hypomorphic variants (Figure 1C).

The patient had higher levels of the DNA damage marker γH2AX and the DNA sensor cGAS, but lower stimulator of IFN genes (STING) levels compared to his parents. TBK1 and autophagy markers were similar across the trio (Figures 2A,B).

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Figure 2.

Compound heterozygous missense DNASE2 variants lead to increased DNA damage and IFN response. (A,B) Western blots of protein lysates from lymphoblastoid cell lines of the patient and parents. Whole cell extracts were separated by SDS-PAGE and probed with antibodies against markers of DNA damage and IFN response, with GAPDH as a loading control. (C) IFN gene scores were calculated from whole blood RNA based on the expression of 28 IFN-regulated genes (Supplementary Table S1). Scores were expressed as the geometric mean of the target genes and scaled by dividing by 10 to approximate z score ranges. IFN: interferon; SDS-PAGE: sodium dodecyl-sulfate polyacrylamide gel electrophoresis; STING: stimulator of interferon genes.

The patient had elevated IFN signaling, with scores ranging from 620.1 to 1483.6 over 3 years. In contrast, his parents’ IFN scores remained within the normal range (mother 91.7, father 73.6; Figure 2C).

We identified 2 novel DNASE2 variants in a male patient with NALF, who later developed lupus nephritis and SLE. In the absence of transfection studies, functional studies showed impaired DNase2 activity and elevated IFN-stimulated gene expression compared to his unaffected parents. These findings link novel compound heterozygous DNASE2 variants to a clinical phenotype resembling prior reports of patients homozygous for hypomorphic DNASE2 variants.¹ Their features included neonatal cholestasis, hepatosplenomegaly, cytopenias, glomerulonephritis, and autoantibody positivity.^1,4 To our knowledge, this is the first report of compound heterozygous DNASE2 variants in monogenic SLE.

Our work suggests that functionally impaired DNase2 led to reduced DNA degradation and increased DNA damage (γH2AX) and cytosolic DNA (cGAS) in the patient. This occurred despite comparable DNASE2 transcript and protein levels in the proband and his parents, suggesting hypomorphic variants.

Once cGAS senses cytosolic DNA, it catalyzes the synthesis of cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) and activates the STING pathway.⁵ Despite elevated cGAS in our patient, STING levels were lower than that of his parents, possibly due to age-related increases or negative feedback from persistent IFN activation.^6,7 This STING reduction corresponds with the patient’s status at the time of sample collection, as he was clinically quiescent and maintained on immunosuppressants.

We observed elevated IFN levels in our patient compared to that of his parents. Prolonged IFN induction contributes to SLE pathogenesis, including lupus nephritis and hepatic inflammation.^1,8 These findings suggest that the compound heterozygous DNASE2 variants may induce an IFN inflammatory state that drives his clinical phenotype, supporting an association of these variants with SLE and lupus-like disease. This mechanism is similar to that observed with other monogenic forms of SLE linked with pathogenic variants in DNASE1 and DNASE1L3. Bilallelic carriers of pathogenic variants in these genes similarly have activated type I IFN pathways as well as biopsy confirmed lupus nephritis.⁹

In summary, we demonstrated how novel compound heterozygous DNASE2 variants led to an IFN-mediated inflammatory state and the clinical presentation of NALF and monogenic SLE in a young boy.

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