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Gene & Protein in Disease Monogenic lupus and interferonopathies

immune complex deposition. Several immune phenomena,
such as defective regulatory T cells, impaired lymphocyte
homeostasis, and defects in the clearance of apoptotic cells
and immune complexes, may contribute to these features.
8,9
Despite remarkable advancements in understanding the
etiopathogenesis of SLE, its precise etiology remains elusive.
SLE is widely accepted as a polygenic, multifactorial disease
influenced by a complex interplay of genetic, epigenetic,
environmental, and hormonal factors. 10,11 Notably, a subset
of patients exhibits lupus features linked to a single genetic
mutation, classifying them as having monogenic lupus. 12-15
Interestingly, the genetic mutations responsible for these
pathogenic pathways lead to a robust production of IFN-I,
which drives monogenic lupus pathogenesis by promoting
inflammatory reactions, plasmacytoid dendritic cell
maturation, autoreactive T and B cell activation, and tissue Figure 1. Multiple finger contractures
damage, similar to the phenomena proposed for polygenic
or multifactorial lupus. 16 included a positive direct Coombs test, pancytopenia,
elevated erythrocyte sedimentation rate, positive
In this work, we explore the intersection between antinuclear antibody (ANA), double-stranded DNA
monogenic lupus and systemic autoinflammatory (dsDNA) antibodies, and anti-cardiolipin antibodies
disorders (SAIDs) by reporting two cases of monogenic (IgG and IgM), along with a low complement (C ) level.
3
lupus that were classified as SAIDs. Bilateral hand X-rays showed soft tissue swelling with non-
2. Patients and methods erosive deformities of the fifth fingers. Initial treatment
consisted of systemic corticosteroids, methotrexate, and an
This retrospective report analyzed two monogenic lupus anti-tumor necrosis factor (TNF) agent (adalimumab) for
patients carrying pathogenic genetic mutations. Medical 3 months. Due to poor response, the anti-TNF agent was
records were reviewed to collect demographic and clinical switched to rituximab, which led to partial improvement,
data, laboratory results, genetic findings, imaging and though frequent relapses were still observed. Follow-up
histopathology results, and therapeutic responses. assessments revealed progressive headache and bilateral
This study adheres to the ethical principles outlined papilledema. Further laboratory assessment revealed
in the Declaration of Helsinki (2000); the Research a negative neuromyelitis optica antibody test. Brain
Advisory Council guidelines of King Faisal Specialist magnetic resonance imaging (MRI) showed multiple
Hospital and Research Center, Riyadh; and the Saudi scattered patchy hyperintense lesions in the bilateral
Arabian legislation. This work was conducted as part of cerebral white matter, with unremarkable intracranial
a previously approved study (study number 2221105). magnetic resonance angiography and magnetic resonance
All clinical and laboratory assessments were performed venography (Figure 2). Whole exome sequencing identified
as part of the standard medical care. Informed consent a homozygous c.902C>T (p.S301P) variant in the DNase II
for genetic testing was obtained from the parents during gene, leading to the diagnosis of monogenic lupus due to
blood extraction, as part of patient care. All collected data DNase II deficiency.
were examined under confidentiality practices, ensuring The second case has been previously reported. In
17
no personal information was disclosed. Verbal consent brief, the patient was diagnosed with monogenic lupus,
was obtained from each patient’s parents for publication of initially presenting with constitutional symptoms,
their data and/or images. oral ulceration, polyarthritis, and myositis involving
3. Results pelvic and thigh muscles, confirmed by MRI findings.
Laboratory results showed elevated muscle enzymes, high
The first case involves a 12-year-old boy who initially acute-phase reactants, low complement (C and C ) levels,
4
3
presented at 3 years of age with intermittent fever and and elevated ANA and dsDNA antibodies. Whole exome
painful polyarthritis affecting the small joints of hands, sequencing identified a homozygous splicing site, ISG15
elbows, knees, and ankles. In addition, he exhibited variant (c.4-1G˃A). Table 1 presents the pathogenic
multiple finger contractures (Figure 1). Other systemic genetic variants identified in our patients with monogenic
assessments were unremarkable. Laboratory findings lupus.

Volume 4 Issue 3 (2025) 2 doi: 10.36922/GPD025080019