Submission Details

The DNASE1 (Deoxyribonuclease 1) gene is located on chromosome 16 (16p13.3) and encodes a protein that cleaves protein-free double-stranded DNA and single-stranded DNA via endonucleolytic cleavage to 5'-phosphodinucleotide and 5'-phosphooligonucleotide end-products. It plays a key role in degrading neutrophil extracellular traps (NETs) and is responsible for DNA fragmentation in the process of apoptosis (PMID: 16103871). Variants in DNASE1 were first reported in relation to autosomal dominant (AD) systemic lupus erythematosus (SLE) in 2001 (PMID: 11479590).

The SLE clinical presentation is characterized by variable onset phenotypes including two or more of the following: antinuclear antibodies (ANA), leukopenia, thrombocytopenia, autoimmune hemolysis, delirium, psychosis, seizures, non-scarring alopecia, oral ulcers, subcutaneous or discoid lupus, pleural or pericardial effusion, acute pericarditis, joint involvement, proteinuria, lupus nephritis, positive antiphospholipid antibodies, anti-dsDNA antibodies or anti-Sm antibodies (OMIM:125505; phenotype: 152700). Genetic evidence reviewed in the curation of this gene-disease relationship included 7 probands with 6 unique heterozygous variants.

The molecular mechanism of disease is unknown. While animal models show that loss of DNASE1 recapitulates lupus-like phenotypes in mice (PMID:10835632, 30758851), the mixed genetic background of these 129 and B6 mice was later been shown to develop spontaneous autoimmunity. The first reported SLE patients with DNASE1 variants had truncations predicted to cause loss of function (LOF), but DNASE1 gene is not constrained for LOF (gnomAD) and hundreds of presumably unaffected individuals with LOF variants are present in population databases (gnomAD). All subsequently reported DNASE1-related SLE patients were heterozygous for missense variants, most of which occur at a higher frequency than expected for a pathogenic variant. However, this gene-disease relationship is also supported by biochemical function and functional alterations. DNASE1L3, another deoxyribonuclease, is also known to cause SLE (PMID: 22019780), and mice missing both DNASE1 and DNASE1L3 genes have different cfDNA phenotypes than those missing either gene alone (PMID: 30593563, 36928522). SLE patients with variants in DNASE1 display low DNase activity and high levels of autoantibodies diagnostic for lupus (PMID:11479590, 15593183,15333586). While there is considerable experimental evidence that DNASE1 is altered in lupus patients, and disruption of DNASE1 results in lupus-like phenotypes in some model systems, more recent model systems do not recapitulate autoreactivity in DNASE1-deficient mice from different strains (PMID: 36928522).

There is also limited clinical genetic evidence supporting that DNASE1-related lupus is a single-gene AD disorder. No segregation of DNASE1 variants with SLE has been reported in families. While one DNASE1 variant did segregate with low DNASE1 activity, one family member without the variant also had low DNASE1 activity (PMID:15593183). Clinical reports of SLE patients with DNASE1 variants found that they also harbored variants in other SLE-associated genes (PMID: 35964089, 30707351). While common variants in DNASE1 are associated with increased risk of SLE and/or SLE-related phenotypes in SLE cases compared to healthy controls (PMID: 15333586, 16449364), these associations have not been replicated in genome-wide association studies. Therefore, this LIMITED classification was approved by the ClinGen Monogenic Systemic and Incomplete Lupus Erythematosus GCEP in the meeting on June 14, 2024 (SOP Version 10).