Submission Details

DNASE1L3 is encoded on chromosome 3. It is one of several human homologs of DNase I. The family of enzymes includes DNASE1, DNASE1L1, DNASE1L2 and DNASE1L3. These function as endonucleases capable of cleaving DNA. DNASE1L3, predominantly expressed in macrophages and dendritic cells (unlike the other DNase homologs, which are expressed at much lower levels in hematopoietic cells), is secreted into the circulation and is thought to have a role in the fragmentation of free plasma DNA, clearing it from circulation and reducing risk of cell-free DNA antigenicity.

DNASE1L3 was first reported in relation to autosomal recessive monogenic Systemic Lupus Erythematosus (SLE) in 2011 (PMID: 22019780). At least 5 loss-of-function genetic variants (missense, nonsense, frameshift, large deletion) have been reported in humans, commonly in children from consanguineous marriages. Evidence supporting this gene-disease relationship includes multiple reports of case-level data. The initial 2011 report (PMID: 22019780) described a homozygous 1-bp deletion (c.289_290 del) in DNASE1L3 in six individuals diagnosed with childhood-onset SLE, based on clinical and serological criteria. Additional cases of childhood-onset SLE with the same base-pair deletions were reported in 2017 (PMID: 27821515), 2018 (PMID: 30008451) and 2020 (PMID: 34161863). Additional variants in the DNASE1L3 gene with manifestations of SLE and/or lupus nephritis were reported in a case series in 2021 (PMID: 35670985).

This gene-disease relationship is supported by expression studies showing that the c.289_290 deletion mutation is associated with decreased expression of DNASE1L3 RNA levels (PMID: 23666765). A SNP in DNASE1L3 that is associated with increased SLE risk was also shown to be associated with decreased protein secretion of DNASE1L3 (PMID: 33455918). Decreased serum levels of DNASE1L3 are observed in the general SLE (and inflammatory myositis) population as compared to healthy controls; in SLE, lower DNASE1L3 levels are associated with higher clinical disease scores (PMID: 28039554). Animal models show that mice with DNASE1L3 deletion develop anti-DNA autoantibodies and lupus nephritis (PMID: 28039554). Deletion of DNASE1L3 resulted in aberrations in the fragmentation of plasma DNA (PMID: 30593563); these aberrant DNA fragments were also present in the circulation of patients with the DNASE1L3 disease-associated variants, but not in healthy controls (PMID: 33022220). In mice with the DNASE1L3 deletion, the phenotype of aberrant DNA fragments in the peripheral circulation could be rescued by restoring DNASE1L3 production using viral vectors (PMID: 33022220).

More evidence is available in the literature, but the maximum score for genetic and experimental evidence (18 pts.) has been reached. The mechanism for disease is homozygous loss of function.

In summary, there is definitive evidence to support the relationship between DNASE1L3 and autosomal recessive monogenic Systemic Lupus Erythematosus. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.