DNASE1L3
3 variant(s) documented across Hypocomplementemic Urticarial Vasculitis Syndrome
Variants
| Variant | Type | Frequency in disease | Significance | Also found in |
|---|---|---|---|---|
| c.289_290delAC (frameshift) | germline | Familial cases only (autosomal recessive) | First identified genetic cause of familial HUVS. Homozygous frameshift mutation causes complete loss of endonuclease activity via nonsense-mediated mRNA decay. Impairs clearance of extracellular chromatin from apoptotic cells. | Monogenic SLE (SLE-16) (Causative); Familial SLE with ANCA positivity (Subset of cases) |
| c.320+4delAGTA (splice-site) | germline | Familial cases only (autosomal recessive) | Second identified DNASE1L3 mutation in an unrelated HUVS family. Causes exon skipping and abolished endonuclease activity as demonstrated by plasmid nicking assay. | Monogenic SLE (SLE-16) (Causative) |
| c.572A>G, p.Asn191Ser | germline | Identified in 3 Emirati families with SLE/HUVS overlap | Novel variant that does not affect enzyme production but impairs secretion. DNASE1L3 191S protein is overexpressed intracellularly but absent in supernatant, demonstrating a distinct loss-of-function mechanism. | SLE with hypocomplementemic urticarial vasculitis (7 patients in 3 families) |
Clinical implications
c.289_290delAC (frameshift)
Genetic testing for DNASE1L3 recommended in pediatric-onset or familial HUVS. Carriers inevitably progress to SLE.
Testing: Whole-exome sequencing, Targeted gene panel, Sanger sequencing
c.320+4delAGTA (splice-site)
Confirms DNASE1L3 as causative gene across multiple families. Supports genetic counselling for at-risk families.
Testing: Whole-exome sequencing, Targeted gene panel
c.572A>G, p.Asn191Ser
Expands the spectrum of DNASE1L3 mutations. Demonstrates that secretion defects, not just loss of production, can cause disease.
Testing: Whole-exome sequencing, Functional secretion assays
Related molecules in pathway
Extracellular DNA clearance enzyme — Lost (in familial HUVS)