PLD4

Inheritance Pattern: AR

Disease ID:MONDO:1060185

Submitter: ClinGen

The *PLD4* gene encodes a 5’->3’ exonuclease that localizes in endolysosomes and cleaves single-stranded RNA and DNA, restricting overactivation of TLR7 and TLR9 and their inflammatory signaling pathways. *PLD4* was first reported in relation to systemic lupus erythematosus (SLE) in 2019 by Akizuki et al. (PMID: 30679154), who performed a GWAS meta-analysis for SLE which identified significance in a region containing *PLD4*. Genetic evidence was reported in 2025 by Wang et al. (PMID: 40931063). One frameshift and six missense variants in *PLD4* were identified; the variants were present in either homozygous or proven/suspected compound heterozygous states in five affected individuals. Exonuclease activity assays were performed for the six unique missense variants identified in this study as well as on a patient sample, all of which showed impaired exonuclease activity compared to controls. Additional experimental evidence includes two mouse models. Akizuki et al. (PMID: 30679154) showed that mice homozygous for a *PLD4* nonsense variant had notably increased anti-dsDNA production, splenomegaly, and lymphadenopathy. Wang et al. (PMID: 40931063) showed that homozygous *PLD4* knockout mice had autoimmune phenotypes, including significantly elevated dsDNA antibodies, as well as severe nephritic phenotypes. In summary, there is **moderate** evidence supporting the relationship between *PLD4* and autosomal recessive Systemic Lupus Erythematosus. This classification was approved by the ClinGen Monogenic Systemic and Incomplete Lupus Erythematosus GCEP on the meeting date November 12, 2025 (SOP Version 11).