Novel C1QB Variant Causes Functional Complement Deficiency in Lupus Case Study

A newly reported medical investigation has identified a novel homozygous genetic variant in the C1QB gene that causes functional C1q deficiency in a pediatric systemic lupus erythematosus patient who also carries a concurrent somatic TNFAIP3 variant.

The clinical case centered on a four-year-old girl who was referred to the hospital presenting with a complex array of severe inflammatory manifestations and autoimmune features. Her medical history and clinical evaluation documented recurrent fevers, arthritis, and distinctive chilblain-like rashes, alongside recurring seizure episodes. Further diagnostic investigations revealed multiple positive autoantibodies as well as the presence of intracranial calcifications.

Initial whole-exome sequencing conducted by the research team detected a somatic pathogenic variant in the TNFAIP3 gene, leading to a diagnosis of haploinsufficiency of A20, also known as HA20. While this specific somatic alteration provided a plausible biological explanation for the recurrent febrile episodes, the patient failed to respond adequately to standard first-line tumor necrosis factor inhibitors recommended for HA20 management. The lack of clinical response to targeted TNF inhibition prompted the researchers to expand their genomic inquiry, utilizing both whole-exome sequencing and droplet digital polymerase chain reaction to detect additional pathogenic variants and determine variant allele frequencies.

Through this extended genetic screening, the researchers identified a novel homozygous variant located in the C1QB gene. To characterize the biological consequences of this mutation, the investigators performed complement component assessments using enzyme-linked immunosorbent assays and dedicated C1q reconstitution assays. The experimental measurements revealed that the patient experienced functional C1q deficiency despite maintaining normal circulating levels of the C1q protein.

To explore the broader activation of inflammatory pathways driving the patient’s refractory pathology, the investigators performed bulk RNA sequencing alongside quantitative polymerase chain reaction validation. Subsequent molecular monitoring confirmed that targeted therapy with deucravacitinib successfully suppressed the pronounced type I interferon gene expression signature in the patient.

In parallel with addressing the elevated interferon pathway, the clinical team targeted the functional complement impairment through therapeutic fresh frozen plasma infusions. Complement assays confirmed that fresh frozen plasma administration effectively restored complement hemolytic activity that was missing due to the dysfunctional C1QB gene product.

The researchers concluded that this case represents systemic lupus erythematosus driven by a novel C1QB variant that impairs C1q function without reducing total protein quantity, responsive to targeted complement-restoring therapy. Furthermore, the findings indicated that the co-existing somatic TNFAIP3 variant contributed to distinct aspects of the overall clinical phenotype, notably the persistent recurrent fevers.

Subject of Research: Identification and targeted treatment of functional C1q deficiency in systemic lupus erythematosus

Article Title: Functional C1q deficiency in a systemic lupus erythematosus patient with a concurrent somatic TNFAIP3 variant

Article References: Peng, S., Zhou, Y., Yu, Z., Li, T., Gao, S., Wang, X., Feng, G., Wang, T., Jian, S., Ma, M., & Song, H. (2026). Functional C1q deficiency in a systemic lupus erythematosus patient with a concurrent somatic TNFAIP3 variant. BMC Medical Genomics. https://doi.org/10.1186/s12920-026-02509-0

Image Credits: AI Generated

DOI: 10.1186/s12920-026-02509-0

Keywords: systemic lupus erythematosus, C1QB variant, functional C1q deficiency, TNFAIP3 variant, haploinsufficiency of A20, deucravacitinib, tyrosine kinase 2 inhibitor, fresh frozen plasma, whole-exome sequencing, droplet digital PCR, type I interferon signature, complement hemolytic activity, intracranial calcifications, chilblain-like rashes, C1q reconstitution assay, bulk RNA sequencing, pediatric rheumatology