Submission Details

C1QA encodes the A-chain of the complement component C1Q, a core part of the C1 complex—the first component of the classical complement pathway. Together with C1R and C1S, C1Q forms a complex essential for immune defense by binding to pathogens or immune complexes and initiating complement activation. C1QA was first reported in relation to autosomal recessive systemic lupus erythematosus (SLE) in 1995 (PMID: 7594474).

Twelve variants (4 nonsense, 4 frameshift, 1 splicing and 3 missense) that have been reported in 26 probands in 12 publications (PMIDs: 7594474, 8840296, 9039514, 9225968, 21654842, 26563161, 29739689, 30008451, 35086391, 39196411, 38263665, 22576477) are included in this curation. These variants are identified in both homozygous and compound heterozygous states in affected individuals. All probands exhibit confirmed C1Q deficiency, presenting with SLE or SLE-like clinical features and recurrent infections. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached.

The mechanism of pathogenicity is known to be loss of function. This gene-disease association is further supported by substantial experimental evidence, including gene expression analyses, animal models, and in vitro functional assays. In affected individuals, C1Q protein is undetectable in serum, and classical pathway hemolytic complement activity (CH50) is absent. Anti-C1Q autoantibodies, which are commonly observed in SLE patients, have been shown to correlate with renal disease activity and serve as a predictive biomarker for lupus nephritis (PMID: 15286009). Moreover, C1QA-deficient mice develop a lupus-like autoimmune phenotype characterized by antinuclear autoantibodies and glomerulonephritis (PMIDs: 9590289, 11859149, 29724957). Mechanistically, C1QA deficiency leads to defective clearance of apoptotic cells, resulting in increased exposure to self-antigens and breakdown of immune tolerance (PMIDs: 9590289, 10934224). Elevated production of interferon-alpha (IFN-α) has also been implicated in disease pathogenesis, representing a potential link between C1Q deficiency and autoimmunity (PMID: 19790049). Notably, C1Q may also limit autoreactivity in CD8+ T cells by modulating mitochondrial metabolism (PMID: 29724957). Bone marrow transplantation restores C1Q production and function in deficient mice (PMIDs: 11564823, 15517607), and treatment with fresh frozen plasma has been utilized to manage SLE associated with C1Q deficiency in human cases (PMID:29113537).

In summary, there is definitive evidence supporting the relationship between C1QA and autosomal recessive Systemic Lupus Erythematosus. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Monogenic Systemic and Incomplete Lupus Erythematosus GCEP on the meeting date March 12, 2025 (SOP Version 11).