C1QA – C1q deficiency

C1QA encodes the A chain of complement component C1q, the recognition subunit of the classical complement pathway critical for immune complex clearance. Biallelic variants in C1QA result in complete C1q deficiency, an autosomal recessive immunodeficiency marked by absent serum C1q, recurrent infections, and early-onset lupus-like autoimmunity. The strong genotype–phenotype correlation supports clinical testing in unexplained SLE-like presentations with hypocomplementemia (C1QA; C1q deficiency).

Genetic studies have identified eight probands across four unrelated families with biallelic C1QA variants. A Turkish patient harbored a homozygous missense variant c.91G>C (p.Gly31Arg), absent in 105 controls (PMID:22576477). Two consanguineous siblings presented with homozygous truncating alleles, chilblain lesions, and neuropsychiatric involvement (PMID:40316395). An African-American pedigree carried a start-codon Met1Arg mutation in two affected siblings (PMID:22472776). In a multiplex family, a frameshift allele c.209del (p.Gln70fs) segregated in three affected individuals (PMID:7594474).

Segregation analysis demonstrated four additional affected relatives with homozygous pathogenic alleles, confirming autosomal recessive inheritance. The variant spectrum includes missense (n=1), start-loss (n=1), frameshift (n=1), and nonsense alleles (n=1), with no recurrent or founder variants described to date.

Functional assays corroborate pathogenicity: patient sera lack C1q by ELISA and western blot, indicating defective assembly of the A–B–C subunit complex (PMID:7594474). Regular fresh frozen plasma infusions restore C1q levels and ameliorate clinical symptoms in affected individuals (PMID:22576477). These data support a loss-of-function mechanism leading to haploinsufficiency.

No conflicting evidence has been reported, and secondary C1q deficiency in other immunodeficiencies is attributed to consumption rather than primary C1QA defects. The absence of heterozygous carrier phenotypes further reinforces complete loss-of-function as pathogenic.

Integration of genetic and experimental data yields a strong gene–disease association between C1QA and complete C1q deficiency. Clinical genetic testing for C1QA variants is recommended in early-onset SLE-like disease with classical complement pathway deficiency. Key take-home: biallelic C1QA variants cause complete C1q deficiency with high penetrance for lupus-like autoimmunity, which is diagnosable by genetic testing and responsive to complement replacement therapy.

References

• Clinical rheumatology • 2012 • C1q deficiency: identification of a novel missense mutation and treatment with fresh frozen plasma. PMID:22576477
• Reumatologia clinica • 2025 • Rare C1q deficiency presenting as pediatric SLE: A case study of two consanguineous siblings. PMID:40316395
• Lupus • 2012 • Identification of novel coding mutation in C1qA gene in an African-American pedigree with lupus and C1q deficiency. PMID:22472776
• Journal of immunology • 1995 • Non-sense and missense mutations in the structural genes of complement component C1q A and C chains are linked with two different types of complete selective C1q deficiencies. PMID:7594474

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