C1S – Complement Component C1s Deficiency

Complement component C1s deficiency is an autosomal recessive disorder caused by biallelic loss-of-function variants in C1S, leading to absent classical complement pathway activity and predisposition to severe pyogenic infections and autoimmune manifestations. Initial reports in a Japanese family described a compound heterozygosity involving a nonsense variant and a novel missense variant, presenting with virus-associated hemophagocytic syndrome, prolonged loss of consciousness, and fatal outcome in one sibling (PMID:19155518). A second patient from the same pedigree harbored a compound heterozygous genotype including c.1567C>T (p.Arg523Ter) and a maternal Gly630Glu change, exhibiting similarly low C1s activity and overlapping clinical features (PMID:19155518). In an unrelated Caucasian proband with early-onset lupus-like syndrome, Hashimoto thyroiditis, and autoimmune hepatitis, a homozygous c.1567C>T (p.Arg523Ter) variant was identified, with carrier parents and four additional heterozygotes segregating the allele in the family (PMID:11390518).

Segregation analysis across two unrelated families showed clear recessive transmission, with parents and unaffected relatives carrying single alleles without clinical phenotype. Functional assays consistently demonstrated undetectable CH50 activity, absent C1s antigen in serum, and failure of recombinant C1s variants to restore complement cleavage of C4 and C2, confirming a loss-of-function mechanism (PMID:19155518; PMID:11390518).

Collectively, three affected individuals from two independent families, segregation in carriers, and concordant biochemical and recombinant protein data support a Moderate level of clinical validity under ClinGen guidelines. Genetic evidence is rated Moderate for autosomal recessive inheritance, compound heterozygosity and homozygosity of truncating variants in C1S. Functional evidence is rated Moderate based on consistent loss-of-function across serum and recombinant assays.

No conflicting reports have been described. Additional unpublished cases may further refine prevalence, but current data suffice for diagnostic gene screening in patients with early complement deficiency. Key Take-home: Biallelic truncating and missense variants in C1S cause complement component C1s deficiency, warranting inclusion of C1S in genetic panels for recurrent infections and early autoimmune features.

References

• Journal of immunology (Baltimore, Md. : 1950) | 2009 | Unique phenotypes of C1s deficiency and abnormality caused by two compound heterozygosities in a Japanese family. PMID:19155518
• Journal of immunology (Baltimore, Md. : 1950) | 2001 | Molecular basis of a selective C1s deficiency associated with early onset multiple autoimmune diseases. PMID:11390518

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