A commercial C3c ELISA as a diagnostic tool for complete complement factor I deficiency

Complete complement Factor I (FI) deficiency is an ultra-rare inborn error of immunity characterized by invasive encapsulated bacterial infections and/or sterile neuroinflammation (DEFICIT syndrome). Acute episodes can progress rapidly to life-threatening illness, so prompt diagnosis is critical. Genetic confirmation is time-consuming; antigenic FI quantification is blind to qualitative (type II) variants; and the consumptive profile is mimicked by other complement deficiencies and secondary consumptive states. Functional readouts have been proposed: because C3 and C4 cleavage fragments arise downstream of FI, their absence reports loss of FI function irrespective of variant class. Commercial assays have not been compared for this purpose, so we assessed whether they distinguish complete FI deficiency from these mimics. We measured C3c, C3d, C4d and iC3b in EDTA plasma from six genetically confirmed FI-deficient patients and 52 controls comprising other complement deficiencies, consumptive states, and healthy individuals. C3c and C4d were also measured in serum. Only C3c separated complete FI deficiency from every comparator. Plasma C3c was below the quantification limit (160 ng/mL) in all patients, whereas all controls were quantifiable (lowest 394 ng/mL). Serum reproduced the separation, including in two patients with type II variants. C4d was unquantifiable in patients, but the low control baseline left no reliable cut-off. C3d and iC3b were elevated rather than reduced, suggesting possible cross-reactivity with C3b-containing complexes. A commercial C3c ELISA provides a rapid functional readout of FI activity, independent of variant class and applicable in serum. It could support earlier triage of suspected cases while genetic confirmation is pending.