Novel Variants in Biallelic Complement Factor I Deficiency

Complement factor I (CFI) deficiency is a rare autosomal recessive disorder resulting from homozygous or compound heterozygous variants in CFI, which encodes a crucial regulatory protein in the alternative complement pathway. We report two families with novel genetic variants in CFI. Patient A, a 3-year-old girl, presented with recurrent infections, including three hospitalizations for pneumonia and giardiasis starting at 19 months. Immune testing revealed low C3 (28; 82.0-173 mg/dL), CH50 (30; 31-60 U/mL), and Factor I levels (<16; 29-59 mcg/mL). Genetic testing identified two in trans variants: a likely pathogenic variant (p.E434Kfs*2) inherited from her father and a variant of uncertain significance (p.V152M) inherited from her mother. The maternal history was notable for autoimmune and inflammatory conditions. Patients B and C, 2.5-month-old identical female twins, also presented with severe infections. Patient B developed meningitis, pneumonia, and bacteremia due to Streptococcus pneumoniae and died from complications. Patient C experienced recurrent fevers and infections, including enteroviral meningitis and multidrug-resistant Escherichia coli urinary tract infection. Immune testing revealed low C3 (151; 11249-42887 units/mL), CH50 (<10; 31-60 U/mL), and Factor I levels (<11.3; 29.3-58.5 mcg/mL). Genetic testing identified biallelic pathogenic variants in CFI: p.N103Kfs11 and p.W393Yfs5. Their older sister, with recurrent otitis media and bronchitis, and their younger asymptomatic brother were found to carry the same genetic variants, exhibiting low or absent AH50 levels and low CH50 and Factor I levels. The sister's CH50 was <10 (31-60 U/mL), AH50 < 10 (≥46%), and CFI levels < 12.7 (29.3-58.5 mcg/mL). The brother’s CH50 was 44 (176-382 U/mL), AH50 0 (77-159 U/mL), and CFI levels < 16 (29-59 mcg/mL). Complete CFI deficiency is rare, with only a limited number of cases documented. Our report introduces three new pathogenic variant associations and highlights the variability in clinical presentation. Physicians should consider CFI deficiency in children with invasive or recurrent bacterial infections, even when pathogens are nonencapsulated. Of note, unlike many alternative complement protein deficiencies that typically present with isolated low AH50 and normal CH50, regulatory component deficiencies like Factor I deficiency led to uncontrolled complement activation and C3 consumption, affecting both pathways, leading to low CH50 and AH50 levels.