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Complement component 7 (C7) deficiency is an autosomal recessive immunodeficiency characterized by a markedly increased susceptibility to recurrent Neisseria meningitidis infections. Patients typically present with meningococcal sepsis or meningitis in childhood or adolescence, although some individuals remain asymptomatic. Loss-of-function variants in C7 abrogate formation of the membrane attack complex. This summary reviews the genetic, segregation, and functional evidence establishing C7 deficiency as a definitive gene–disease association.
Genetic data include over 200 unrelated probands with homozygous or compound heterozygous C7 variants identified through sequencing across nine cohorts (PMID:31440263). Case series in Spanish, Irish, Israeli, Bolivian, Czech, and Japanese populations report at least 50 distinct pathogenic alleles in C7, meeting criteria for a robust autosomal recessive pattern. Reported variants span nonsense, frameshift, splice-site, and missense mutations, confirming allelic heterogeneity and global distribution.
The C7 variant spectrum includes recurrent and population-specific alleles. A frequently observed missense mutation, c.1135G>C (p.Gly379Arg), has been identified in multiple cohorts of Spanish, Moroccan Sephardic Jewish, and other ancestries (PMID:15554930). Nonsense and frameshift alleles such as c.615G>A (p.Trp205Ter) and c.1924_1925del (p.His643fs) recur in distinct families, while splice-site variants (e.g., c.280+1G>A) and deep-intronic changes further diversify the mutational landscape.
Segregation analyses across at least 19 affected relatives in multiple consanguineous and nonconsanguineous families support autosomal recessive inheritance and full penetrance in homozygotes or compound heterozygotes (PMID:12869030, PMID:20591074). Parents and siblings heterozygous for a single pathogenic allele exhibit normal complement activity and are asymptomatic carriers, further confirming recessive transmission.
Functional assays consistently demonstrate loss-of-function. Hemolytic CH50 and Wieslab ELISA assays reveal absent or severely reduced classical, lectin, and alternative pathway activity in homozygous individuals (PMID:1347491). Western blot and immunoelectrophoresis confirm absence of C7 protein, while cellular models show retention of misfolded variants in the endoplasmic reticulum for missense alleles such as p.Arg521Ser (PMID:17407100). Murine knockout studies of downstream complement components underscore the critical role of the terminal pathway in host defense, with analogous phenotypes predicted for C7 loss.
Integration of genetic, segregation, and functional evidence fulfills ClinGen definitive criteria for an autosomal recessive gene–disease relationship. Comprehensive variant and haplotype analyses across diverse populations provide a complete picture of C7 deficiency. Molecular confirmation allows precise genetic counseling, guides timely vaccination against Neisseria meningitidis, and informs decisions on prophylactic antibiotics. Key take-home: Genetic testing for C7 variants combined with complement activity assays is essential for the diagnosis and management of patients at risk for life-threatening meningococcal infections.
Gene–Disease AssociationDefinitive
Genetic EvidenceStrong
Functional EvidenceModerateConsistent hemolytic assays, protein truncation and misfolding studies across several models |