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X-linked chronic granulomatous disease (CGD) is caused by pathogenic variants in CYBB (HGNC:2578), encoding gp91^phox, a critical subunit of the phagocyte NADPH oxidase complex. CGD manifests with recurrent bacterial and fungal infections, granuloma formation, and impaired oxidative burst in neutrophils. The disorder follows an X-linked recessive inheritance mode, with hemizygous males affected and carrier females showing variable lyonization and milder phenotypes CYBB; Chronic granulomatous disease.
CYBB variants disrupt gp91^phox function, leading to undetectable or severely reduced superoxide production in neutrophils. Over 100 unique CYBB mutations—including nonsense, missense, splice-site, frameshift, and large deletions—have been reported in more than 500 unrelated CGD patients, fulfilling robust genetic criteria (Definitive). Segregation analysis in multiple families shows full co-segregation of CYBB variants with disease in affected males and carrier females [3 relatives] (PMID:1438069).
Inheritance is X-linked recessive. Segregation: the c.252+5G>A splice-site variant segregated with CGD status in a multi-generation kindred, including two affected male fetuses diagnosed prenatally and three carrier females [PMID:1438069]. Case series document recurrent de novo and familial LoF mutations causing early-onset severe CGD.
A representative pathogenic variant is c.1499A>G (p.Asp500Gly), identified in a patient with normal gp91^phox levels but defective p47^phox and p67^phox translocation and oxidase assembly; this single-residue change abrogates electron transfer from NADPH and underlies variant X-CGD (X91+) [PMID:8182143].
Functional assays in patient neutrophils and cell models confirm that CYBB mutations abolish NADPH oxidase activity. Gene targeting of CYBB in PLB-985 cells eliminates respiratory burst, which is fully rescued by expression of wild-type gp91^phox cDNA, demonstrating haploinsufficiency and the therapeutic potential of gene replacement [PMID:8234321].
Biochemical studies of X91+ variants reveal that specific missense substitutions in gp91^phox impair FAD/NADPH binding and oxidase complex assembly, pinpointing residues essential for electron transfer and cytosolic factor docking. Rescue experiments using thapsigargin and FAD restore trafficking-defective gp91^phox to the cell surface and rescue ROS production in selected patient leukocytes, highlighting potential ex vivo treatments [PMID:19631269].
The association between CYBB and X-linked CGD is definitive, supported by extensive genetic and functional data over 30 years. Genetic testing for CYBB variants enables accurate diagnosis, carrier detection, prenatal testing, and informs family counseling. Functional assays (NBT, DHR) guide diagnostic confirmation and genotype–phenotype correlation. Emerging therapeutic strategies, including gene therapy and small-molecule rescue agents, offer future avenues for personalized management.
Key Take-home: CYBB mutation analysis is essential for definitive diagnosis and management of X-linked CGD, and functional studies inform both prognosis and novel therapeutic strategies.
Gene–Disease AssociationDefinitiveOver 100 CYBB mutations across >500 unrelated CGD patients with consistent X-linked inheritance and functional concordance Genetic EvidenceStrongMore than 100 pathogenic CYBB variants identified in multiple families; prenatal segregation confirmed in 3 relatives [PMID:1438069] Functional EvidenceStrongExtensive in vitro oxidase assays, PLB-985 gene targeting and rescue, and biochemical studies confirm gp91phox defects |