NFKB2 – NFKB2-related Common Variable Immunodeficiency

Common variable immunodeficiency (CVID) is an autosomal dominant primary immunodeficiency characterized by hypogammaglobulinemia, recurrent infections, poor vaccine responses, and frequent autoimmune manifestations. Heterozygous germline mutations in NFKB2 have been repeatedly identified as a monogenic cause, implicating defective noncanonical NF-κB signaling in disease pathogenesis.

Genetic evidence supports an autosomal dominant inheritance mode, with disease-segregating variants reported in multiple families. Initial exome sequencing in a CVID family uncovered a heterozygous frameshift mutation c.2564del (p.Lys855SerfsTer8) in NFKB2, and subsequent screening of 33 unrelated CVID cases identified a second heterozygous nonsense mutation c.2557C>T (p.Arg853Ter) ([PMID:24140114]). In two unrelated pedigrees, four additional affected relatives harboring C-terminal truncating variants (including p.Arg635Ter) further confirm familial segregation ([PMID:30953794]).

The variant spectrum comprises predominantly heterozygous truncating mutations clustering in the C-terminus (frameshifts and stop gains) with occasional missense changes disrupting the p100 processing site (e.g., p.Ser866Arg). Recurrent alleles such as p.Arg853Ter have been observed in at least eight patients across diverse populations. A single representative variant used in diagnostic panels is c.2564del (p.Lys855SerfsTer8).

Functional studies provide moderate experimental evidence for a loss-of-function mechanism via impaired proteasomal processing of the p100 precursor and failure of p52 nuclear translocation. Immunoblot and immunofluorescence assays in patient B cells demonstrate aberrant p100 phosphorylation and accumulation of unprocessed protein ([PMID:24140114]). Nfkb2 knockout mice recapitulate hypogammaglobulinemia and poor humoral responses, aligning with human phenotypes.

A minority of heterozygous nonsense variants in the ankyrin repeat domain (e.g., p.Arg611Ter) have been reported without clinical CVID, suggesting incomplete penetrance or compensatory mechanisms ([PMID:30863427]). No large-scale case–control data dispute the overall gene–disease link, but asymptomatic carriers underscore the need for functional validation of novel alleles.

In summary, heterozygous truncating and select missense NFKB2 variants cause autosomal dominant CVID by disrupting noncanonical NF-κB signaling. Genetic testing for C-terminal NFKB2 mutations informs diagnosis, enables family counseling, and guides immunoglobulin replacement therapy. Key take-home: NFKB2 sequencing should be included in CVID gene panels to confirm etiology and facilitate targeted management.

References

• American Journal of Human Genetics • 2013 • Germline mutations in NFKB2 implicate the noncanonical NF-κB pathway in the pathogenesis of common variable immunodeficiency [PMID:24140114]
• Frontiers in Immunology • 2019 • Clinical and Immunological Phenotype of Patients With Primary Immunodeficiency Due to Damaging Mutations in NFKB2 [PMID:30941118]
• Clinical Immunology • 2019 • Pathogenic NFKB2 variant in the ankyrin repeat domain (R635X) causes a variable antibody deficiency [PMID:30953794]

Evidence Based Scoring (AI generated)