NFKB1 – Common Variable Immunodeficiency (CVID)

Heterozygous loss-of-function variants in NFKB1 (HGNC:7794) have been established as a monogenic cause of autosomal dominant common variable immunodeficiency (CVID) ([PMID:26279205]). In the initial report, a splice-donor mutation (c.730+1G>A) causing p105ΔEx8 and absence of p50 was identified in a Dutch-Australian family, with additional in‐frame exon-skipping and frameshift alleles in German and New Zealand pedigrees segregating with hypogammaglobulinemia and recurrent infections ([PMID:26279205]). Subsequent single-patient reports described truncating variants such as c.1149del (p.Gly384GlufsTer48) in a patient with severe gastrointestinal manifestations ([PMID:30063981]) and c.904dup (p.Ser302PhefsTer7) in a mother–daughter pair with CVID and short stature ([PMID:37600787]). A large Finnish cohort (n=31 carriers in six families) further delineated incomplete penetrance and a spectrum of (auto)inflammatory sequelae in NFKB1 haploinsufficiency ([PMID:36356849]).

Genetically, NFKB1‐related CVID displays autosomal dominant inheritance with evidence of segregation in multiple families. At least five distinct heterozygous truncating or splicing variants have been confirmed to co‐segregate with disease in >31 affected relatives across six families ([PMID:36356849]). The variant spectrum comprises canonical splice-site, frameshift, and nonsense mutations leading to p105/p50 haploinsufficiency, with an absence of detectable mutant protein and preservation of wildtype p105/p50 levels. A representative pathogenic allele is c.1149del (p.Gly384GlufsTer48), which abrogates p50 generation and accelerates precursor decay, consistent with loss of function in vitro ([PMID:30063981]).

Functionally, NFKB1 haploinsufficiency operates via insufficient canonical NF-κB signaling. Overexpression and reporter assays demonstrate that select missense and truncating variants disrupt p105 processing or p50 DNA-binding without dominant-negative effects, confirming haploinsufficiency as the predominant mechanism ([PMID:34473196]). Electrophoretic mobility shift assays and co-transfection studies in HEK293T cells verified loss of p50 activity for deleterious alleles, while population variants remain neutral. Cellular phenotyping of patient NK and B cells reveals impaired maturation, hypogammaglobulinemia, reduced memory B cells, and skewed T‐cell cytokine profiles, mirroring key clinical features of CVID ([PMID:27923702]).

Conflicting evidence is limited but includes incomplete clinical penetrance within pedigrees, with some carriers displaying subclinical immunophenotypes or late‐onset manifestations ([PMID:36356849]; [PMID:37600787]). No studies refute the core association, and variant interpretation is guided by combined genetic, functional, and cosegregation data.

In summary, heterozygous loss-of-function NFKB1 variants cause autosomal dominant CVID by p105/p50 haploinsufficiency, leading to hypogammaglobulinemia, recurrent infections, and variable inflammatory complications. This conclusive genetic and experimental evidence supports NFKB1 testing in patients with CVID and informs prognosis, counseling, and potential targeted therapies.

Key Take-home: NFKB1 haploinsufficiency is a definitive, autosomal dominant etiology of CVID with clear diagnostic and prognostic utility.

References

• American Journal of Human Genetics | 2015 | Haploinsufficiency of the NF-κB1 Subunit p50 in Common Variable Immunodeficiency PMID:26279205
• Clinical Immunology (Orlando, Fla.) | 2018 | Th1-skewed profile and excessive production of proinflammatory cytokines in a NFKB1-deficient patient with CVID and severe gastrointestinal manifestations PMID:30063981
• Frontiers in Immunology | 2023 | A child with NFKB1 haploinsufficiency explaining the linkage between immunodeficiency and short stature PMID:37600787
• Clinical Immunology (Orlando, Fla.) | 2023 | Long-term follow up of families with pathogenic NFKB1 variants reveals incomplete penetrance and frequent inflammatory sequelae PMID:36356849
• The Journal of Experimental Medicine | 2021 | Biochemically deleterious human NFKB1 variants underlie an autosomal dominant form of common variable immunodeficiency PMID:34473196

Evidence Based Scoring (AI generated)