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However, the causal link between NFKB1 variants and CVID has not been demonstrated experimentally and genetically, and there has been insufficient biochemical characterization and enrichment analysis. We show that the cotransfection of NFKB1-deficient HEK293T cells (lacking both p105 and its cleaved form p50) with a \u03baB reporter, NFKB1\/p105, and a homodimerization-defective RELA\/p65 mutant results in p50:p65 heterodimer\u2013dependent and p65:p65 homodimer\u2013independent transcriptional activation. We found that 59 of the 90 variants in patients with CVID or related conditions were loss of function or hypomorphic. By contrast, 258 of 260 variants in the general population or patients with unrelated conditions were neutral. None of the deleterious variants displayed negative dominance. The enrichment in deleterious NFKB1 variants of patients with CVID was selective and highly significant (P = 2.78 \u00d7 10\u221215). NFKB1 variants disrupting NFKB1\/p50 transcriptional activity thus underlie AD CVID by haploinsufficiency, whereas neutral variants in this assay should not be considered causal.<\/jats:p>","DOI":"10.1084\/jem.20210566","type":"journal-article","created":{"date-parts":[[2021,9,2]],"date-time":"2021-09-02T13:39:33Z","timestamp":1630589973000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":59,"title":["Biochemically deleterious human <i>NFKB1<\/i> variants underlie an autosomal dominant form of common variable immunodeficiency"],"prefix":"10.1084","volume":"218","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4376-7781","authenticated-orcid":true,"given":"Juan","family":"Li","sequence":"first","affiliation":[{"name":"St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 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