NF-κB1 is a key transcription factor involved in immune regulation, and pathogenic variants in this gene can lead to a spectrum of primary immunodeficiencies, including common variable immunodeficiency (CVID). We report a family with a novel heterozygous NFKB1 variant segregating across three generations with variable expressivity of immunodeficiency and chronic fungal infections.
The index case is a 6.5-year-old girl who presented with severe hypogammaglobulinemia affecting all three immunoglobulin isotypes, impaired polysaccharide vaccine response, recurrent respiratory infections, chronic diarrhea, and candida onychomycosis. B cells were present but showed a disrupted maturation profile with reduced memory B cells and abnormal pre- and post-switched subsets. His 43-year-old father had recurrent infections, moderate hypogammaglobulinemia (IgG and IgM), facial fungal infections with hyaline branching hyphae on biopsy, chronic diarrhea, and severe intestinal polyposis. The 68-year-old grandmother also had a history of recurrent respiratory infections and hypogammaglobulinemia. Whole exome sequencing identified a novel heterozygous NFKB1 variant (c.202G>A, p.Gly68Ser) in the index case, which was confirmed in both the father and grandmother.
The variant lies within the functional Rel homology DNA-binding domain (PM1_Moderate), a region enriched in known pathogenic variants. It is absent from population databases (PM2_Supporting), and in silico prediction using REVEL yields a high pathogenicity score (0.797; PP3_Moderate). The phenotype across three generations is consistent with reported clinical manifestations of NFKB1 haploinsufficiency, including CVID, impaired class-switch recombination, and chronic infections (PP4_Supporting). The variant cosegregates with the disease in the family (PP1_Supporting), supporting a pathogenic role. Based on the American College of Medical Genetics and Genomics/ClinGen guidelines, the variant is classified as a likely pathogenic variant.
We report a novel familial NFKB1 variant associated with a CVID-like phenotype and chronic fungal infections. Functional validation is needed to confirm pathogenicity and to guide targeted therapeutic approaches.
