Clinical and immunological characterization of NFKB1 haploinsufficiency in Japan

NFKB1 haploinsufficiency caused by monoallelic loss-of-function variants in NFKB1 results in a CVID-like phenotype or other forms of hypogammaglobulinemia.

This study aims to characterize the clinical and immunological profiles of 21 individuals from nine families with this disorder.

Gene panel sequence and/or whole exome sequence, followed by Sanger sequencing, were used to identify and confirm NFKB1 variants. Immunophenotyping were performed by flow cytometry. The type I interferon signature was determined by quantitative PCR.

Of the nine NFKB1 variants, seven novel heterozygous variants were identified in this study. Ten individuals were clinically asymptomatic, while 11 were symptomatic, resulting in clinical penetrance of 52%. However, immunologic abnormalities were observed in all asymptomatic family members tested (n=9). The main presenting symptoms in symptomatic individuals were respiratory tract infections (7/11) and autoimmune or autoinflammatory features (7/11). Interestingly, two patients had Moyamoya disease, and one patient was complicated by alopecia and rheumatoid arthritis. Immunological analyses were performed in 19 individuals, including 9 asymptomatic, and revealed that 58% had low absolute T cell counts and that 72% of individuals displayed inverted CD4/CD8 T-cell ratio. B-cell lymphopenia and decreased switch memory B cells were observed in 42% and 61% of individuals, respectively. A type I interferon signature was not observed.

In addition to hypogammaglobulinemia/CVID-like phenotype, NFKB1 variants have been associated with a wide range of manifestations, ranging from various organ involvements to autoimmunity. Autoinflammatory features have also been reported; however, the presence of type I interferon signatures was not specifically addressed in this study.