Genotype-phenotype analysis in 333 individuals with heterozygous variants in NFKB1

Heterozygous germline variants in NFKB1 can be classified into variants with "known protein defect" and "unknown protein effect." However, beyond this, NFKB1 variants may be additionally categorized into at least eight distinct variant classes. We conducted a literature review of 67 papers reporting on NFKB1 variants and included four additional individuals, carrying previously unreported NFKB1 variants. We identified 333 individuals with unique variants in NFKB1. Our compiled data revealed that there is no sex predilection, the penetrance-including all heterozygous carriers-was 78%, and the mean age of onset for the "known protein defect cohort" was 21.2 years. Individuals harboring variants with a known protein defect demonstrated a higher frequency of malignancies and autoimmune disorders. However, these individuals were less frequently classified as affected than individuals with variants with unknown protein defect. Carriers of whole NFKB1 gene deletions had a significantly higher penetrance to being designated as "affected," but beyond this, the clinical manifestations did not differ between variant classes.