IKAROS deficiency and IKAROS-GOF disease. (A) Structure of the IKZF1/IKAROS protein is depicted, highlighting the N-terminal ZFs (ZF1–ZF4) responsible for DNA binding and the C-terminal ZFs (ZF5–ZF6) involved in homo- and heterodimerization, indicated by gray boxes. Exon boundaries within the structure are marked by dotted lines. Above the schematic, disease-causing variants associated with IKAROS deficiency and IKAROS-GOF disease are mapped to their respective positions, along with the number of individuals carrying each variant and the corresponding disease penetrance. Below the structure, the spectrum of clinical phenotypes reported in all known individuals with IKZF1-associated IEI is shown. (B) Amino acid sequences of ZF2 and ZF3 from IKAROS, HELIOS, and AIOLOS are shown. Essential amino acids for ZF structure formation are highlighted in orange, and those critical for mediating DNA binding are highlighted in gray. Numbers on both sides indicate amino acid positions within the protein. Positions relative to the start of the alpha helix are marked above the sequence: residues at positions −2, 2, 3, and 6 are critical for DNA binding. Amino acids associated with variants in IEI are indicated in bold. The pathogenic mechanisms of these variants are color-coded. (C) Onset of overall disease (first clinical manifestation), infections, immune dysregulation, and hematological malignancies or lymphoproliferation. *: when the onset was described as occurring in childhood without a specific age provided, it was represented as age 6 in the graph. (D) Frequencies of symptomatic individuals for each phenotype are summarized. Color codes represent variant types linked to IKAROS deficiency. C, cysteine; H, histidine; LPD, lymphoproliferative disorder.