Germline mutations and their impact on immunity: IKAROS-associated diseases and pathophysiology.

: The transcription factor IKAROS and IKAROS family members are critical for the development of lymphocyte and other blood cell lineages. Germline heterozygous mutations have been described in primary immunodeficiency as well as in human hematologic malignancies, affecting both B and T cells. Depending on the allelic variants of mutations (haploinsufficiency and dominant negative) clinical phenotypes vary from bacterial, viral, or fungal infection to autoimmune disease and malignancy.: In this review, the authors provide an overview of genotype-phenotype correlation and clinical manifestations in patients with mutations. The importance of accurate diagnosis and monitoring immunological changes is also discussed for the management of these complex and rare diseases. IKZF1/IKAROS, immunodeficiency, and CVID were used as the search terms in PubMed and Google Scholar.: Over the past 5 years both genetic and molecular studies have unveiled surprisingly diverse roles of mutations in primary immunodeficiency. While an increasing number of novel variants are being reported, limited, and complex laboratory testing is necessary to verify the mutation's pathogenicity. Therefore, the combination of understanding mechanistic concepts and clinical and immunological follow-up is necessary to increase our knowledge of IKAROS-associated diseases.