Germline IKZF1 mutations and their impact on immunity: IKAROS-associated diseases and pathophysiology

ABSTRACT

Introduction: The transcription factor IKAROS and IKAROS family members are critical for the development of lymphocyte and other blood cell lineages. Germline heterozygous IKZF1 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 IKZF1 mutations (haploinsufficiency and dominant negative) clinical phenotypes vary from bacterial, viral, or fungal infection to autoimmune disease and malignancy.

Areas covered: In this review, the authors provide an overview of genotype-phenotype correlation and clinical manifestations in patients with IKZF1 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.

Expert opinion: Over the past 5 years both genetic and molecular studies have unveiled surprisingly diverse roles of IKZF1 mutations in primary immunodeficiency. While an increasing number of novel IKZF1 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.

KEYWORDS:

• IKZF1
• IKAROS
• primary immunodeficiency
• common variable immunodeficiency (CVID)
• combined immunodeficiency (CID)
• autoimmunity
• malignancy

Article highlights

• While somatic IKZF1 alterations are associated with increased risk of B-progenitor acute lymphoblastic leukemia (B-ALL), autosomal dominant heterozygous germline mutations in IKZF1 are associated with immunodeficiency as well as B-ALL.

• Heterozygous germline IKZF1 mutations can be categorized into three allelic variants acting by haploinsufficiency (HI), dominant-negative (DN), or dimerization defective (DD).

• Patients with germline HI variants mostly present with a CVID phenotype that includes hypogammaglobulinemia, defective vaccine responses, progressive loss of B cell numbers, recurrent bacterial infections, and increased risk of autoimmunity/immune dysregulation and malignancy.

• Patients carrying DN mutations present with an early onset (<2 years) CID phenotype with severe immunological and clinical manifestations including opportunistic infections (i.e., Pneumocystis jirovecii) and increased leukemia susceptibility.

• Patients with DD variants show a higher incidence of autoimmune diseases/immune dysregulation and malignancy compared to the other allelic variants; recurrent or severe infections are less frequently seen in patients within this allelic variant.

Acknowledgments

This work was supported by the Intramural Research Program, National Institutes of Health Clinical Center. The content of this article does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government.

Author contributions

Hye Sun Kuehn and Cristiane J Nunes-Santos contributed equally

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by the Intramural Research Program, National Institutes of Health Clinical Center.