IKZF1

Inheritance Pattern: AD

Disease ID:MONDO:0014810

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0014810

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0014810

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0014810

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0014810

Submitter: ClinGen

​The IKZF1 gene encodes ​the protein IKAROS. The first report of IKAROS deficiency was described in 2012 in a patient suffering pancytopenia (Goldman et al, 2012; PMID: 21548011). This report described the ​importance of ​the IKZF1 gene as a crucial transcription factor for hematopoiesis with relevance in immune development. IKAROS deficiency is a heterogeneous disease characterized by lymphopenia, hypogammaglobulinemia, immune dysregulation, and depending on the mechanism of disease, it can confer common variable immunodeficiency, combined immunodeficiency, or immune dysregulation. According to the criteria outlined by the ClinGen Lumping and Splitting Working Group, ​the molecular mechanism of this disease can be described as loss of function, gain of function, or somatic. Furthermore, the loss of function and gain of function mutations have been split into two disease entities, pancytopenia due to IKZF1 mutations (MONDO: 0014810) and autoimmune diseases (MONDO:0007179), respectively. . The somatic mutations that have been associated with leukemias were not considered for this curation because they are beyond the scope of the Immunology Clinical Domain Working Group. Pancytopenia due to IKZF1 mutations (MONDO: 0014810) have been associated with the partial or complete loss of function of the IKAROS protein. A total of 13 variants (Missense, deletions or splicing) that have been reported in 22 probands in 6 publications (PMIDS: 21548011, 26981933, 27939403, 28096536, 29889099, 31069201) are included in this curation. The mechanism of pathogenicity is loss of function, which is typically determined based on the DNA binding capability of the IKAROS protein. This gene-disease association is also supported by experimental evidence, including impaired protein expression, homodimer formation, nuclear translocation and biochemical function of IKAROS protein in in vitro cell lines and patient´s cells (PMIDS: 21548011, 26981933, 27939403, 28096536, 29889099). IKZF1 heterozygous mutations cause a wide spectrum of clinical manifestations such as B cell lymphopenia, hypogammaglobulinemia, autoimmune manifestations and in some cases development of leukemia. The molecular mechanism evaluated by biochemical function is haploinsufficiency . The majority of patients with haploinsufficiency in IKAROS are diagnosed with common variable immunodeficiency. On the other hand, another molecular mechanism was described in 2018 (PMID: 29889099) in where a point mutation N159S or N159T cause a dominant negative effect causing a much severe clinical phenotype characterized by B cell lymphopenia, T cell lymphopenia and myeloid differentiation defects. All patients carrying dominant negative variants had early onset with severe life threatening infections, these patient´s were diagnosed with combined immunodeficiency. In summary, IKZF1 is definitively associated with pancytopenia due to ikaros mutations. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Inheritance Pattern: AD

Disease ID:MONDO:0007179

Submitter: ClinGen

​The IKZF1 gene encodes ​the protein IKAROS. The first report of IKAROS deficiency was described in 2012 in a patient suffering pancytopenia (Goldman et al, 2012; PMID: 21548011). This report described the ​importance of ​the IKZF1 gene as a crucial transcription factor for hematopoiesis with relevance in immune development. IKAROS deficiency is a heterogeneous disease characterized by lymphopenia, hypogammaglobulinemia, immune dysregulation, and depending on the mechanism of disease, it can confer common variable immunodeficiency, combined immunodeficiency, or immune dysregulation. According to the criteria outlined by the ClinGen Lumping and Splitting Working Group, ​the molecular mechanism of this disease can be described as loss of function, gain of function, or somatic. Furthermore, the loss of function and gain of function mutations have been split into two disease entities, pancytopenia due to IKZF1 mutations (MONDO: 0014810) and autoimmune diseases (MONDO:0007179), respectively. . The somatic mutations that have been associated with leukemias were not considered for this curation because they are beyond the scope of the Immunology Clinical Domain Working Group. Autoimmune diseases (MONDO:0007179) ​have been associated with gain of function variants in ​the IKZF1 gene. To date, two gain of function variants have been described, p.R183H and p.R183C, found in eight patients (PMID: 35333544). The mechanism of pathogenicity is reported to be gain of function, which was determined by the increased DNA binding activity of the mutated IKAROS protein. This gene-disease association is also supported by experimental evidence including normal expression, protein interaction, biochemical function, and cell phenotype description in patients' cells (PMID: 3533544). IKZF1 gain of function variants R183H and R183C were proven to be expressed in T lymphocytes ​and display increased DNA binding activity. They are capable of forming homodimers with the WT protein and its elevated DNA binding activity causes the increased transcription of genes important for late T cell differentiation leading to a skewed Th2 cell phenotype. In summary, IKZF1 gain of function variants show a moderate association with autoimmune diseases. Note from SCID-CID GCEP added 11/06/2026: IKZF1 (located at 7p12.2) encodes the IKAROS transcription factor, a zinc-finger protein that is a critical regulator of hematopoiesis and lymphoid differentiation, with disease relevance spanning hematologic malignancies, primary immunodeficiencies and immune dysregulation (autoimmunity). Germline IKZF1 variants, similar to somatic variants, also confer predisposition to both B-ALL and T-ALL, with up to 0.9% of sporadic B-ALL cases harboring coding germline IKZF1 variants. Thus, IKZF1 as a recognized leukemia predisposition gene with autosomal dominant inheritance (PMID: 29681510; PMCID: PMC5953820). In addition, germline heterozygous IKZF1 mutations cause a spectrum of primary immunodeficiency/inborn errors of immunity (IEI) phenotypes.

Inheritance Pattern: AD

Disease ID:MONDO:0014810

Submitter: Illumina