The IKZF3 gene encodes the transcription factor Aiolos. Aiolos is a member of the Ikaros family; as a transcription factor, it can bind DNA in essential regions to control hematopoiesis and cell functions of immune cells. Immunodeficiency 84 or immunodeficiency due to IKZF3 deficiency (MONDO:0030333), is characterized by profound defects in B cell differentiation, and severe hypogammaglobulinemia in patients. A total of two missense variants have been reported in 7 patients in 2 publications only (PMID: 34155405, 34694366). The two variants: p.G159R and p.N160S were found in autosomal dominant traits. Experimental evidence includes loss of the ability to form pericentromeric heterochromatin foci in the dimer IKZF1-IKZF3 affecting the transcriptional activity of genes under IKZF3 regulation. Additionally, the Aiolos knock in mice evaluating the homologous variants for p.G159R, and p.N160S showed that mice have profound defects in B cell development and low immunoglobulin levels (IgG, IgM and IgA), which is consistent with the phenotype seen in patients.
In summary, there is moderate evidence to support this gene-disease relationship with only two variants identified in two publications.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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