The IKZF2 gene encodes the transcription factor HELIOS. Helios is a member of the Ikaros family; as a transcription factor, it can bind DNA in essential regions to control hematopoiesis, cell cycle, apoptosis, and cell function of immune cells. HELIOS deficiency (MONDO:0800139) has a wide range of phenotypes: lymphadenopathy, hypogammaglobulinemia, recurrent infections, and immune dysregulation with incomplete penetrance. A total of seven variants, including nonsense and missense, have been reported in 10 patients in 3 publications only (PMID: 34826260, 34826259, 34920454). All variants except for one were found in an autosomal dominant trait, for that reason the model of inheritance used for this curation was autosomal dominant. Experimental evidence includes a reduction of HELIOS expression in the patient´s cells (Lymphocytes, NK cells), loss of the dimerization ability and DNA binding activity, and disruption of the protein-protein interaction and transcriptional activity. Additionally, the HELIOS knockout mouse recapitulates most of the cellular phenotypes and the development of autoimmunity seen in patients with HELIOS deficiency. In summary, there is moderate evidence to support this gene-disease relationship.
The IKZF2 gene encodes the transcription factor HELIOS. Helios is a member of the Ikaros family; as a transcription factor, it can bind DNA in essential regions to control hematopoiesis, cell cycle, apoptosis, and cell function of immune cells. HELIOS deficiency (MONDO:0800139) has a wide range of phenotypes: lymphadenopathy, hypogammaglobulinemia, recurrent infections, and immune dysregulation with incomplete penetrance. A total of seven variants, including nonsense and missense, have been reported in 10 patients in 3 publications only (PMID: 34826260, 34826259, 34920454). All variants except for one were found in an autosomal dominant trait, for that reason the model of inheritance used for this curation was autosomal dominant. Experimental evidence includes a reduction of HELIOS expression in the patient´s cells (Lymphocytes, NK cells), loss of the dimerization ability and DNA binding activity, and disruption of the protein-protein interaction and transcriptional activity. Additionally, the HELIOS knockout mouse recapitulates most of the cellular phenotypes and the development of autoimmunity seen in patients with HELIOS deficiency. A recuration was conducted on March 11 of 2025, with the review of new evidence seen in patients with IKZF2-ICHAD (Immunedysregulation, craniofacial anomalies, hearing impairment, athelia and developmental delay ) phenotype. However, the experts agreed to split the IKZF2-ICHAD phenotype. In summary, there is moderate evidence to support this gene-disease relationship.
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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