IKZF5

Inheritance Pattern: AD

Disease ID:MONDO:0030867

Submitter: ClinGen

The IKZF5 gene encodes a transcription factor that plays a role in hematopoietic development, in particular megakaryocytopoiesis. IKZF5 was first reported in relation to thrombocytopenia-7 (THC7) (Lentaigne et al., PMID 31217188) in 5 families with thrombocytopenia inherited in an autosomal-dominant manner. 5 different variants (His155Tyr; Cys140Arg; Arg96Thr; Gly134Gln; Tyr89Cys) were identified in 23 members from the 5 pedigrees with thrombocytopenia. 8 unique variants, all missense, have been reported in humans. The mechanism of disorder is not completely clear, however, it has been proposed that heterozygous mutations in the DNA-binding Znf domains of IKZF5 exert a dominant-negative effect, resulting in dimers that lack transcriptional activity, the same mechanism described for IKZF1. Indeed, IKZF5 variants cause abnormal cellular localization and decreased chromatin binding and, in vivo, this would be expected to affect transcription. Evidence supporting this gene-disease relationship includes genetic evidences (case-level data) and experimental evidences (functional evidence of biochemical functions, expression and protein interactions; functional alteration in patient cells and non-patient cells). Summary of Case Level Data: 7.7 POINTS Variants in this gene have been reported in at least 8 probands in 3 publications (PMIDs: 31217188, 32419556, 41017962). Affected patients show thrombocytopenia, deficiency of platelet alpha-granules, variable defective expression of platelet glycoprotein GPIba and mild or absent bleeding. Summary of Experimental Data: 3 POINTS Perdomo et al. showed that IKZF5 is expressed in peripheral blood lymphocytes and megakaryocytic cell lines (MEG-01 and M07e). (PMID 10978333). Lanteigne et al. showed that the ability of mutant IKZF5 to bind chromatin, therefore its transcription factor activity, is impaired. Maturation and differentiation of the megakaryocytes cultured from patients were normal, however proplatelet formation was reduced. Finally, RNA sequencing revealed that platelet transcriptome of patients with IKZF5 variants was altered. In particular genes linked to platelet formation and function were deregulated and this explains thrombocytopenia and reduced platelet alpha-granules (PMID:31217188). De Wispelaere K et al showed that imMKCL cells expressing a mutant IKZF5 protein showed reduced proplateelt formation, deregulation of genes related to cell cycle and consequent impairment of cell cycle, with a significant reduction of cells in S and G2 phases (PMID:41017962). Given the apparent lack of abnormalities in any cell types other than platelets, this may be the first transcription factor-associated thrombocytopenia which is completely lineage specific. In summary, we obtained moderate association of IKZF5 with thrombocytopenia-7. This gene-disease pair was originally evaluated by the HT GCEP on 26/05/2021. It was reevaluated on 06/09/2023. As a result of this reevaluation no new evidence was identified and the classification remained at Moderate (SOP Version 9). It was reevaluated on 02/02/2026, novel genetic and experimental evidences were added but the classification remained moderate.

Inheritance Pattern: AD

Disease ID:MONDO:0030867

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0015679

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0030867

Submitter: PanelApp Australia