Germline mutations in the transcription factor IKZF5 cause thrombocytopenia

Claire Lentaigne, Daniel Greene, Suthesh Sivapalaratnam, Remi Favier, Denis Seyres, Chantal Thys, Luigi Grassi, Sarah Mangles, Keith Sibson, Matthew James Stubbs, Frances Burden, Jean-Claude Bordet, Corinne Armari-Alla, Wendy Erber, Samantha Farrow, Nicholas Gleadall, Keith Gomez, Karyn Megy, Sofia Papadia, Christopher J. Penkett, Matthew C. Sims, Luca Stefanucci, Jonathan C. Stephens, Randy J. Read, Kathleen E. Stirrups, Willem H. Ouwehand, Michael A. Laffan, Mattia Frontini, Kathleen Freson and Ernest Turro

Key Points

  • Mutations in the transcription factor IKZF5 cause autosomal dominant thrombocytopenia and a paucity of alpha granules

  • Although IKZF5 is expressed across hematopoietic lineages, misregulation in IKZF5 cases is restricted to the megakaryocytic lineage


To identify novel causes of hereditary thrombocytopenia, we performed a genetic association analysis of whole-genome sequencing (WGS) data from 13,037 individuals enrolled in the NIHR BioResource, including 233 cases with isolated thrombocytopenia. We found an association between rare variants in the transcription factor (TF)-encoding gene IKZF5 and thrombocytopenia. We report five causal missense variants in or near IKZF5 zinc fingers (Znfs), of which two occurred de novo and three co-segregated in three pedigrees. A canonical DNA-Znf binding model predicts that three of the variants alter DNA recognition. Expression studies showed that chromatin binding was disrupted in mutant compared to wild-type (WT) IKZF5 and electron microscopy (EM) revealed a reduced quantity of alpha granules in normally sized platelets. Proplatelet formation (PPF) was reduced in megakaryocytes (MKs) from seven cases relative to six controls. Comparison of RNA-seq data from platelets, monocytes, neutrophils and CD4+ T-cells from three cases and 14 healthy controls showed 1,194 differentially expressed genes (DEGs) in platelets but only four DEGs in each of the other blood cell types. In conclusion, IKZF5 is a novel transcriptional regulator of megakaryopoiesis and the eighth transcription factor associated with dominant thrombocytopenia in humans.

  • Submitted March 26, 2019.
  • Revision received June 14, 2019.
  • Accepted June 10, 2019.