2. Academic Validation
  3. Germline mutations in the transcription factor IKZF5 cause thrombocytopenia

Germline mutations in the transcription factor IKZF5 cause thrombocytopenia

  • Blood. 2019 Dec 5;134(23):2070-2081. doi: 10.1182/blood.2019000782.
Claire Lentaigne 1 2 3,  Daniel Greene 3 4 5,  Suthesh Sivapalaratnam 3 6,  Remi Favier 7 8,  Denis Seyres 3 4 9,  Chantal Thys 10,  Luigi Grassi 3 4 9,  Sarah Mangles 11,  Keith Sibson 12,  Matthew Stubbs 1,  Frances Burden 3 4 9,  Jean-Claude Bordet 13,  Corinne Armari-Alla 14,  Wendy Erber 3 15 16,  Samantha Farrow 3 4 9,  Nicholas Gleadall 3 4,  Keith Gomez 17,  Karyn Megy 3 4 9,  Sofia Papadia 3 4 9,  Christopher J Penkett 3 4 9,  Matthew C Sims 3,  Luca Stefanucci 3 4,  Jonathan C Stephens 3 4 9,  Randy J Read 18,  Kathleen E Stirrups 3 4 9,  Willem H Ouwehand 3 4 9 19,  Michael A Laffan 1 2,  NIHR BioResource,  Mattia Frontini 3 9 20,  Kathleen Freson 3 10,  Ernest Turro 3 4 5 9
Affiliations

Affiliations

  • 1 Centre for Haematology, Hammersmith Campus, Imperial College Academic Health Sciences Centre, Imperial College London, London, United Kingdom.
  • 2 Imperial College Healthcare National Health Service (NHS) Trust, London, United Kingdom.
  • 3 National Institute for Health Research (NIHR) BioResource, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, United Kingdom.
  • 4 Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.
  • 5 Medical Research Council Biostatistics Unit, Cambridge Biomedical Campus, Cambridge, United Kingdom.
  • 6 Department of Haematology, Barts Health National Health Service Trust, London, United Kingdom.
  • 7 Assistance Publique-Hôpitaux de Paris, French Reference Center for Inherited Platelet Disorders, Armand Trousseau Children's Hospital, Paris, France.
  • 8 INSERM UMR 1170, Gustave Roussy Institute, Villejuif, France.
  • 9 NHS Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom.
  • 10 Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium.
  • 11 Department of Haematology, Hampshire Hospitals NHS Foundation Trust, Basingstoke, United Kingdom.
  • 12 Haemophilia, Haemostasis and Thrombosis Centre, Great Ormond Street Hospital for Children National Health Service Trust, London, United Kingdom.
  • 13 Hemostasis Laboratory, Biology Center, Hospices Civils de Lyon, Bron, France.
  • 14 Paediatric Oncology Hematology Unit, Michalon Hospital, La Tronche, France.
  • 15 School of Biomedical Science, University of Western Australia, Crawley, WA, Australia.
  • 16 PathWest Laboratory Medicine, Nedlands, WA, Australia.
  • 17 Katharine Dormandy Haemophilia Centre and Thrombosis Unit, The Royal Free Hospital, London, United Kingdom.
  • 18 Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.
  • 19 Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom; and.
  • 20 British Heart Foundation Centre of Excellence, Cambridge Biomedical Campus, Cambridge, United Kingdom.
PMID: 31217188 DOI: 10.1182/blood.2019000782
Abstract

To identify novel causes of hereditary thrombocytopenia, we performed a genetic association analysis of whole-genome sequencing data from 13 037 individuals enrolled in the National Institute for Health Research (NIHR) BioResource, including 233 cases with isolated thrombocytopenia. We found an association between rare variants in the transcription factor-encoding gene IKZF5 and thrombocytopenia. We report 5 causal missense variants in or near IKZF5 zinc fingers, of which 2 occurred de novo and 3 co-segregated in 3 pedigrees. A canonical DNA-zinc finger binding model predicts that 3 of the variants alter DNA recognition. Expression studies showed that chromatin binding was disrupted in mutant compared with wild-type IKZF5, and electron microscopy revealed a reduced quantity of α granules in normally sized platelets. Proplatelet formation was reduced in megakaryocytes from 7 cases relative to 6 controls. Comparison of RNA-sequencing data from platelets, monocytes, neutrophils, and CD4+ T cells from 3 cases and 14 healthy controls showed 1194 differentially expressed genes in platelets but only 4 differentially expressed genes 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.

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