Blood Journal
Leading the way in experimental and clinical research in hematology

Gray platelet syndrome: natural history of a large patient cohort and locus assignment to chromosome 3p

  1. Meral Gunay-Aygun1,2,
  2. Yifat Zivony-Elboum3,
  3. Fatma Gumruk4,
  4. Dan Geiger5,
  5. Mualla Cetin4,
  6. Morad Khayat3,
  7. Robert Kleta1,
  8. Nehama Kfir3,
  9. Yair Anikster1,
  10. Judith Chezar6,
  11. Mauricio Arcos-Burgos1,
  12. Adel Shalata3,
  13. Horia Stanescu1,
  14. Joseph Manaster6,
  15. Mutlu Arat7,
  16. Hailey Edwards1,
  17. Andrew S. Freiberg8,
  18. P. Suzanne Hart1,
  19. Lauren C. Riney1,
  20. Katherine Patzel1,
  21. Pranoot Tanpaiboon1,
  22. Tom Markello1,
  23. Marjan Huizing1,
  24. Irina Maric9,
  25. McDonald Horne9,
  26. Beate E. Kehrel10,
  27. Kerstin Jurk10,
  28. Nancy F. Hansen11,
  29. Praveen F. Cherukuri11,12,
  30. Marypat Jones11,
  31. Pedro Cruz11,
  32. Jim C. Mullikin11,
  33. Alan Nurden13,
  34. James G. White14,
  35. William A. Gahl1, and
  36. Tzippora Falik-Zaccai3,15
  1. 1Section on Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health (NIH), Bethesda, MD;
  2. 2Office of Rare Disease Research, Office of the Director, NIH, Bethesda, MD;
  3. 3Institute of Human Genetics, Western Galilee Hospital, Naharia, Israel;
  4. 4Pediatric Hematology Unit, Hacettepe University Children's Hospital, Ankara, Turkey;
  5. 5Department of Computer Sciences, Technion, Israel Institute of Technology, Haifa, Israel;
  6. 6Department of Hematology, Western Galilee Hospital, Naharia, Israel;
  7. 7Department of Hematology, Ankara University Faculty of Medicine, Ankara, Turkey;
  8. 8Division of Pediatric Hematology/Oncology, Penn State Hershey Children's Hospital, Hershey, PA;
  9. 9Department of Laboratory Medicine, NIH Clinical Center, Bethesda, MD;
  10. 10Department of Anaesthesiology and Intensive Care, Experimental and Clinical Haemostasis, University Hospital Münster, Münster, Germany;
  11. 11NIH Intramural Sequencing Center, NIH, Bethesda, MD;
  12. 12Genome Technology Branch, NIH, Bethesda, MD;
  13. 13Centre de Reference des Pathologies Plaquettaires, Plateforme Technologique et d'Innovation Biomedicale, Hopital Xavier Arnozan, Pessac, France;
  14. 14Department of Laboratory Medicine, University of Minnesota, Minneapolis, MN; and
  15. 15Ruth and Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel


Gray platelet syndrome (GPS) is an inherited bleeding disorder characterized by macrothrombocytopenia and absence of platelet α-granules resulting in typical gray platelets on peripheral smears. GPS is associated with a bleeding tendency, myelofibrosis, and splenomegaly. Reports on GPS are limited to case presentations. The causative gene and underlying pathophysiology are largely unknown. We present the results of molecular genetic analysis of 116 individuals including 25 GPS patients from 14 independent families as well as novel clinical data on the natural history of the disease. The mode of inheritance was autosomal recessive (AR) in 11 and indeterminate in 3 families. Using genome-wide linkage analysis, we mapped the AR-GPS gene to a 9.4-Mb interval on 3p21.1-3p22.1, containing 197 protein-coding genes. Sequencing of 1423 (69%) of the 2075 exons in the interval did not identify the GPS gene. Long-term follow-up data demonstrated the progressive nature of the thrombocytopenia and myelofibrosis of GPS resulting in fatal hemorrhages in some patients. We identified high serum vitamin B12 as a consistent, novel finding in GPS. Chromosome 3p21.1-3p22.1 has not been previously linked to a platelet disorder; identification of the GPS gene will likely lead to the discovery of novel components of platelet organelle biogenesis. This study is registered at as NCT00069680 and NCT00369421.

  • Submitted May 25, 2010.
  • Accepted August 2, 2010.
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