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

Meral Gunay-Aygun, Yifat Zivony-Elboum, Fatma Gumruk, Dan Geiger, Mualla Cetin, Morad Khayat, Robert Kleta, Nehama Kfir, Yair Anikster, Judith Chezar, Mauricio Arcos-Burgos, Adel Shalata, Horia Stanescu, Joseph Manaster, Mutlu Arat, Hailey Edwards, Andrew S. Freiberg, P. Suzanne Hart, Lauren C. Riney, Katherine Patzel, Pranoot Tanpaiboon, Tom Markello, Marjan Huizing, Irina Maric, McDonald Horne, Beate E. Kehrel, Kerstin Jurk, Nancy F. Hansen, Praveen F. Cherukuri, Marypat Jones, Pedro Cruz, Jim C. Mullikin, Alan Nurden, James G. White, William A. Gahl and Tzippora Falik-Zaccai


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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