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 PatzelPranoot 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, Tzippora Falik-Zaccai

Research output: Contribution to journalArticle

84 Citations (Scopus)

Abstract

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 genomewide 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 www.clinicaltrials.gov as NCT00069680 and NCT00369421.

Original languageEnglish (US)
Pages (from-to)4990-5001
Number of pages12
JournalBlood
Volume116
Issue number23
DOIs
StatePublished - Dec 2 2010

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Gray Platelet Syndrome
Chromosomes
Platelets
Natural History
Blood Platelets
Genes
Primary Myelofibrosis
Hemorrhage
Splenomegaly
Organelle Biogenesis
Vitamin B 12
Thrombocytopenia
Molecular Biology
Exons

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Gunay-Aygun, M., Zivony-Elboum, Y., Gumruk, F., Geiger, D., Cetin, M., Khayat, M., ... Falik-Zaccai, T. (2010). Gray platelet syndrome: Natural history of a large patient cohort and locus assignment to chromosome 3p. Blood, 116(23), 4990-5001. https://doi.org/10.1182/blood-2010-05-286534
Gunay-Aygun, Meral ; Zivony-Elboum, Yifat ; Gumruk, Fatma ; Geiger, Dan ; Cetin, Mualla ; Khayat, Morad ; Kleta, Robert ; Kfir, Nehama ; Anikster, Yair ; Chezar, Judith ; Arcos-Burgos, Mauricio ; Shalata, Adel ; Stanescu, Horia ; Manaster, Joseph ; Arat, Mutlu ; Edwards, Hailey ; Freiberg, Andrew S. ; Hart, P. Suzanne ; Riney, Lauren C. ; Patzel, Katherine ; Tanpaiboon, Pranoot ; Markello, Tom ; Huizing, Marjan ; Maric, Irina ; Horne, McDonald ; Kehrel, Beate E. ; Jurk, Kerstin ; Hansen, Nancy F. ; Cherukuri, Praveen F. ; Jones, Marypat ; Cruz, Pedro ; Mullikin, Jim C. ; Nurden, Alan ; White, James G. ; Gahl, William A. ; Falik-Zaccai, Tzippora. / Gray platelet syndrome : Natural history of a large patient cohort and locus assignment to chromosome 3p. In: Blood. 2010 ; Vol. 116, No. 23. pp. 4990-5001.
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abstract = "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 genomewide 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 www.clinicaltrials.gov as NCT00069680 and NCT00369421.",
author = "Meral Gunay-Aygun and Yifat Zivony-Elboum and Fatma Gumruk and Dan Geiger and Mualla Cetin and Morad Khayat and Robert Kleta and Nehama Kfir and Yair Anikster and Judith Chezar and Mauricio Arcos-Burgos and Adel Shalata and Horia Stanescu and Joseph Manaster and Mutlu Arat and Hailey Edwards and Freiberg, {Andrew S.} and Hart, {P. Suzanne} and Riney, {Lauren C.} and Katherine Patzel and Pranoot Tanpaiboon and Tom Markello and Marjan Huizing and Irina Maric and McDonald Horne and Kehrel, {Beate E.} and Kerstin Jurk and Hansen, {Nancy F.} and Cherukuri, {Praveen F.} and Marypat Jones and Pedro Cruz and Mullikin, {Jim C.} and Alan Nurden and White, {James G.} and Gahl, {William A.} and Tzippora Falik-Zaccai",
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Gunay-Aygun, M, Zivony-Elboum, Y, Gumruk, F, Geiger, D, Cetin, M, Khayat, M, Kleta, R, Kfir, N, Anikster, Y, Chezar, J, Arcos-Burgos, M, Shalata, A, Stanescu, H, Manaster, J, Arat, M, Edwards, H, Freiberg, AS, Hart, PS, Riney, LC, Patzel, K, Tanpaiboon, P, Markello, T, Huizing, M, Maric, I, Horne, M, Kehrel, BE, Jurk, K, Hansen, NF, Cherukuri, PF, Jones, M, Cruz, P, Mullikin, JC, Nurden, A, White, JG, Gahl, WA & Falik-Zaccai, T 2010, 'Gray platelet syndrome: Natural history of a large patient cohort and locus assignment to chromosome 3p', Blood, vol. 116, no. 23, pp. 4990-5001. https://doi.org/10.1182/blood-2010-05-286534

Gray platelet syndrome : Natural history of a large patient cohort and locus assignment to chromosome 3p. / Gunay-Aygun, Meral; Zivony-Elboum, Yifat; Gumruk, Fatma; Geiger, Dan; Cetin, Mualla; Khayat, Morad; Kleta, Robert; Kfir, Nehama; Anikster, Yair; Chezar, Judith; Arcos-Burgos, Mauricio; Shalata, Adel; Stanescu, Horia; Manaster, Joseph; Arat, Mutlu; Edwards, Hailey; Freiberg, Andrew S.; Hart, P. Suzanne; Riney, Lauren C.; Patzel, Katherine; Tanpaiboon, Pranoot; Markello, Tom; Huizing, Marjan; Maric, Irina; Horne, McDonald; Kehrel, Beate E.; Jurk, Kerstin; Hansen, Nancy F.; Cherukuri, Praveen F.; Jones, Marypat; Cruz, Pedro; Mullikin, Jim C.; Nurden, Alan; White, James G.; Gahl, William A.; Falik-Zaccai, Tzippora.

In: Blood, Vol. 116, No. 23, 02.12.2010, p. 4990-5001.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Gray platelet syndrome

T2 - Natural history of a large patient cohort and locus assignment to chromosome 3p

AU - Gunay-Aygun, Meral

AU - Zivony-Elboum, Yifat

AU - Gumruk, Fatma

AU - Geiger, Dan

AU - Cetin, Mualla

AU - Khayat, Morad

AU - Kleta, Robert

AU - Kfir, Nehama

AU - Anikster, Yair

AU - Chezar, Judith

AU - Arcos-Burgos, Mauricio

AU - Shalata, Adel

AU - Stanescu, Horia

AU - Manaster, Joseph

AU - Arat, Mutlu

AU - Edwards, Hailey

AU - Freiberg, Andrew S.

AU - Hart, P. Suzanne

AU - Riney, Lauren C.

AU - Patzel, Katherine

AU - Tanpaiboon, Pranoot

AU - Markello, Tom

AU - Huizing, Marjan

AU - Maric, Irina

AU - Horne, McDonald

AU - Kehrel, Beate E.

AU - Jurk, Kerstin

AU - Hansen, Nancy F.

AU - Cherukuri, Praveen F.

AU - Jones, Marypat

AU - Cruz, Pedro

AU - Mullikin, Jim C.

AU - Nurden, Alan

AU - White, James G.

AU - Gahl, William A.

AU - Falik-Zaccai, Tzippora

PY - 2010/12/2

Y1 - 2010/12/2

N2 - 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 genomewide 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 www.clinicaltrials.gov as NCT00069680 and NCT00369421.

AB - 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 genomewide 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 www.clinicaltrials.gov as NCT00069680 and NCT00369421.

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Gunay-Aygun M, Zivony-Elboum Y, Gumruk F, Geiger D, Cetin M, Khayat M et al. Gray platelet syndrome: Natural history of a large patient cohort and locus assignment to chromosome 3p. Blood. 2010 Dec 2;116(23):4990-5001. https://doi.org/10.1182/blood-2010-05-286534