Gray platelet syndrome: natural history of a large patient cohort and locus assignment to chromosome 3p.
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 B(12) 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.
Gunay-Aygun
Meral
M
Section on Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. mgaygun@mail.nih.gov
Zivony-Elboum
Yifat
Y
Gumruk
Fatma
F
Geiger
Dan
D
Cetin
Mualla
M
Khayat
Morad
M
Kleta
Robert
R
Kfir
Nehama
N
Anikster
Yair
Y
Chezar
Judith
J
Arcos-Burgos
Mauricio
M
Shalata
Adel
A
Stanescu
Horia
H
Manaster
Joseph
J
Arat
Mutlu
M
Edwards
Hailey
H
Freiberg
Andrew S
AS
Hart
P Suzanne
PS
Riney
Lauren C
LC
Patzel
Katherine
K
Tanpaiboon
Pranoot
P
Markello
Tom
T
Huizing
Marjan
M
Maric
Irina
I
Horne
McDonald
M
Kehrel
Beate E
BE
Jurk
Kerstin
K
Hansen
Nancy F
NF
Cherukuri
Praveen F
PF
Jones
Marypat
M
Cruz
Pedro
P
Mullikin
Jim C
JC
Nurden
Alan
A
White
James G
JG
Gahl
William A
WA
Falik-Zaccai
Tzippora
T
D000293:Adolescent; D000328:Adult; D001792:Blood Platelets / Q000648:ultrastructure; D002469:Cell Separation; D002648:Child; D002675:Child, Preschool; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005434:Flow Cytometry; D008040:Genetic Linkage; D055106:Genome-Wide Association Study; D055652:Gray Platelet Syndrome / Q000097:blood / Q000235:genetics* / Q000503:physiopathology*; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D009504:Neutrophils / Q000648:ultrastructure; D010375:Pedigree; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D014805:Vitamin B 12 / Q000097:blood; D055815:Young Adult
D014805:Vitamin B 12