Gray platelet syndrome: natural history of a large patient cohort and locus assignment to chromosome 3p
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 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.
Article: Filling a void in Gray PlateletsBlood 12/2010; 116(23):4738-40. DOI:10.1182/blood-2010-09-304378 · 10.43 Impact Factor
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ABSTRACT: Gray platelet syndrome (GPS) is an inherited bleeding disorder characterized by thrombocytopenia and the absence of α-granules in platelets. Patients with GPS present with mild to moderate bleeding and many develop myelofibrosis. The genetic cause of GPS is unknown. We present 2 Native American families with a total of 5 affected persons and a single affected patient of Pakistani origin in which GPS appears to be inherited in an autosomal recessive manner. Homozygosity mapping using the Affymetrix 6.0 chips demonstrates that all 6 GPS-affected persons studied are homozygous for a 1.7-Mb region in 3p21. Linkage analysis confirmed the region with a logarithm of the odds score of 2.7. Data from our families enabled us to significantly decrease the size of the critical region for GPS from the previously reported 9.4-Mb region at 3p21.Blood 03/2011; 117(12):3430-4. DOI:10.1182/blood-2010-12-322990 · 10.43 Impact Factor
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ABSTRACT: The investigation of children with suspected inherited platelet disorders is challenging. The causes of mucocutaneous bleeding are many, and specialized testing for platelet disorders can be difficult to access or interpret. An algorithm developed for the investigation of suspected platelet disorders provides a sequential approach to evaluating both platelet function abnormalities and thrombocytopenia. Investigation begins with a clinical evaluation and laboratory testing that is generally available, including platelet counting, peripheral blood cell morphology, and aggregometry. Based on results of initial investigations, the algorithm recommends specialized testing for specific diagnoses, including flow cytometry, immunofluorescence microscopy, electron microscopy, and mutational analysis.Pediatric Blood & Cancer 06/2011; 56(6):975-83. DOI:10.1002/pbc.22988 · 2.56 Impact Factor