Germline mutations in the GATA1 gene located on the X chromosome result in variable defects in platelet and sometimes erythrocyte and neutrophil formation. Affected boys usually have moderate to severe bruising and bleeding problems, marked thrombocytopenia, and average to large-sized platelets. Other clinical features may include erythrocytic anemia, globin gene transcription defects, and porphyria. Female carriers may show mild symptoms. Unlike X-linked Wiskott-Aldrich Syndrome, eczema and immunodeficiency are absent. Molecular diagnosis of this disorder is important to distinguish it from the more common immune thrombocytopenia purpura, and to establish optimal treatment. Mutations in GATA1 are also known to cause transient myeloproliferative disorder and megakaryoblastic leukemia in children with Down syndrome.
GATA1 mutations are inherited in an X-linked recessive fashion. GATA1 encodes a transcription factor involved in differentiation of erythrocytes and megakaryocytes. Nearly all causative mutations reported to date have been missense mutations involving amino acids 205-218 encoded in exon 4. However, an exon 2 splicing mutation was recently reported that led to patients with macrocytic anemia and neutropenia, but with normal platelet counts. Connections are beginning to be forged between the specific mutation and phenotype. For example, deletions or duplications in exon 2 of the GATA1 gene that result in a frameshift and premature protein termination are often associated with transient myeloproliferative disorder and megakaryoblastic leukemia in children with Down syndrome
Methodology: Sequencing of entire coding region
Purpose: Confirmation of Clinical Diagnosis
Test Requisition: Sequencing Requisition
Specimen Requirements: 2-5 mL Blood- Lavender Top Tube
CPT Codes: 81479 Cost: $600.00
Turn-around-time: 5-6 weeks
1. Cabelof DC, Patel HV, Chen Q, van Remmen H, Matherly LH, Ge Y, Taub JW. (2009) "Mutational spectrum at GATA1 provides insights into mutagenesis and leukemogenesis in Down syndrome". Blood. 24;114(13):2753-63.
2. Kobayashi M, Yamamoto M.(2007) "Regulation of GATA1 gene expression". J Biochem. 142(1):1-10. Epub 2007 Jun 13. Review.
3. Balduini, C. L., et.al. (2002). "Inherited thrombocytopenias: from genes to therapy." Haematologica 87(8): 860-80. PubMed ID: 12161364
4. Drachman, J. G. (2004). "Inherited thrombocytopenia: when a low platelet count does not mean ITP." Blood 103(2): 390-8. PubMed ID: 14504084
5. Freson, K., et.al. (2002). "Different substitutions at residue D218 of the X-linked transcription factor GATA1 lead to altered clinical severity of macrothrombocytopenia and anemia and are associated with variable skewed X inactivation." Hum Mol Genet 11(2): 147-52. PubMed ID: 11809723
6. Geddis, A. E., Kaushansky, K. (2004). "Inherited thrombocytopenias: toward a molecular understanding of disorders of platelet production." Curr Opin Pediatr 16(1): 15-22. PubMed ID: 14758109
7. Hitzler, J.K. et al. (2003). "GATA1 mutations in transient leukemia and acute megakaryoblastic leukemia of Down syndrome". Blood 101(11):4301-4. PubMed ID: 12586620
8. Melissa A Kacena, et.al. (2007). "GATA1-Related X-Linked Cytopenia." PubMed ID: 20301538
9. Mundschau, G. et al. (2003). "Mutagenesis of GATA1 is an initiating event in Down syndrome leukemogenesis". Blood101(11):4298-300. PubMed ID: 12560215
10. Muntean, A.G. et al. (2006). "Transcription factor GATA-1 and Down syndrome leukemogenesis". Leuk Lymphoma 47(6):986-97. PubMed ID: 16840187
11. Rainis, L. et al. (2003). "Mutations in exon 2 of GATA1 are early events in megakaryocytic malignancies associated with trisomy 21". Blood 102(3):981-6. PubMed ID: 12649131