Thrombocytopenia and Related Hematopoietic Disorders via the GATA1 Gene

Germline variants in the GATA1 gene are associated with X-linked thrombocytopenia that may be accompanied by additional clinical manifestations including dyserythropoietic anemia (Nichols et al. 2000. PubMed ID: 107001880), beta-thalassemia (Yu et al. 2002. PubMed ID: 12200364), and anemia with or without neutropenia (Hollanda et al. 2006. PubMed ID: 16783379). Affected males usually have moderate to severe bruising and bleeding, marked thrombocytopenia (10-40/nl), and average to large-sized platelets. Female carriers may show mild symptoms. Unlike X-linked Wiskott-Aldrich Syndrome, eczema and immunodeficiency are absent in GATA1-related X-linked disorders.

Somatic variants in GATA1 are also known to cause transient myeloproliferative disorder (TMD) and megakaryoblastic leukemia in both male and female children with Down syndrome (Hitzler et al. 2003. PubMed ID: 12586620; Mundschau et al. 2003. PubMed ID: 12560215; Rainis et al. 2003. PubMed ID: 12649131; Muntean et al. 2006. PubMed ID: 16840187). Children with Down syndrome have a much greater risk of developing leukemia - up to 20 times the risk for children without Down syndrome. TMD is characterized by an abundance of undifferentiated blast cells in blood and tissues that undergoes spontaneous regression in most cases within a few months, but that progresses to megakaryocytic leukemia in up to 30% of cases (Taub et al. 2002. PubMed ID: 11902744). Variants in GATA1 resulting in premature protein termination and loss of wild type GATA1 protein are the primary type of variant found in Down syndrome patients with TMD.

Pathogenic GATA1 variants for thrombocytopenia are inherited in an X-linked recessive manner. GATA1 encodes a transcription factor involved in differentiation of erythrocytes and megakaryocytes. Nearly all causative variants reported to date have been missense variants involving amino acids 205-218 encoded in exon 4. A few splice site variants have also been reported. Large, multi-exon or whole gene deletions or duplications have not been reported for the GATA1 gene, though variants resulting in production of a truncated GATA1 protein are a frequent cause of TMD in patients with Down syndrome (Hitzler et al. 2003. PubMed ID: 12586620; Mundschau et al. 2003. PubMed ID: 12560215; Rainis et al. 2003. PubMed ID: 12649131; Muntean et al. 2006. PubMed ID: 16840187).

In a recent study of 272 patients with macrothrombocytopenia, ~48% of patients harbored pathogenic variants in either the MYH9 gene (~ 38%), the Bernard Soulier genes (~ 10%), or the GATA1 gene (< 1%) (Kunishima, Thrombocytopenia, ISTH Webinar 2015: WEB150325). In general, ~ 50% of inherited thrombocytopenias are not yet characterized (Balduini et al. 2013. 23397552).

To date, no large multi-exon or whole gene deletions or duplications have been reported for the GATA1 gene.

This test provides full coverage of all coding exons of the GATA1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).