Abstract Number: PB0896
Meeting: ISTH 2021 Congress
Background: The GATA1 transcription factor is essential for normal erythropoiesis and megakaryocytic development. Germline GATA1 pathogenic variants (PV) are typically associated with X-linked thrombocytopenia, dyserythropoietic anemia and/or platelet dysfunction. Phenotype/genotype correlation is important to better understand the diversity of rare GATA1 PV.
Aims: To characterize bleeding and platelet phenotype in two patients with a novel GATA1 variant identified by high throughput sequencing (HTS).
Methods: Two male index patients, (G1, 14 y; S2, 46 y), who presented with lifelong bleeding tendency have been investigated. Bleeding score (BS) was recorded with ISTH-BAT. Platelet phenotyping included full blood count (FBC), aggregometry (LTA), flow cytometry (FC), and electron microscopy (EM). Molecular analysis was performed by HTS panel.
Results: Patient characteristics are shown in table 1.
|Patient||German 1 (G1)||Spanish 2 (S2)|
|Bleeding symptoms||Epistaxis, ecchymosis, prolonged bleeding after dental surgery, impaired wound healing||Epistaxis, ecchymosis, prolonged bleeding after dental surgery (required profylaxis with tranexamic acid and DDVAP) impaired wound healing|
|3.73 (N: 3,7-5,5)
11.5 (N: 11-15)
97 (N: 70-90)
256 (N: 100-436)
7.9 (N: 7-12)
|4.1 (N: 3.5-5.8)
12.8 (N: 13-18)
123, 215, 134 (N: 150-400)
10.9 (N: 6.8-11.8)
ADP (4µM) / (5µM)
ADP (20 µM) / (10 µM)
Epinephrine (8µM) / (5µM)
Arachidonic (1.5 mM)
TRAP (25 uM)
|41 (N >70)
61 (N >85)
12 (N >70)
37 (N >70)
6 (N >70)
8 (N >70)
46 (N >70)
GP expression (GPIb/IX, GPIIb/IIIa and GPVI)
|EM||Not conducted||Mild defect in α-granules|
BS, for both patients, was 10. FBC showed mild anemia and anisocytosis and poikilocytosis in both patients, and normal platelet count in G1 but variable in S2 ranging from 123-215 G/L in multiple analysis. In both patients, LTA showed severe impaired response to Col, ADP, Epi, TRAP and CRP but normal expression of platelet glycoproteins. FC revealed severely decreased agonist-induced alpha and moderate dense granules secretion. EM (S2) also showed moderated alpha-granule defect. HTS panel identified a novel missense variant (c.865C>T; p.His289Tyr) in GATA1 classified as a likely PV that is absent in gnomAD population database. This variant is located in the C-terminal Zn-finger domain and disrupts a highly conserved amino acid residue. G1 mother´s, a heterozygous carrier, presented with menorrhagia (BS=2). Five females in the S2 pedigree were also heterozygous carriers of the variant but only two of these present with a bleeding diathesis.
Conclusions: The GATA-1 p.His289Tyr variant resulted in mild anemia, impaired platelet aggregation and secretion in hemizygous carriers. This is the first variant located in the GATA-1 C-terminal Zn-finger associated with platelet dysfunction and bleeding.
To cite this abstract in AMA style:Bastida JM, Boeckelmann D, Palma-Barqueros V, Wolter M, L Lozano M, Glonnegger H, Benito R, H Schilling F, Morgan N, Freson K, Rivera J, Zieger B. A Novel Hemizygous Variant in GATA1 Associated with Bleeding Diathesis and Platelet Dysfunction in Two Unrelated Patients [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/a-novel-hemizygous-variant-in-gata1-associated-with-bleeding-diathesis-and-platelet-dysfunction-in-two-unrelated-patients/. Accessed November 30, 2023.
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