Novel <i>GATA1</i> Variant Causing a Bleeding Phenotype Associated with Combined Platelet α-/δ-Storage Pool Deficiency and Mild Dyserythropoiesis Modified by a <i>SLC4A1</i> Variant
Kerstin Jurk,
Anke Adenaeuer,
Stefanie Sollfrank,
Kathrin Groß,
Friederike Häuser,
Andreas Czwalinna,
Josef Erkel,
Nele Fritsch,
Dana Marandiuc,
Martin Schaller,
Karl J. Lackner,
Heidi Rossmann,
Frauke Bergmann
Affiliations
Kerstin Jurk
Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany
Anke Adenaeuer
Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany
Stefanie Sollfrank
Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany
Kathrin Groß
Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany
Friederike Häuser
Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany
Germline defects in the transcription factor GATA1 are known to cause dyserythropoiesis with(out) anemia and variable abnormalities in platelet count and function. However, damaging variants closely located to the C-terminal zinc finger domain of GATA1 are nearly unknown. In this study, a 36-year-old male index patient and his 4-year-old daughter suffered from moderate mucocutaneous bleeding diathesis since birth. Whole exome sequencing detected a novel hemizygous GATA1 missense variant, c.886A>C p.T296P, located between the C-terminal zinc finger and the nuclear localization sequence with non-random X-chromosome inactivation in the heterozygous daughter. Blood smears from both patients demonstrated large platelet fractions and moderate thrombocytopenia in the index. Flow cytometry and electron microscopy analysis supported a combined α-/δ (AN-subtype)-storage pool deficiency as cause for impaired agonist-induced platelet aggregation (light transmission aggregometry) and granule exocytosis (flow cytometry). The absence of BCAM in the index (Lu(a-b-)) and its low expression in the daughter (Lu(a-b+)) confirmed a less obvious effect of defective GATA1 also on erythrocytes. Borderline anemia, elevated HbF levels, and differential transcription of GATA1-regulated genes indicated mild dyserythropoiesis in both patients. Furthermore, a mild SLC4A1 defect associated with a heterozygous SLC4A1 c.2210C>T p.A737V variant maternally transmitted in the daughter may modify the disease to mild spherocytosis and hemolysis.
