Novel GATA1 Variant Causing a Bleeding Phenotype Associated with Combined Platelet α-/δ-Storage Pool Deficiency and Mild Dyserythropoiesis Modified by a SLC4A1 Variant

Abstract

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.

Enhancement of PRMT6 binding to a novel germline <i>GATA1</i> mutation associated with congenital anemia

“…Very few C-terminal GATA1 mutation reports and pathogenic investigations have been done. Out of the documented cases, T296P was found with thrombocytopenia and insignificant erythroid impact, 43 Stop414Arg caused an erythroid Lu(a-b-) phenotype and mild thrombocytopenia, 44 R307C/H caused mild thrombocytopenia and hemolytic anemia with elevated adenosine deaminase (ADA) levels. 45 Although these cases varied in appearance, they seemed to have a shared deficiency in platelet production.…”

Recent progress in analyses of GATA1 in hematopoietic disorders: a mini-review

“…Affected males carrying either L268M, H289Y or T296P mutations suffer from bleeding disorders caused by platelet dysfunction, while platelet numbers indicate borderline or mild-to-moderate thrombocytopenia. Red blood cell parameters are only marginally influenced (56,58,59). The clinical characteristics of the H289R mutation are not significant in either males or females.…”

“…Of note, several substitutions in the C-finger and downstream region have also been identified (Figure 2A) and have intriguing pathological impacts (38,56,(58)(59)(60)(61)(62). Affected males carrying either L268M, H289Y or T296P mutations suffer from bleeding disorders caused by platelet dysfunction, while platelet numbers indicate borderline or mild-to-moderate thrombocytopenia.…”

Inherited Platelet Disorders: A Short Introduction

“…34 However, a platelet granule secretion defect is reported even in cases with mild thrombocytopenia or normal platelet counts and GATA1 variants. 35,36 Other defects affecting the megakaryopoiesis are summarized in ►Table 5.…”