GATA-1 Defects in Diamond-Blackfan Anemia: Phenotypic Characterization Points to a Specific Subset of Disease

Abstract

Diamond−Blackfan anemia (DBA) is one of the inherited bone marrow failure syndromes marked by erythroid hypoplasia. Underlying variants in ribosomal protein (RP) genes account for 80% of cases, thereby classifying DBA as a ribosomopathy. In addition to RP genes, extremely rare variants in non-RP genes, including GATA1, the master transcription factor in erythropoiesis, have been reported in recent years in patients with a DBA-like phenotype. Subsequently, a pivotal role for GATA-1 in DBA pathophysiology was established by studies showing the impaired translation of GATA1 mRNA downstream of the RP haploinsufficiency. Here, we report on a patient from the Dutch DBA registry, in which we found a novel hemizygous variant in GATA1 (c.220+2T>C), and an Iranian patient with a previously reported variant in the initiation codon of GATA1 (c.2T>C). Although clinical features were concordant with DBA, the bone marrow morphology in both patients was not typical for DBA, showing moderate erythropoietic activity with signs of dyserythropoiesis and dysmegakaryopoiesis. This motivated us to re-evaluate the clinical characteristics of previously reported cases, which resulted in the comprehensive characterization of 18 patients with an inherited GATA-1 defect in exon 2 that is presented in this case-series. In addition, we re-investigated the bone marrow aspirate of one of the previously published cases. Altogether, our observations suggest that DBA caused by GATA1 defects is characterized by distinct phenotypic characteristics, including dyserythropoiesis and dysmegakaryopoiesis, and therefore represents a distinct phenotype within the DBA disease spectrum, which might need specific clinical management.

Keywords: DBA-like disease; Diamond–Blackfan anemia; GATA-1; dyserythropoiesis; dysmegakaryopoiesis.

Figure 1

Diagnostic and supporting criteria for the diagnosis of DBA, as established by Vlachos et al. [3].

Figure 2

Bone marrow analysis of GATA-1 DBA patients. Bone marrow aspirates demonstrating dysplastic erythroid precursor cells (arrows), and aberrant shapes (small panel) in patient 1 (A) and dyserytropoiesis (arrows) and dysplastic megakaryocytes (small panel) in patient V-I (B). Trephine biopsies, demonstrating normocellular bone marrow with increased, dysplastic megakaryopoiesis (arrows) in patient 1 (C) and reduced cellularity and erythropoiesis with dysmegakaryopoiesis in patient V-I (D).

Figure 3

Functional characteristics of GATA-1 DBA. (A) Overview of genetic defects at exon 2 in GATA1, inducing GATA1s exclusively (figure adapted from Ling & Crispino) [40]. (B) Bone marrow responsiveness index (BMRI), calculated as [(absolute reticulocyte count) × (patient’s Hb/normal Hb)], depicted for DBA patients with GATA1 defects, ribosomal protein defects from the Dutch DBA Registry and healthy controls.