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.
Highlights
Diamond–Blackfan anemia (DBA) is a rare, inherited bone marrow failure syndrome that is characterized by hypoplastic anemia, congenital malformations and a predisposition to cancer [1,2]
In the Dutch DBA registry, a male patient was identified with a novel de novo GATA1 c.220+2T>C splice site variant, which was predicted to cause the skipping of exon 2 and produce predominantly GATA-1s protein
We reported on two new DBA-like patients with variants in exon 2 of the erythroid transcription factor GATA-1 and reviewed all published cases
Summary
Diamond–Blackfan anemia (DBA) is a rare, inherited bone marrow failure syndrome that is characterized by hypoplastic anemia, congenital malformations (in ~50% of patients) and a predisposition to cancer [1,2]. The diagnosis of DBA is mainly based on clinical consensus criteria (Figure 1) [3]. RPS19 variants as the underlying cause for DBA in 25% of cases [4], loss of function consensus criteria (Figure 1) [3]. Since the first groundbreaking study identifying RPS19 variants or deletions in more than 20 genes encoding ribosomal proteins (RPs) have been variants as the underlying cause for DBA in 25% of cases [4], loss of function variants or linked to DBA and can be identified in almost 75% of patients [5,6]. These variants cause deletions in more than 20 genes encoding ribosomal proteins (RPs) have been linked to ribosomal haploinsufficiency, leading to impaired ribosome biogenesis and DBA and protein can be identified in almost 75%
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