GATA-1 Defects in Diamond–Blackfan Anemia: Phenotypic Characterization Points to a Specific Subset of Disease
van Dooijeweert, Birgit; Kia, Sima Kheradmand; Dahl, Niklas; Fenneteau, Odile; Leguit, Roos; Nieuwenhuis, Edward; van Solinge, Wouter; van Wijk, Richard; Da Costa, Lydie; Bartels, Marije
(2022) Genes, volume 13, issue 3, pp. 1 - 12
(Article)
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
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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.
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Keywords: DBA-like disease, Diamond–Blackfan anemia, Dyserythropoiesis, Dysmegakaryopoiesis, GATA-1, GATA1 Transcription Factor, Ribosomal Proteins/genetics, Phenotype, Iran, Erythropoiesis/genetics, Anemia, Diamond-Blackfan/diagnosis, Humans, Diamond-Blackfan anemia, dysmegakaryopoiesis, dyserythropoiesis, Genetics(clinical), Genetics, Journal Article, Research Support, Non-U.S. Gov't
ISSN: 2073-4425
Publisher: Multidisciplinary Digital Publishing Institute (MDPI)
Note: Funding Information: Funding: European Union’s Horizon 2020 research and innovation program under the EJP RD COFUND-EJP No 825575 (L.D.C. and M.B.), ANR EJPRD/ANR-19-RAR4-0016 and Laboratory of Excellence for Red Cells [(LABEX GR-Ex)-ANR Avenir-11-LABX-0005-02 (L.D.C.). Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.
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