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

Genes

Odile Fenneteau¹  Lydie Da Costa¹  Birgit van Dooijeweert²  Wouter van Solinge²  Richard van Wijk²  Niklas Dahl³  Roos Leguit⁴  Marije Bartels⁵  Edward Nieuwenhuis⁶  Sima Kheradmand Kia⁷ 

[1] AP-HP, Service d’Hématologie Biologique, Hôpital Robert Debré, University of Paris Cité, Hematim EA 4666, UPJV, F-75019 Paris, France;Central Diagnostic Laboratory Research, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands;Department of Immunology, Genetics and Pathology, Uppsala University and Children’s Hospital, 751 85 Uppsala, Sweden;Department of Pathology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands;Department of Pediatric Hematology, van Creveldkliniek, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands;Department of Pediatrics, University Medical Center Utrecht, 3508 AB Utrecht, The Netherlands;Laboratory for Red Blood Cell Diagnostics, Sanquin, 1006 AD Amsterdam, The Netherlands;

关键词: Diamond–Blackfan anemia;    GATA-1;    DBA-like disease;    dyserythropoiesis;    dysmegakaryopoiesis;   

DOI  :  10.3390/genes13030447

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown