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MYELODYSPLASTIC SYNDROME

Germline GATA1 exon 2 mutation associated with chronic cytopenia and a non-down syndrome transient abnormal myelopoiesis with clonal trisomy 21

Leukemia volume 36, pages 2347–2350 (2022)Cite this article

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Transient Abnormal Myelopoiesis (TAM) is a transient myeloproliferative disorder that frequently occurs in children with Down syndrome (DS) or trisomy 21 mosaicism. Acquired mutations in exon 2 of GATA1 are cooperating events necessary for the development of TAM [1, 2]. It is currently accepted that the leukemogenic process typically arises with the sequential acquisition of events where trisomy 21 alone arises as to the first hit, followed by the occurrence of GATA1 mutation. Conversely, in our research subject presenting the picture of neonatal TAM, we show germline GATA1 exon 2 mutations for the first time to precede the emergence of clonal trisomy 21.

GATA1 is an essential X-linked gene that encodes for a transcription factor and is central to the differentiation and proliferation of erythroid and megakaryocytic lineages [3]. Homozygous Gata1-null mice are embryonically lethal leading to death between E10.5 and 11.5 due to severe anemia with erythroid maturation arrest [4]. In humans, germline variants in GATA1 have been associated with different hematological abnormalities that are considered non-malignant. It is the location and type of genetic variation in GATA1 that dictates the clinical phenotype. Heterozygous GATA1 germline mutations in exons 3 & 4 are associated with myeloid conditions, including thrombocytopenia and/or anemia and/or neutropenia (e.g., familial dyserythropoietic anemia with thrombocytopenia, X-linked thrombocytopenia, and X-linked thalassemia with thrombocytopenia) [5,6,7]. Exon 2 GATA1 aberrations are primarily somatic and were related to acute megakaryoblastic leukemia and TAM disorder. Constitutional exon 2 GATA1 mutations are rare and to date only 13 affected cases were reported, of which the majority were males (11/13) [8,9,10,11]. The phenotypic presentation of these known cases varied from moderate to severe anemia and neutropenia [8] or Diamond-Blackfan anemia-like phenotype [9] or MDS/AML predisposition with karyotype mosaicism and trisomy 21 clone [10, 11] (Table 1). The current study further expands the GATA1 clinical spectrum by describing germline GATA1 exon 2 mutation as a genetic predisposition to non-DS TAM.

Table 1 Germline GATA1 mutations and associated disease phenotype.
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Fig. 1: Inheritance and pathogenic effect of germline GATA1 c.94delG mutation.

References

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Funding

This work was supported by Fundação de Ensino e Pesquisa em Ciências da Saúde (FEPECS), Distrito Federal, Brazil. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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  1. These authors contributed equally: Ricardo Camargo, Sushree S. Sahoo.

Authors and Affiliations

  1. Hospital da Criança de Brasília, Distrito Federal, Brazil

    Ricardo Camargo, José Carlos Córdoba & Isis Quezado Magalhães

  2. St. Jude Children’s Research Hospital, Memphis, TN, USA

    Sushree S. Sahoo

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  1. Ricardo Camargo
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  3. José Carlos Córdoba
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  4. Isis Quezado Magalhães
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Contributions

IQM supervised the study, RC, SSS performed the research and wrote the manuscript, and JCC and IQM were involved in the clinical care of the patients.

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Correspondence to Isis Quezado Magalhães.

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Camargo, R., Sahoo, S.S., Córdoba, J.C. et al. Germline GATA1 exon 2 mutation associated with chronic cytopenia and a non-down syndrome transient abnormal myelopoiesis with clonal trisomy 21. Leukemia 36, 2347–2350 (2022). https://doi.org/10.1038/s41375-022-01638-6

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