GATA2 is a crucial gene in hematopoiesis, acting in proliferation and maintenance of hematopoietic stem cells. Germline variants of GATA2 are associated with various phenotypes including Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML) of early onset. Mutation of one allele results in haploinsufficiency which can be detected by Next-Generation Sequencing (NGS). Since 2018 the Brazilian Cooperative Group of Pediatric Myelodysplastic Syndrome (GCB-SMD-PED) included NGS as a diagnostic tool, enabling the diagnosis of pediatric MDS and secondary AML associated with GATA2 haploinsufficiency.

Clinical and laboratory characterization of MDS patients with GATA2 variants from GCB-SMD-PED registry.

Patients from 2018‒2024 with MDS/AML diagnosis and GATA2 variant detected were included. Clinical and laboratory data including Peripheral Blood Count (PB), morphology evaluation, Flow Cytometry Immunophenotyping (FCI), cytogenetics, and NGS were analyzed.

From 56 NGS performed in MDS and secondary AML patients, GATA2 variants were found in 9, with a mean age of 10.33-years (range: 1–18). A history of recurrent infections was observed in 7/9 patients (77.7%); one patient had a previously diagnose of immunodeficiency. Clinical features included congenital deafness (2/9), interstitial lung disease (2/9), and Emberger syndrome (2/9). Genetic analysis revealed variants in exon 6 (3/9), exon 5 (3/9), exon 4 (2/9), and exon 3 (1/9). Most mutations were frameshift (7/9, 77.7%), while missense mutations accounted for 2/9 cases. Concomitant variants were identified in 6/9 patients as STAG2(2), ASXL1(3), SETBP1(3), with 1–3 additional variants per patient. Family genetic testing was performed in 5/9 cases, revealing familial inheritance in 2 (variant present in the father in both, and in one case, also in the sister). PB analysis showed anemia in 6/9 (66.7%), neutropenia in 6/9 (66.7%), monocytopenia in 5/9 (55.5%), and thrombocytopenia in 4/9 (44.5%). In morphologic evaluation, hypocellular bone marrow was found in 4/9 patients; dismegakaryopoiesis was described in 8/9 patients and micromegakaryocytes in 6/9. FCI was performed, with frequent decrease of B precursors (absence in 78%) and NK cells. 66,6% presented with monosomy 7 by conventional cytogenetics; when this finding was correlated with age groups, all patients with age > 12 years (5) presented monosomy 7 karyotype (p < 0.05%) (3 with advanced MDS, 2 with sAML). Final diagnoses included Myelodysplastic Syndrome with Excess Blasts (MDS-EB) in 5/9 (55.5%), secondary Acute Myeloid Leukemia (sAML) in 2/9 (22.2%), Refractory Cytopenia of Childhood (RCC) in 1/9, and myeloproliferative syndrome in 1/9. Among MDS-EB cases, 4/5 underwent Hematopoietic Stem Cell Transplantation (HSCT); 1 patient died before HSCT and 2 died after the procedure. Of the sAML patients, one died due to invasive fungal infection and the other one is in follow-up after HSCT. The patient with RCC is alive and under follow-up post-HSCT; the only myeloproliferative case is under watch and wait strategy.

Despite the small number of patients, our results are similar to a published cohort of GATA2 haploinsufficiency in pediatric MDS, and was the first attempt to characterize Brazilian population. Detection of germline mutations associated with MDS are essential for a better approach, family screening and counseling.