Germline exon 4 mutations in the N-terminal zinc finger (N-finger) of transcription factor GATA1 cause a variable degree of X-linked dyserythropoiesis with macrothrombocytopenia. Congenital neutropenia and anemia are described in patients with an exon 2 germline splicing mutation resulting in exclusive expression of the short isoform of GATA1 (GATA1s). Similar but acquired somatic GATA1 exon 2 splicing mutations occur in children with Down Syndrome (DS) and congenital transient myeloproliferative syndrome (TMD) or acute megakaryoblastic leukemia (AMKL). The present study describes a somatic exon 4 GATA1 mutation in a 19-year-old boy with myelodysplastic syndrome (MDS) who has a lifelong history of anemia, neutropenia, severe bone pains and hepatosplenomegaly. Bone marrow biopsy demonstrates bilineage dysplasia with deficient granulopoiesis and dysmegakaryopoiesis. The patient has a normal platelet count but an increased Ivy bleeding time and a prolongation of the PFA100 occlusion time. Platelet ATP secretion and platelet aggregation are decreased. The a to g substitution is present in GATA1 mRNA from platelets and bone marrow mononuclear cells. The mutation is also detected in genomic DNA from purified common myeloid progenitors, but not in common lymphoid progenitors, peripheral blood lymphocytes and skin fibroblasts. This GATA1- E200G mutation is located in a highly conserved residue at the beginning of the N-finger, but does not perturb DNA binding to GATA sites nor reduces its interaction with FOG1. In contrast, the mutation is located at the exonic splice site and is associated with alternative splicing and reduced GATA1 protein levels. In conclusion, this study expands the GATA1 phenotype-genotype spectrum with the development of MDS and platelet dysfunction due to a somatic GATA1 splice mutation.

Disclosures: No relevant conflicts of interest to declare.

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