Congenital and Hematologic Abnormalities in an Infant with a Novel GATA1 Mutation: A Case Study

Background: The GATA genes encode a family of transcription factors that are important for the development and differentiation of different cell lines. GATA1 is required for the development of cells of myeloid lineage and has been implicated in many diseases including transient myeloproliferative disorder, acute megakaryoblastic leukemia, and Diamond Blackfan anemia. This case study explores the clinical presentation of a novel GATA1 mutation. Case Presentation: A Caucasian male was born at 36 weeks gestation with a prenatal history significant for pericardial effusion, restrictive patent ductus arteriosus and polyhydramnios. Due to these anomalies, amniocentesis was performed which revealed normal chromosomes. At birth, he presented with decreased tone and respiratory distress so he was placed on continuous positive airway pressure and was transferred to Cook Children’s Medical Center. On physical exam, he had micropenis, hypospadias, bilateral clubfoot and blueberry muffin spots on the abdomen. Persistent leukocytosis, anemia and thrombocytopenia during the first month of life prompted consideration of a primary hematologic condition. A bone marrow exam was performed which showed a small increase in blasts, a significant decrease in erythroid precursors and few megakaryocytes. Subsequently whole exome sequencing (sent during the birth hospitalization) found the patient to be hemizygous for variant p.R307C in exon 6 of the GATA1 gene – a previously unreported mutation. The patient has been free from transfusions since 3 months of age although mild hemolytic anemia and leukocytosis have persisted. Currently he is being monitored for changes in blood counts and developmental milestones. Conclusion: The patient’s congenital anomalies and hematologic abnormalities have not been explained by another cause. His bone marrow has been sent to a research lab in Boston for functional analysis of the mutation. Additionally, the missense mutation discovered in sequencing has not been reported in the medical literature, but a mutation of the same exon of GATA1 has been previously described. The phenotype similarities between these two patients suggest that the congenital and blood anomalies are related to the missense mutation in exon 6 of the GATA1 gene. It is unclear why the mutation seems to affect mature red blood cells but not erythropoiesis. Work is ongoing to identify which targets are being modified by this mutation and how those changes impact phenotype.