Recently, somatic mutations in exon 2 of the transcription factor GATA1 gene have been detected in essentially all Down syndrome (DS) megakaryocytic leukemia (AMkL) and transient myeloproliferative disorder (TMD) cases. 1 This is the most specific genetic abnormality other than trisomy 21 in DS AMkL cases and is likely linked to the estimated 500-fold higher risk of DS children to develop AMkL compared with non-DS children. 2 In this study, GATA1 mutations were screened in hematopoietic tissues from DS fetuses and infants that had no pathologic evidence of leukemia to establish the stage of development at which GATA1 mutations may arise.

DS liver and/or bone marrow samples were obtained from archival autopsy specimens (ages, 10 days to 10 months) from the Department of Pediatric Pathology, Children’s Hospital of Michigan and fetal liver tissue blocks, from therapeutically terminated pregnancies (gestational ages, 18-23 weeks) from the Department of Pathology, Hutzel Women’s Hospital. The research protocol was approved by the institutional review boards of Wayne State University and the University of Chicago. Following deparaffinization according to the manufacturer’s instructions (Qiagen, Valencia, CA), genomic DNA was isolated by standard techniques. All fetuses and infants were confirmed to have trisomy 21 by standard karyotype analysis. Screening for GATA1 exon 2 mutations was performed by single-strand polymorphism assay (SSCP) as previously described. 3 Altered migration products were excised, and DNA was eluted and amplified by PCR and then sequenced. GATA1 mutations were detected in 2 of 9 liver samples from fetuses (gestational ages, 21 and 23 weeks) and in 2 of 5 DS infant autopsy bone marrow samples (ages, 4 and 6 months; Table 1). It is unknown whether the fetuses would have survived to term without the development of TMD and/or AMkL, though the detection of GATA1 mutations in hematopoietic tissues obtained postnatally suggests that mutations may exist in the absence of leukemia and