GATA1 Mutations in Newborns with Down Syndrome.

Somatic mutations of the GATA1 gene have been detected in almost all cases of Down syndrome (DS)-associated acute megakaryoblastic leukemia (AMKL) and transient leukemia (TL). There is emerging evidence that the protein product of GATA1 mutations, GATA1s, directly contributes to leukemogenesis. Although an in utero origin of GATA1 mutations is established, a comprehensive study using a large number of cases is required to determine the overall incidence and clinical relevance of GATA1 mutations in DS newborns. We screened 575 DS infants born between January 1997 and December 1999 for GATA1 exon 2 mutations by single-strand conformation polymorphism analysis of PCR products. We used Gunthrie cards obtained from the New York Congenital Malformation Registry. Registry data was blinded until after the GATA1 mutation analyses were completed. Twenty-eight (4.9%) infants were identified as having a GATA1 mutation. There was no significant difference in the frequency of GATA1 mutations based on gender or maternal average age (p = 0.93 and 0.31, respectively). There was no significant difference in the GATA1 mutation frequency between those classified as black, white, or Asian, but Hispanics had a borderline non-significant increase in frequency of GATA1 mutations compared to non-Hispanics (8.5% compared to 4.0%, p=0.06). Based on data from the New York Cancer Registry reviewed in 2005, two of the patients with a GATA1 mutation subsequently developed leukemia; one patient developed AMKL and the other had a leukemia of unspecified phenotype. Out of the 547 GATA1-negative patients, there was only one case of leukemia, but it was AML excluding AMKL. These results confirm a pre-natal origin of GATA1 mutations in DS patients. The frequency in this study was lower than the 10 percent previously reported (2 of 21 DS blood spots). Obtaining Gunthrie card blood spots for GATA1 mutation analysis serves as a relatively non-invasive screening approach. The presence of a GATA1 mutation at the time of birth might serve as a biomarker for an increased risk of developing DS-related AMKL.