Clinical significance of preleukemic somatic GATA1 mutations in children with Down syndrome.

Children with Down syndrome (DS) have a high risk of GATA1-associated myeloid leukemia (ML-DS) before age 4. Somatic N-terminal GATA1 mutations (GATA1s) are necessary, but not sufficient, for ML-DS, but their significance at birth for individual babies and whether mutations occur after birth is unclear. To address these questions, we performed a prospective study of DS newborns using next-generation sequencing-based GATA1 mutation analysis with detailed hematologic and clinical evaluation and follow-up for the window of ML-DS risk. Of 450 DS neonates, 113 (25%) had GATA1s mutations of which 20/113 (17.7%) were multiple and 59 (52%) were clinically silent. Variant allele frequency (VAF) varied from 0.3-89%. VAF positively correlated (p<0.0001) with % blasts, leukocytes, dyserythro- and dysmegakaryopoiesis scores and clinical disease and negatively with hemoglobin, although only 4/113 were anemic. GATA1s mutations were detected from 28 weeks(w) gestation; the highest frequency (45%) was at 34-35w while mutation frequency in early fetal samples (<20w) was only <4% (2/57). GATA1s clones (VAF, % blasts) fell rapidly post-natally becoming undetectable by 6 months (6m) except in neonates who developed ML-DS. 7/110 surviving neonates (6.4%) developed ML-DS at a median age of 17.5m. GATA1s clone size at birth was the only predictor of subsequent ML-DS. No neonates lacking GATA1s mutations acquired mutations after birth or developed ML-DS. Taken together, the fetal environment is essential for GATA1s mutation selection and expansion of GATA1s clones. Rates of leukemic transformation of GATA1s clones detected at birth are low but clones that persist beyond 6 months transformed.