Somatic mutations in children with GATA2-associated myelodysplastic syndrome who lack other features of GATA2 deficiency

Approximately 10% of children with primary myelodysplastic syndrome (MDS) have germ line GATA2 mutations, leading to the proposal that all children with primary MDS and certain cytogenetic findings, including monosomy 7, be tested for germ line GATA2 mutations regardless of family history or other clinical features associated with GATA2 deficiency. In adults with familial GATA2-MDS, those with somatic mutations in ASXL1 experience rapid disease progression to acute myeloid leukemia (AML) and poor prognosis after stem cell transplantation; however, the prevalence of somatic mutations in primary pediatric GATA2-MDS is unclear. Here, we studied a cohort of 8 pediatric patients with MDS and lacking additional GATA2-associated clinical features or significant family history and identified heterozygous germ line GATA2 mutations in 5 patients, including 1 with a normal karyotype. For those with GATA2-MDS, we screened for somatic mutations in genes with prognostic relevance in AML/MDS, using a targeted next-generation sequencing panel. Although no somatic mutations in ASXL1 were observed, somatic mutations were found in RUNX1, SETBP1, IKZF1, and CRLF2. One subject with deleterious mutations in RUNX1, SETBP1, and IKZF1 rapidly progressed to AML with disease that was refractory to treatment. Our findings confirm the importance of GATA2 testing in primary pediatric MDS, even in the absence of other clinical features of GATA2 deficiency. Further, similar to what has been observed in adults with GATA2-MDS, somatic mutations with potential prognostic effect occur in children with MDS associated with mutations in GATA2.