GATA2 Deficiency and the MonoMAC Syndrome

The aim of this study was to identify the germline mutation(s) in an extended family with individuals having MonoMAC Syndrome/GATA2 deficiency but lacking a canonical GATA2 mutation. GATA2 deficiency patients develop bone marrow failure, severe immunodeficiency and may progress to myeloid malignancies, including myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and chronic myelomonocytic leukemia (CMML). The definitive treatment for GATA2 deficiency is a bone marrow transplant. Approximately 90% of GATA2 deficiency patients have a known de novo or inherited germline mutation in the GATA2 gene, but ~10% have no identified mutation. The study was initiated with the first patient and her second cousin, both of whom were treated for MonoMAC Syndrome and received bone marrow transplants at the NIH. Pedigree analysis and clinical evaluation identified the individuals in several generations of these patients' near and distant relatives who are/were presenting or carrying the disease manifestations of GATA2 deficiency. Whole Genome Sequencing (WGS) was employed on these patients' two related nuclear families to identify variants that segregated with the disease trait and carrier status of their families. Genotyping was confirmed with direct DNA sequencing of these and other family members within the extended family across generations. A single base adenine-to-thymidine change was identified in a highly conserved enhancer element ~117,000 bp upstream of the GATA2 gene. It creates a new Composite Element, a DNA motif known to be critical in the regulation of hematopoiesis. This variant is unique to this family and is not present in dbSNP or other variant databases. It segregates with the disease trait and obligate carriers throughout a large pedigree. In vitro studies show that this variant drives allele-specific overexpression of the GATA2 gene in cultured cells and luciferase assays. The WGS sequence from the nuclear families will be shared on dbGaP. ]]>
Inclusion CriteriaParticipants must have met one of the following criteria:Have been previously enrolled in the NIAID clinical protocol 13-I-1057; OR,Be family members of patients previously enrolled in the NIAID clinical protocol 13-I-1057 Exclusion CriteriaInability to provide informed consent]]>
2011: Second MonoMAC patient was seen at NIH and diagnosed with aplastic anemia. 2012: First MonoMAC patient was referred to the NIH with a hypocellular bone marrow, severe immunodeficiency and trisomy 8, and diagnosed with MonoMAC Syndrome. 2013: Blood was drawn from first patient and nuclear family and used for genetic studies. 2013: First patient received a bone marrow transplant from a matched, unrelated donor. 2014: Second patient returned to NIH with a hypocellular bone marrow, severe immunodeficiency, and trisomy 8, and was diagnosed with MonoMAC syndrome. 2014: Blood was drawn from a second patient and nuclear family and used for genetic studies. 2014: Family histories determined that the two MonoMAC patients are second cousins.2015: Blood was drawn from additional family members and used for genetic studies. 2016: Second patient received bone marrow transplant from a matched, unrelated donor.]]>