Submission Details

GATA2 was first reported in relation to autosomal dominant GATA2-deficiency with susceptibility to myelodysplastic syndrome/acute myelogenous leukemia (MDS/AML) in 2011. This occurred over several publications, referring to the condition as Emberger Syndrome, when presenting with primary lymphedema (Ostergaard et al., 2011 PMID 21892158), familial MDS (Hahn et al., 2011 PMID 21895162), DCML deficiency (Dickinson et al., 2011 PMID: 21765025, 21810969), and MonoMac (Hsu et al., 2011 PMID 21670465). In addition, Warts, Immunodeficiency, Lymphedema, and anogenital Dysplasia (WILD) syndrome (PMID: 28373026) is another clinical entity described in the literature that falls under the umbrella of GATA2 deficiency with susceptibility to MDS/AML. Due to the deficiency of several white blood cell subsets (B cells, NK cells, dendritic cells, monocytes, CD4+ T cells) (PMID: 30047422, 23365458) and susceptibility to viral, bacterial and fungal infections (PMID: 25397911), as well as the presence of dysplastic megakaryocytes in the bone marrow (PMID: 30047422) and other phenotypes such as pulmonary alveolar proteinosis (PMID: 34089740), the GATA2 gene, and associated haploinsufficiency is considered an inborn error of immunity (Tangye S et al., 2020 PMID 31953710). At least 40 variants (including missense, nonsense, frameshift, and large deletions) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 19 probands in 7 publications (PMIDs: 21892158, 21895162, 21670465, 22147895, 23223431, 23502222, 25624456). Variants in this gene segregated with disease in 46 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is haploinsufficiency (Hsu et al., 2013 PMID 23502222). This gene-disease association is supported by its biochemical function as part of the transcriptional program for blood (Gottgens et al., 2002 PMID 12065417), expression in hematopoietic cells (Kazenwadel et al., 2012 PMID 22147895), functional alteration in both patient and non-patient cells leading to altered gene expression (PMIDs: 21892162, 23502222, 25624456), and two mouse model organisms with limited utility due to lethality (PMIDs: 8078582, 22996665). In summary GATA2 is definitively associated with autosomal dominant GATA2-deficiency with susceptibility to MDS/AML. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanisms, inheritance pattern, or phenotypic variability underlying the these many disease entities: Emberger Syndrome (MIM 614038), Immunodeficiency 21 (MIM 614172), susceptibility to acute myeloid leukemia (MIM 601626) and susceptibility to Myelodysplastic syndrome (MIM 614286). Today it is well accepted that all these clinical manifestations belong to the broad spectrum of a single genetic disease; the term GATA2 deficiency or haploinsufficiency has been widely accepted to describe GATA2-related disorders (Wlodarski et al., 2017 PMID 28637621). Therefore, all of the disease entities have been lumped into one disease entity, dominant GATA2-deficiency with susceptibility to MDS/AML.