GATA2 – Monocytopenia with Susceptibility to Infections

GATA2 encodes a zinc‐finger transcription factor essential for the survival and self‐renewal of hematopoietic stem and progenitor cells. Heterozygous germline mutations in GATA2 cause autosomal dominant monocytopenia with susceptibility to infections (MonoMAC syndrome), characterized by profound monocyte, B‐cell and NK‐cell deficiency, recurrent nontuberculous mycobacterial and viral infections, cytopenias, and high risk of myelodysplastic syndrome or acute myeloid leukemia (PMID:24227816).

Numerous case reports and series have described over 500 individuals with GATA2 deficiency across more than 50 kindreds, supporting a Definitive gene–disease association. This classification is justified by frequent de novo and familial loss‐of‐function variants, multi‐generation segregation, and concordant functional data demonstrating haploinsufficiency (PMID:24227816).

Inheritance is autosomal dominant. The variant spectrum includes missense mutations in the second zinc finger (e.g., c.1061C>T (p.Thr354Met)), frameshifts (e.g., c.989_992dup (p.Leu332fs)), splice‐site changes (e.g., c.1017+2T>G), and large deletions (e.g., c.-45-155_871+527del). The recurrent c.1061C>T (p.Thr354Met) variant has been reported in multiple unrelated families with MonoMAC and myelodysplasia (PMID:22147895).

Segregation analysis in large multigenerational pedigrees demonstrated at least 19 affected relatives carrying pathogenic GATA2 alleles, with complete penetrance for immunodeficiency features by early adulthood (PMID:22147895).

Functional studies reveal that GATA2 mutations cause haploinsufficiency. Intronic point mutations within a conserved enhancer markedly reduce GATA2 transcriptional activity, leading to DCML deficiency (PMID:23502222). Induced pluripotent stem cell models from patients show impaired hemogenic endothelial differentiation and failure to generate mature hematopoietic progenitors.

In vivo, Gata2 haploinsufficient mice exhibit defects in lymphatic valve development, bone marrow hypocellularity, and myeloid bias, recapitulating key human phenotypes. Rescue experiments restoring GATA2 expression normalize hematopoietic and lymphatic defects, supporting a Strong functional evidence tier (PMID:30301799).

GATA2 deficiency exemplifies the impact of heterozygous loss‐of‐function on immune and hematopoietic homeostasis. Early genetic diagnosis enables timely surveillance for infections and preemptive hematopoietic stem cell transplantation. Key take‐home: Autosomal dominant GATA2 haploinsufficiency is a Definitive cause of monocytopenia with susceptibility to infections, with robust genetic and experimental evidence supporting clinical utility for diagnosis and management.

References

• Blood • 2012 • Loss-of-function germline GATA2 mutations in patients with MDS/AML or MonoMAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature. PMID:22147895
• Blood • 2014 • GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity. PMID:24227816
• Blood • 2013 • GATA2 haploinsufficiency caused by mutations in a conserved intronic element leads to MonoMAC syndrome. PMID:23502222
• Proceedings of the National Academy of Sciences • 2018 • Human leukemia mutations corrupt but do not abrogate GATA-2 function. PMID:30301799

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