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. 2021 Nov;42(11):1399-1421.
doi: 10.1002/humu.24271. Epub 2021 Aug 31.

GATA2 deficiency syndrome: A decade of discovery

Claire C Homan  1   2 , Parvathy Venugopal  1   2 , Peer Arts  1   2 , Nur H Shahrin  1   2 , Simone Feurstein  3 , Lesley Rawlings  1 , David M Lawrence  4 , James Andrews  4 , Sarah L King-Smith  1   2   5 , Natasha L Harvey  2 , Anna L Brown  1   2   6   7 , Hamish S Scott  1   2   4   5   6   7 , Christopher N Hahn  1   2   6   7
Affiliations

GATA2 deficiency syndrome: A decade of discovery

Claire C Homan et al. Hum Mutat. 2021 Nov.

Abstract

GATA2 deficiency syndrome (G2DS) is a rare autosomal dominant genetic disease predisposing to a range of symptoms, of which myeloid malignancy and immunodeficiency including recurrent infections are most common. In the last decade since it was first reported, there have been over 480 individuals identified carrying a pathogenic or likely pathogenic germline GATA2 variant with symptoms of G2DS, with 240 of these confirmed to be familial and 24 de novo. For those that develop myeloid malignancy (75% of all carriers with G2DS disease symptoms), the median age of onset is 17 years (range 0-78 years) and myelodysplastic syndrome is the first diagnosis in 75% of these cases with acute myeloid leukemia in a further 9%. All variant types appear to predispose to myeloid malignancy and immunodeficiency. Apart from lymphedema in which haploinsufficiency seems necessary, the mutational requirements of the other less common G2DS phenotypes is still unclear. These predominantly loss-of-function variants impact GATA2 expression and function in numerous ways including perturbations to DNA binding, protein structure, protein:protein interactions, and gene transcription, splicing, and expression. In this review, we provide the first expert-curated ACMG/AMP classification with codes of published variants compatible for use in clinical or diagnostic settings.

Keywords: GATA2 deficiency syndrome; germline variants; immunodeficiency; lymphedema; myeloid malignancy; predisposition.

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Conflict of interest statement

The authors declare that there are no conflict of interests.

Figures

Figure 1
Figure 1
Germline GATA2 variants. All ascertained germline GATA2 variants are visualized using the ProteinPaint web application (https://pecan.stjude.cloud/home) (Zhou et al., 2016). Variants (displayed as protein changes where possible) are color‐coded according to mutation effect. The number of probands for each variant is indicated within the circle where the number is greater than one. All variants are annotated to NM_032638.5
Figure 2
Figure 2
Prevalence of GATA2 variant type and associated G2DS phenotypes. (a) Number and type of unique GATA2 variants. (b) Total number and variant type of GATA2 individuals. (c) Percentage of individuals with each GATA2 variant type associated with each phenotype. (d) Percentage of individuals with each GATA2 variant type with associated hematological malignancies. Loss‐of‐function (LOF), frameshift (FS), nonsense (NS), missense (MS), splice site (SPL), large deletion (DEL), small insertion/deletion (INDEL), regulatory (REG), all variants combined (total). Overall phenotypes: L, lymphedema; M/A, MDS and/or AML; ID, immunodeficiency; malignancy types: myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), myeloproliferative neoplasm (MPN). B‐ or T‐cell acute lymphoblastic leukemia (ALL), acute leukemia (AL).
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