GATA2-Related Disorders and Predisposition to Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) via the GATA2 Gene

Germline variants in the GATA2 gene are associated with several different disorders characterized by lymphedema, neutropenia and other immunodeficiencies, and predisposition to hematopoietic malignancies including myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CML), and acute myeloid leukemia (AML) (Drazer et al. 2018. PubMed ID: 29365323). MDS and AML are most often sporadic, late-onset malignancies, but recent data indicate that hereditary MDS/AML may have a higher incidence than was thought previously and may have a younger age of onset than sporadic cases. MDS/AML are associated with several primary bone marrow failure disorders including Diamond-Blackfan anemia, Fanconi anemia, severe congenital neutropenia, Shwachman-Diamond syndrome, and dyskeratosis congenita (Owen et al. 2008. PubMed ID: 18173751; Auerbach 2009. PubMed ID: 19622403). Several additional MDS/AML predisposition syndromes have also been recognized including syndromes associated with variants in GATA2 such as primary lymphedema and Emberger syndrome (Ostergaard et al. 2011. PubMed ID: 21892158), monocytopenia and mycobacterial infection syndrome (aka MonoMAC) (Hsu et al. 2011. PubMed ID: 21670465), and combined immunodeficiencies such as dendritic cell, monocyte, B and NK lymphoid deficiency (aka DCML) (Dickinson et al. 2011. PubMed ID: 21765025). GATA2 variants have also been reported in patients with familial MDS/AML with no accessory phenotype (Pasquet et al. 2013. PubMed ID: 23223431; Hahn et al. 2011. PubMed ID: 21892162). Germline variants in GATA2 are the most frequent variants reported in pediatric patients with hereditary MDS (Hahn et al. 2011. PubMed ID: 21892162). A variety of chromosomal rearrangements, in particular monosomy 7, have also been found in cancer cells from patients with GATA2-associated MDS/AML (Wlodarski et al. 2016. PubMed ID: 26702063; Hahn et al. 2011. PubMed ID: 21892162).

GATA2-related disorders are inherited in an autosomal dominant manner. GATA2 encodes a zinc-finger transcription factor that plays a major role in hematopoiesis (Rodrigues et al. 2005. PubMed ID: 15811962) and vascular, urogenital, and neural development (Kazenwadel et al. 2012. PubMed ID: 22147895; Zhou et al. 1998. PubMed ID: 9822612; Kala et al. 2009. PubMed ID: 19088086). Missense, nonsense, splicing variants, and small or large deletions are associated with all of the GATA2-related phenotypes. These variants are all thought to result in haploinsufficiency (Ostergaard et al. 2011. PubMed ID: 21892158; Hahn et al. 2011. PubMed ID: 21892162). Reported pathogenic variants show variable penetrance and are located throughout the GATA2 gene and include several variants within a regulatory region in intron 5 (Wlodarski et al. 2016. PubMed ID: 26702063; Hahn et al. 2011. PubMed ID: 21892162; Hsu et al. 2013. PubMed ID: 23502222).

In one study of familial myelodysplastic syndromes and acute myeloid leukemia (MDS/AML), 4 out of 10 families were found to harbor GATA2 gene variants suggesting that variants in GATA2 are a frequent cause of hereditary MDS/AML (Holme et al. 2012. PubMed ID: 22533337). Germline variants in GATA2 are also the most frequent variants reported in pediatric patients with hereditary MDS, in particular patients with monosomy 7 (Wlodarski et al. 2016. PubMed ID: 26702063; Hahn et al. 2011. PubMed ID: 21892162). In one report, 72% of adolescents with MDS and monosomy 7 were found to have a GATA2 deficiency (Wlodarski et al. 2016. PubMed ID: 26702063).

This test provides full coverage of all coding exons of the GATA2 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

This test also includes targeted testing of an enhancer region in intron 5 where pathogenic variants have been reported (Hsu et al. 2013. PubMed ID: 23502222).