Curious cases of GATA2 deficiency: clonal evolution or dual diagnoses?

Abstract

GATA2 deficiency can often predispose individuals to hematologic malignancies. While many pathogenic/likely pathogenic germline variants have been characterized in GATA2 deficiency, less is known about other variants that arise during clonal evolution of hematologic malignancies or as potential dual diagnoses in these patients. Here, we present two cases enrolled in the NIAID Centralized Sequencing Program with GATA2 variants and additional pathogenic/likely pathogenic variants in WT1 and KRAS detected via genome sequencing.The first case is a 9-year-old female with myelodysplastic syndrome with monosomy 7, pulmonary alveolar proteinosis, and sepsis. Genome sequencing in the proband detected 3 rare variants in GATA2: one pathogenic heterozygous NM_032638.5:c.202del (p.Ala68ArgfsTer12) frameshift variant, one heterozygous c.1031_1087dup (p. Arg344_Arg362dup) duplication variant of uncertain significance (VUS), and one apparently somatic mosaic c.1306_1307insTCCA p. (His436LeufsTer101) frameshift VUS. Two variants were also detected in WT1: a likely pathogenic, apparently somatic mosaic, NM_024426.6: c.1159_1163del (p.Ala387Ter) nonsense variant and a heterozygous c.887G>A (p.Ser296Asn) missense VUS. The WT1 p.Ser296Asn variant was previously published in a female affected with Wilms tumor who inherited the variant from her unaffected father, however our participant does not have a personal history of Wilms tumor.The second case is a 6-year-old male diagnosed with acute myeloid leukemia (AML). Genome sequencing detected a heterozygous GATA2 NM_032638.5(GATA2):c.575C>T (p.Ser192Phe) missense VUS that has not been previously published in individuals with GATA2 deficiency. Additionally, a pathogenic, apparently somatic mosaic, NM_004985.5: c.173C>T (p.Thr58Ile) missense variant in KRAS was detected, which has been reported in the literature as a germline variant in individuals with Noonan syndrome and cardiofaciocutaneous syndrome. The variant allele fraction of the KRAS p.Thr58Ile variant was 27%, however it is unknown if this variant could be somatic mosaic in association with the subject's AML clone, or if the subject has a genetic diagnosis of RAS-associated autoimmune lymphoproliferative syndrome (RALD). Future studies include segregation analysis in family members.These cases highlight the importance of additional variants found in patients with GATA2 variants that may be contributing to dual diagnoses or acting as secondary mutations via clonal evolution of myeloid malignancies.