Germ-line GATA2 p.THR354MET mutation in familial myelodysplastic syndrome with acquired monosomy 7 and ASXL1 mutation demonstrating rapid onset and poor survival

Abstract

While most myelodysplastic syndrome/acute myeloid leukemia cases are sporadic, rare familial cases occur and provide some insight into leukemogenesis. The most clearly defined familial cases result from inherited mutations in RUNX1 or CEBPA. Recently, novel germline mutations in GATA2 have been reported. We, therefore, investigated individuals from families with one or more first-degree relatives with myelodysplastic syndrome/acute myeloid leukemia with wild-type RUNX1 and CEBPA, for GATA2 mutations. Screening for other recurrent mutations was also performed. A GATA2 p.Thr354Met mutation was observed in a pedigree in which 2 first-degree cousins developed high-risk myelodys-plastic syndrome with monosomy 7. They were also observed to have acquired identical somatic ASXL1 mutations and both died despite stem cell transplantation. These findings confirm that germline GATA2 mutations predispose to familial myelodysplastic syndrome/acute myeloid leukemia, and that monosomy 7 and ASXL1 mutations may be recurrent secondary genetic abnormalities triggering overt malignancy in these families.

Figure 1.

Genogram for the GATA2-mutated pedigree. The squares denote males and circles denote females. The black boxes indicate individuals with MDS/AML. GATA2 mutations were detected in the MDS/AML sample for IV-1 and IV-6 but DNA was not available for the other affected individuals (I-2, II-2, II-3). The gray boxes indicate individuals with detectable GATA2 mutations without myeloid malignancy (III-5, III-7 and IV-10). The hatched box indicates an obligate carrier for whom DNA was not available to confirm GATA2 mutation. IV-7, IV-8 and IV-9 were tested and showed wild-type (wt) GATA2. No DNA was available from other family members.

Figure 2.

(A) The heterozygous germline GATA2 p.T354M (c.1061C>T) mutation resulting in conversion of a conserved threonine to methio-nine and (B) the somatic ASXL1 p.Gly646TrpfsX12 (c.1934dupG) frameshift mutation detected in 2 first-degree cousins.