In the latest revision of WHO classification (2017) the new category `myeloid neoplasms with germline predisposition´ was introduced. Pathogenic germline (GL) mutations predisposing to hereditary hematological malignancies (HHMs) have been described in various genes and have largely been identified in families, but may also occur sporadically (Godley, Blood Adv 2019; Rio-Machin et al., Nat Commun 2020). It is estimated that 4-9% of adults with myeloid malignancies have GL predisposition and it is discussed that HHMs could even be more common (Sung and Babushok, Blood 2020). Here, we performed a screening for putative GL variants in the predisposition genes DDX41, ETV6 and GATA2 in a large cohort of 1,228 patients with sporadic AML or MDS.


To determine the frequency of genetic variants in the predisposition genes DDX41, ETV6 and GATA2 in patients with AML or MDS and to characterize the mutational patterns in patients carrying putative GL variants in these genes.

Patients and Methods:

Between 02/2019 and 01/2020 a total of 1,228 patients were diagnosed with AML or MDS by cytomorphological analysis (475 de novo AML, 647 MDS, 60 s-AML from MDS, 46 MDS/AML; M: 753, F: 475; median age: 74 [20-96]) and analyzed by next-generation sequencing for DDX41, ETV6, GATA2 and additional genes associated with AML or MDS (Figure 1). DNA was isolated from bone marrow or peripheral blood; sequencing was performed on NovaSeq after NextFlex library preparation (Illumina, ILMN, San Diego, CA) and hybrid capture according to manufacturer's protocol (IDT Inc. Coralville, IA). Data was analyzed with Pisces and Pindel (for FLT3-ITD) (available via BaseSpace, ILMN) using a minimum of 3% sensitivity. All changes except for synonymous mutations and known polymorphisms were declared as genetic variants.


We identified 73/1,228 patients (5.9%) with genetic variants in DDX41, 28 (2.3%) with variants in ETV6 and 50 (4.1%) with variants in GATA2. Aiming to estimate the proportion of patients carrying a putative GL variant, a variant allele frequency (VAF) higher than 0.3 was considered to be presumptive of a GL origin. We identified 64/1,228 patients (5.2%) with a putative GL variant in DDX41. 37/64 patients harbored DDX41 variants that were previously described as causal GL variants, like for example p.M1I (12/37) or p.D140fs (4/37), and consistent with other studies 43/64 (67.2%) had an additional DDX41 mutation with a lower VAF (<0.3) suggesting somatic acquisition of the second mutation (27/43: p.R525H) (Sébert et al., Blood 2019). 13/1,228 patients (1.1%) were found to have a putative GL variant in ETV6. Two of them carried a p.R353Q mutation which was recently presumed to be a rare GL variant contributing to myeloid malignancy susceptibility (Li et al., Leukemia 2020). 26/1,228 patients (2.1%) carried a putative GL variant in GATA2, including the already in the context of HHMs described mutation p.P41A (3/26) (Holme et al., Br J Haematol 2012).

In total, 102/1,228 patients (8.3%) diagnosed with AML or MDS carried a putative GL variant in one of the predisposition genes DDX41, ETV6 or GATA2. Patients with presumed GL variants were about the same age as patients without (mean: 72 vs. 71 years). The mutational patterns for the 102 patients are illustrated in Figure 1. Genes that were most often additionally mutated were ASXL1, DNMT3A, SRSF2 and TET2. For ETV6 and GATA2, all but one of the patients carrying a putative GL variant harbored at least one genetic variant in an additional gene. In contrast, 16/64 patients (25.0%) carrying a presumed GL variant in DDX41 (and in 12 cases a second somatic DDX41 mutation) had no further genetic variants in other well-known AML- or MDS-related genes indicating that DDX41 and especially the gain of a second somatic mutation drives leukemogenesis, while for ETV6 and GATA2 additional hits are required.


Our data support the hypothesis that GL mutations in predisposition genes could be more common in sporadic cases of AML or MDS than anticipated highlighting the importance of systematic testing for these variants, irrespective of family history or age. Identifying GL mutations can be important for clinical management, including donor choice for allogeneic stem cell transplantation. Routine workflows should be adapted to improve the identification of variants in predisposition-associated genes and to facilitate confirmation of GL origin, e.g. by analyzing reference material.


No relevant conflicts of interest to declare.

Author notes


Asterisk with author names denotes non-ASH members.