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Updated: Aug 4, 2026
Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
AML with germline DDX41 variants is a clinicopathologically distinct entity with an indolent clinical course and
Peng Li1,2, Thomas White3, Wei Xie4
1Division of Hematopathology, Department of Pathology, University of Utah Health, Salt Lake City, UT, USA. pengl.li@aruplab.com.
Abstract:
Germline DDX41 variants in myeloid neoplasms (MNs) are not uncommon, and we explored the prevalence and characterized the clinical and pathologic features in a cohort of 3132 unrelated adult MN patients. By targeted next-generation sequencing, we identified 28 patients (20 men and 8 women) with pathogenic germline DDX41 variants who developed acute myeloid leukemia (AML), in which only 3 (11%) had a family history (FH) of MNs. A subacute clinical course of cytopenia (mean duration of 11.2 months, range 0-72 months) prior to the initial AML diagnosis was accompanied by a low blast count (median at 30%, range 20-70%) in hypocellular marrows (93% of all patients), in vast contrast to the typical proliferative subtypes of AML in the elderly. Most patients had a normal karyotype (75%) and acquired a second DDX41 variant (69%). A favorable overall survival (OS) was observed in comparison to that of common subtypes of AML with wild-type DDX41 in age-matched patients. Our study demonstrated that the frequent germline pathogenic DDX41 variants characterized a clinically distinct AML entity. Features characteristic of DDX41-mutated AML include male predominance, often lack of FH, indolent course, low proliferative potential, frequent somatic DDX41 variants, and a favorable OS.
Insights
Germline DDX41 variants are common in myeloid neoplasms, defining a distinct acute myeloid leukemia (AML) entity. This AML subtype, characterized by specific clinical and genetic features, shows a favorable overall survival.
Area of Science:
- Hematology
- Oncology
- Genetics
Background:
- Germline DDX41 variants are increasingly recognized in myeloid neoplasms (MNs).
- Understanding their clinical and pathological impact is crucial for accurate diagnosis and treatment.
Purpose of the Study:
- To determine the prevalence of germline DDX41 variants in adult MN patients.
- To characterize the clinical, pathological, and survival features of MNs with germline DDX41 variants.
Main Methods:
- Targeted next-generation sequencing was used to identify germline DDX41 variants in 3132 adult MN patients.
- Clinical and pathological data, including family history, cytopenias, blast counts, marrow cellularity, karyotype, and acquisition of somatic variants, were analyzed.
- Overall survival was compared to age-matched AML patients with wild-type DDX41.
Main Results:
- Pathogenic germline DDX41 variants were identified in 28 (0.9%) of 3132 MN patients, predominantly in men (20/28).
- These patients often presented with a subacute course of cytopenia, low blast counts in hypocellular marrows, and normal karyotypes.
- A high rate of acquired secondary DDX41 variants (69%) was observed, and patients exhibited a favorable overall survival compared to common AML subtypes.
Conclusions:
- Germline pathogenic DDX41 variants define a clinically distinct entity of acute myeloid leukemia.
- Key features include male predominance, infrequent family history, indolent clinical course, low proliferative potential, frequent secondary DDX41 mutations, and favorable prognosis.
