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.

髓系肿瘤 (MN) 中的生殖系 DDX41变异并不少见，我们在 3132 名不相关的成年 MN 患者队列中探讨了其患病率并表征了临床和病理特征。通过靶向二代测序，我们确定了 28 名患者（20 名男性和 8 名女性）患有致病性生殖系DDX41发生急性髓性白血病 (AML) 的变体，其中只有 3 (11%) 人有 MN 家族史 (FH)。在最初诊断 AML 之前，亚急性血细胞减少临床病程（平均持续时间 11.2 个月，范围 0-72 个月）伴有低细胞骨髓（93%所有患者），与老年人中典型的增殖性 AML 亚型形成鲜明对比。大多数患者的核型正常 (75%) 并获得了第二个DDX41变体 (69%)。在年龄匹配的患者中，与野生型DDX41的常见 AML 亚型相比，观察到了良好的总生存期 (OS)。我们的研究表明，频繁的种系致病性DDX41变体表征了临床上不同的 AML 实体。DDX41突变的 AML 的特征包括男性优势、经常缺乏 FH、惰性病程、低增殖潜力、频繁的体细胞DDX41变异和有利的 OS。