Kusne Yael, Badar Talha, Lasho Terra, Marando Ludovica, Mangaonkar Abhishek A, Finke Christy, Foran James M, Al-Kali Aref, Palmer Jeanne, Arana Yi Cecilia, Alkhateeb Hassan B, Gangat Naseema, Viswanatha David, Litzow Mark R, Chlon Timothy, Ferrer Alejandro, Patnaik Mrinal M
Division of Hematology/Oncology, Mayo Clinic, Scottsdale, Arizona, USA.
Division of Hematology/Oncology and Bone Marrow Transplant Program, Mayo Clinic, Jacksonville, Florida, USA.
Br J Haematol. 2025 Apr;206(4):1109-1120. doi: 10.1111/bjh.20018. Epub 2025 Mar 4.
Germline variants in DDX41 (DDX41-germline predisposition syndrome [GPS]) are associated with predisposition to haematological malignancies (HM), including lymphoid and myeloid neoplasms (MN). We retrospectively analysed the clinical and molecular features of 195 patients diagnosed and treated at Mayo Clinic with DDX41-GPS. Patients with germline DDX41 pathogenic variants (42.3%) and variants of unknown significance (VUS, 57.6%) were included. The median age was 68.6 years (16.2-93.4). Ninety-two per cent were Caucasian, 64.1% were male and 30.8% had a family history of HM. There were 92 distinct germline variants among our cohort, and the most common was p.Met1? (15.9%), followed by p.Asp140Glyfs*2 (9.2%). Clinical diagnoses included asymptomatic carriers (10.2%), clonal cytopenia of undetermined significance (CCUS, 6.1%), myeloproliferative neoplasms (6.7%), myelodysplastic syndrome (40.5%), acute myeloid leukaemia (20.5%), lymphoid neoplasms (9.2%), plasma cell dyscrasias (6.1%) and solid tumours (22.5%). Patients with MN were older (median age 70 vs. 63.5 years) and more likely to be male (M:F ratio 2.3 vs. 1.0) and most patients (78.8%) with MN had a normal karyotype. The most common somatic variants involved DDX41 (34.4%), followed by TET2 (11.2%), DNMT3A (9.6%) and ASXL1 (9.2%). In summary, we have comprehensively described the spectrum of clinical phenotypes within the Mayo Clinic DDX41-GPS cohort.
DDX41基因种系变异（DDX41种系易感性综合征[GPS]）与血液系统恶性肿瘤（HM）的易感性相关，包括淋巴和髓系肿瘤（MN）。我们回顾性分析了梅奥诊所诊断和治疗的195例DDX41 - GPS患者的临床和分子特征。纳入了具有种系DDX41致病变异（42.3%）和意义未明变异（VUS，57.6%）的患者。中位年龄为68.6岁（16.2 - 93.4岁）。92%为白种人，64.1%为男性，30.8%有HM家族史。我们的队列中有92种不同的种系变异，最常见的是p.Met1?（15.9%），其次是p.Asp140Glyfs*2（9.2%）。临床诊断包括无症状携带者（10.2%）、意义未明的克隆性血细胞减少（CCUS，6.1%）、骨髓增殖性肿瘤（6.7%）、骨髓增生异常综合征（40.5%）、急性髓系白血病（20.5%）、淋巴肿瘤（9.2%）、浆细胞异常增殖症（6.1%）和实体瘤（22.5%）。MN患者年龄较大（中位年龄70岁对63.5岁），男性比例更高（男：女比例2.3对1.0），并且大多数MN患者（78.8%）核型正常。最常见的体细胞变异涉及DDX41（34.4%），其次是TET2（11.2%）、DNMT3A（9.6%）和ASXL1（9.2%）。总之，我们全面描述了梅奥诊所DDX41 - GPS队列中的临床表型谱。
