2022 年 WHO 分类和国际共识分类都强调了种系 (GL) 易感性与骨髓增生异常综合征 (MDS) 的相关性，但其发病率可能被低估，尤其是在年轻成年患者中。我们选择了一组由 31 名连续的新发 MDS 患者组成的队列，这些患者年龄异常年轻（<60 岁）。我们对从非侵入性来源（外周血和唾液）提取的 DNA 进行了外显子组测序 (ES)，筛选出一组 344 个基因，专门用于检测与克隆和非克隆血细胞减少症相关的 GL 变异。我们分别在 7/31 (22.6%) 和 9/31 (29.0%) 的病例中观察到至少一种高置信度或低置信度 GL MDS 变异。 31 名患者中有 4 名 (12.9%) 确认患有 MDS/AML 诱发性疾病。我们在 9/31 (29.0%) 病例中发现了涉及 DNA 修复/癌症易感性的基因（ATM、ATR、FANCM、PARN、BRCA1、BRCA2、CHEK2、MSH2）的杂合变异，以及影响核糖体生物合成 (SBDS)、造血干细胞的变异单个病例中细胞（GATA2）和巨核细胞（ANKRD26）的分化。两个病例存在 RBBP6 变异，该基因先前仅在家族性骨髓增生性肿瘤中被描述。最后，有 4 例病例存在与遗传性贫血相关的基因变异（CUBN 和 PIEZO1 基因）。我们的结果显示，40-60岁的“年轻”MDS患者携带报告和未报告的GL变异体的比例出乎意料地高，并且这些事件与骨髓肿瘤中复发的体细胞突变同时发生。我们采用实用且可扩展的诊断工具探索了年轻成人 MDS 病例的“无人区”，该工具能够检测 GL 变异，避免侵入性方法。© 2024 作者。约翰·威利 (John Wiley) 出版的 HemaSphere

Relevance of germline (GL) predisposition in myelodysplastic syndromes (MDSs) was stressed in both 2022 WHO and International Consensus classifications, but its incidence is probably underestimated, especially in young adult patients. We selected a cohort of 31 consecutive de novo MDS patients with unusual young age (<60 years). We performed exome sequencing (ES) on DNA extracted from noninvasive sources (peripheral blood and saliva), filtering for a panel of 344 genes specifically tailored for detecting GL variants related to clonal and nonclonal cytopenia. We observed at least one high- or low-confidence GL MDS variant in 7/31 (22.6%) and 9/31 (29.0%) of cases, respectively. Four of 31 patients (12.9%) confirmed having established MDS/AML predisposing disorders. We found heterozygous variants in genes involved in DNA repair/cancer predisposition (ATM, ATR, FANCM, PARN, BRCA1, BRCA2, CHEK2, MSH2) in 9/31 (29.0%) cases and variants affecting ribosome biogenesis (SBDS), hematopoietic stem cell (GATA2), and megakaryocyte (ANKRD26) differentiation in single cases. Two cases had variants in RBBP6, a gene previously described exclusively in familial myeloproliferative neoplasms. Lastly, four cases had variants in genes related to inherited anemias (CUBN and PIEZO1 genes). Our results showed that "young" MDS patients aged 40-60 years carried reported and unreported GL variants with an unexpectedly high proportion, and these events co-occurred with somatic mutations recurrent in myeloid neoplasms. We explored the "no man's land" of the young adult MDS cases adopting a practical and scalable diagnostic tool, capable to detect GL variants avoiding invasive methods.© 2024 The Author(s). HemaSphere published by John Wiley & Sons Ltd on behalf of European Hematology Association.