髓系肿瘤，包括急性髓系白血病，传统上一直是有关种系易感性研究较少的癌症类型之一。事实上，具有种系易感性的骨髓肿瘤很难识别，因为通常表现出与散发病例相似的临床和形态学特征，并且诊断时的年龄也相似。然而，对髓系肿瘤的熟悉程度的错误识别对携带者及其亲属的临床管理具有至关重要的影响。我们进行了一项家族隔离研究，以便识别髓系肿瘤中新的癌症易感基因并对新识别的变异进行分类。使用大型定制基因组（256 个基因）Myelo-Panel 进行彻底的基因组分析，针对癌症易感基因。特别是，我们评估了四个家庭的种系和体细胞变异，每个家庭有两个兄弟姐妹，他们患有血液肿瘤：七个急性髓系白血病和一个费城阳性慢性髓系白血病。在每个家族中，我们都鉴定出至少一种新的潜在诱发变异，该变异也影响未包含在当前欧洲白血病网 AML 管理指南中的基因。此外，我们建议将两种种系变异重新分类为致病性：CEPBA 中可能致病的 p.S21Tfs*139 和 DDX41 中的 VUS p.K392Afs*66。我们认为，血液肿瘤的易感性仍然被低估，并且特别难以诊断。考虑到对骨髓肿瘤熟悉程度的错误识别对携带者及其亲属的临床管理具有至关重要的影响，我们的研究强调了在这种临床背景下修订临床实践的重要性，其中应包括彻底重建家族史和-深度基因测试。© 2024 作者。由 Wiley periodicals LLC 出版的癌症报告。

Myeloid neoplasms, including acute myeloid leukemia, have been traditionally among the less investigated cancer types concerning germline predisposition. Indeed, myeloid neoplasms with germline predisposition are challenging to identify because often display similar clinical and morphological characteristics of sporadic cases and have similar age at diagnosis. However, a misidentifications of familiarity in myeloid neoplasms have a critical impact on clinical management both for the carriers and their relatives.We conducted a family segregation study, in order to identify novel cancer predisposing genes in myeloid neoplasms and classify novel identified variants.We performed a thorough genomic analysis using a large custom gene panel (256 genes), the Myelo-Panel, targeted on cancer predisposing genes. In particular, we assessed both germline and somatic variants in four families, each with two siblings, who developed hematological neoplasms: seven acute myeloid leukemia and one Philadelphia-positive chronic myeloid leukemia. In each family, we identified at least one novel potentially predisposing variant, affecting also genes not included in the current European LeukemiaNet guidelines for AML management. Moreover, we suggest reclassification of two germline variants as pathogenic: likely pathogenic p.S21Tfs*139 in CEPBA and VUS p.K392Afs*66 in DDX41.We believe that predisposition to hematological neoplasms is still underestimated and particularly difficult to diagnosed. Considering that misidentification of familiarity in myeloid neoplasms have a critical impact on the clinical management both for the carriers and their relatives, our study highlights the importance of revision, in this clinical context, of clinical practices that should include thorough reconstruction of family history and in-depth genetic testing.© 2024 The Author(s). Cancer Reports published by Wiley Periodicals LLC.