Germline predisposition syndromes (GPS) result from constitutional aberrations in tumor suppressive and homeostatic genes, increasing risk for neoplasia in affected kindred. In this study, we present clinical and genomic data on 144 Mayo Clinic patients with GPS; 59 evaluated prospectively using an algorithm-based diagnostic approach in the setting of a dedicated GPS/ inherited bone marrow failure syndrome (IBMFS) clinic. Seventy-two (50%) patients had IBMFS (telomere biology disorders-32,Fanconi anemia-18, Diamond Blackfan Anemia – 11, congenital neutropenia–5, Schwachman-Diamond Syndrome-5 and Bloom Syndrome-1), 27 (19%) had GPS with antecedent thrombocytopenia (RUNX1-FPD-15, ANKRD26-6, ETV6-2, GATA1-1, MPL-3), 28 (19%) had GPS without antecedent thrombocytopenia (GATA2 haploinsufficiency-16, DDX41-10, CBL-1 and CEBPA-1) and 17 (12%) had general cancer predisposition syndromes (ataxia telangiectasia-7, heterozygous ATM variants-3, CHEK2-2, TP53-2, CDK2NA-1, NF1-1 and Nijmegen Breakage Syndrome-1). Homozygous and heterozygous ATM pathogenic variants were exclusively associated with lymphoproliferative disorders (LPD), while DDX41 GPS was associated with LPD and myeloid neoplasms. The use of somatic NGS-testing identified clonal evolution in GPS patients, with ASXL1, RAS pathway genes, SRSF2 and TET2 being most frequently mutated. Fifty-two (91%) of 59 prospectively identified GPS patients had a change in their management approach, including additional GPS-related screening in 42 (71%), referral for allogenic HSCT workup and screening of related donors in 16 (27%), medication initiation and selection of specific conditioning regimens in 14 (24%), and genetic counseling with specific intent of fertility preservation and preconceptual counseling in 10 (17%) patients; highlighting the importance of dedicated GPS screening, detection and management programs for patients with hematological neoplasms.

中文翻译：

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144 名 Mayo Clinic 生殖系易感综合征患者的血液系统恶性肿瘤谱、克隆进化和结果

生殖系易感综合征 (GPS) 是由肿瘤抑制基因和稳态基因的体质异常引起的，增加了受影响亲属的瘤形成风险。在这项研究中，我们展示了 144 名梅奥诊所 GPS 患者的临床和基因组数据；59 在专门的 GPS/遗传性骨髓衰竭综合征 (IBMFS) 诊所中使用基于算法的诊断方法进行前瞻性评估。72 名 (50%) 患者患有 IBMFS（端粒生物学障碍 - 32、范可尼贫血 - 18、戴蒙德·布莱克范贫血 - 11、先天性中性粒细胞减少症 - 5、施瓦克曼 - 戴蒙德综合症 - 5 和布卢姆综合症 - 1），27 (19%) ) 有 GPS 伴先行血小板减少症 ( RUNX1 -FPD-15, ANKRD26 -6, ETV6 -2, GATA1 -1, MPL-3），28（19％）有无GPS先行血小板减少症（GATA2单倍剂量不足-16，DDX41 -10，CBL -1和CEBPA -1），17（12％）有一般癌症的倾向综合征（毛细血管扩张性共济失调-7，杂ATM变体-3、CHEK2 -2、TP53 -2、CDK2NA -1、NF1 -1 和 Nijmegen Breakage Syndrome-1)。纯合子和杂合子ATM致病变异仅与淋巴组织增生性疾病 (LPD) 相关，而DDX41GPS 与 LPD 和髓系肿瘤有关。使用体细胞 NGS 测试确定了 GPS 患者的克隆进化，具有ASXL1、RAS 通路基因、SRSF2和TET2最常发生变异。59 名前瞻性确定的 GPS 患者中有 52 名 (91%) 改变了他们的管理方法，包括 42 名 (71%) 的额外 GPS 相关筛查、16 名 (27%) 转诊进行同种异体造血干细胞移植和相关供体筛查, 14 名 (24%) 的药物启动和特定调理方案的选择，以及 10 名 (17%) 患者的具有生育保护和孕前咨询的特定意图的遗传咨询；强调专门针对血液肿瘤患者的 GPS 筛查、检测和管理计划的重要性。