基因组学时代促进了导致骨髓衰竭（BMF）和血液恶性肿瘤（HM）的新基因的发现。我们报告发现 ERG 作为一种新型常染色体显性 BMF/HM 易感基因。 ERG 是一种高度受限的转录因子，对于确定的造血、干细胞功能和血小板维持至关重要。 ERG 与其他转录因子（包括 RUNX1 和 GATA2）共定位于协调造血的基因的启动子/增强子上。我们在一个家族的 3 名血小板减少症个体中发现了一种罕见的杂合 ERG 错义变异，并在 BMF/HM 无关个体中发现了 14 种额外的 ERG 变异，其中包括 2 例新发病例和 3 例截短变异。与致病性种系 ERG 变异相关的表型包括 40 岁之前发病的血细胞减少症（血小板减少症、中性粒细胞减少症、全血细胞减少症）和 HMs（急性髓系白血病、骨髓增生异常综合征、急性淋巴细胞白血病）。对 20 个 ERG 变体（19 个错义，1 个截短）包括 3 个错义群体变体进行了功能表征。 13 个潜在致病性 ETS 结构域错义变体表现出功能丧失特征，破坏转录反式激活、DNA 结合和/或核定位。在小鼠胎儿肝细胞中过度表达的选定变体无法驱动培养物中的骨髓分化和细胞因子独立生长，并且在移植到小鼠体内时促进急性红白血病，这与这些变体功能丧失一致。四个个体通过杂合性的拷贝中性丢失表现出体细胞遗传拯救。识别易感种系 ERG 变异对患者/家庭的诊断、咨询、监测和治疗策略（包括选择骨髓捐赠者或细胞/基因治疗）具有临床意义。版权所有 © 2024 美国血液学会。

The genomics era has facilitated discovery of new genes predisposing to bone marrow failure (BMF) and hematological malignancy (HM). We report the discovery of ERG as a novel autosomal dominant BMF/HM predisposition gene. ERG is a highly constrained transcription factor critical for definitive hematopoiesis, stem cell function and platelet maintenance. ERG colocalizes with other transcription factors including RUNX1 and GATA2 on promoters/enhancers of genes orchestrating hematopoiesis. We identified a rare heterozygous ERG missense variant in 3 thrombocytopenic individuals from one family and 14 additional ERG variants in unrelated individuals with BMF/HM including 2 de novo cases and 3 truncating variants. Phenotypes associated with pathogenic germline ERG variants included cytopenias (thrombocytopenia, neutropenia, pancytopenia) and HMs (acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia) with onset before 40 years. Twenty ERG variants (19 missense, 1 truncating) including 3 missense population variants were functionally characterized. Thirteen potentially pathogenic ETS domain missense variants displayed loss-of-function characteristics disrupting transcriptional transactivation, DNA-binding and/or nuclear localization. Selected variants overexpressed in mouse fetal liver cells failed to drive myeloid differentiation and cytokine-independent growth in culture, and to promote acute erythroleukemia when transplanted into mice, concordant with these variants being loss-of-function. Four individuals displayed somatic genetic rescue by copy neutral loss of heterozygosity. Identification of predisposing germline ERG variants has clinical implications for patient/family diagnosis, counselling, surveillance, and treatment strategies including selection of bone marrow donors or cell/gene therapy.Copyright © 2024 American Society of Hematology.