转录因子GATA2中的遗传或de novo生殖细胞系突变已被证明与MonoMAC综合征相关，这是一种由GATA2缺陷引起的疾病，其特征包括：分散性非结核分枝杆菌感染、单核细胞、自然杀伤细胞和B淋巴细胞严重缺陷，以及骨髓增生异常综合征。GATA2基因的突变在约90%的GATA2缺陷表型患者中发现，主要是保守的第二结构域的错义突变，或者是编码序列其他位置的截短突变。GATA2缺陷中也已经明确描述了在第5内含子调节增强子元素中的突变。本文介绍了一例具有GATA2缺陷临床特征的大型多代家系，但未发现明显的GATA2突变。全基因组测序发现，在GATA2基因ATG起始位点116,855bp的位置上存在一种独特的腺嘌呤-胸腺嘧啶变异体。突变在一个已有的GATA-box位置与一个新的E-box共同组成一个新的造血调节复合元件。突变位点在家系的多代人中与疾病模式相关。患者骨髓细胞中观察到GATA2表达的细胞特异性等位差异，突变位点的基因剂量较高。通过CRISPR/Cas9修饰的HL-60培养细胞和荧光素酶假定实验中观察到GATA2等位基因特异性过表达。本研究证明了MonoMAC综合征患者中一个上游调节增强子元件中的单核苷酸变化导致GATA2过表达。本研究中的患者参与了美国过敏和传染病研究所临床试验（Clinicaltrials.gov编号NCT01905826）和美国国家癌症研究所临床试验（Clinicaltrials.gov编号NCT01861106）。版权©2023年美国血液学会。

Inherited or de novo germline mutations in the transcription factor GATA2 have been shown to be responsible for MonoMAC syndrome, a GATA2 deficiency disease characterized by a constellation of findings, including: disseminated non-tuberculous mycobacterial infections, severe deficiencies of monocytes, natural killer cells, and B-lymphocytes, and myelodysplastic syndrome. Mutations in the GATA2 gene are found in ~90% of patients with a GATA2 deficiency phenotype and are largely missense mutations in the conserved second zinc-finger domain or truncation mutations elsewhere in the coding sequence. Mutations in an intron 5 regulatory enhancer element are also well described in GATA2 deficiency. Here we present a large multigeneration kindred with the clinical features of GATA2 deficiency, but lacking an apparent GATA2 mutation. Whole Genome Sequencing revealed a unique adenine-to-thymine variant in the GATA2 -110 enhancer 116,855bp upstream of the GATA2 gene ATG start site. The mutation creates a new E-box consensus in position with an existing GATA-box to generate a new hematopoietic regulatory composite element. The mutation segregates with the disease pattern in several generations of the family pedigree. Cell-type specific allelic imbalance of GATA2 expression is observed in a patient's bone marrow with higher expression from the mutant-linked allele. Allele-specific overexpression of GATA2 is observed in CRISPR/Cas9-modified HL-60 cultured cells and in luciferase assays with the enhancer mutation. This study demonstrates overexpression of GATA2 resulting from a single nucleotide change in an upstream regulatory enhancer element in patients with MonoMAC syndrome. Patients in this study were enrolled in National Institute of Allergy and Infectious Diseases clinical trial Clinicaltrials.gov identifier NCT01905826 and National Cancer Institute clinical trial Clinicaltrials.gov identifier NCT01861106.Copyright © 2023 American Society of Hematology.