Gain of function variants in SAMD9 cause MIRAGE syndrome, a rare Mendelian disorder that results in myeloid dysplastic syndrome (MDS), poor immune response, restricted growth, adrenal insufficiency, ambiguous genitalia, feeding difficulties and most often significantly reduced lifespan. In this study, we describe histomorphologic and genetic changes occurring in serial bone marrow measurements in a patient with MIRAGE syndrome and untreated MDS of 9 years. Histomorphological analysis during childhood showed progressive hypocellularity with erythroid and megakaryocytic dysplasia and cytogenetic testing demonstrated monosomy 7. Serial leukemia gene panel testing performed over a seven year period revealed multiple pre-leukemic clones arising at age 7 years followed by sequential mutational events in ETV6 and RUNX1 driving acute myeloid leukemia (AML) at age 9. Comprehensive genotype-phenotype analysis with 28 previously reported patients found the presence of MDS did not impact overall survival, but in silico variant pathogenicity prediction scores for SAMD9 distinguished patients with poor prognosis. Overall, our analysis shows progression of MDS to AML can be monitored by following mutation evolution in leukemia related genes in patients with MIRAGE syndrome, and specific SAMD9 mutations likely influence disease severity and overall survival.

在SAMD9中获得功能变异会导致MIRAGE综合征，这是一种罕见的孟德尔疾病，可导致骨髓增生异常增生综合征（MDS），免疫应答差，生长受限，肾上腺功能不全，生殖器模棱两可，进食困难，并且通常会显着缩短寿命。在这项研究中，我们描述了在连续9年的MIRAGE综合征和未经治疗的MDS患者的连续骨髓测量中发生的组织形态和遗传变化。儿童期的组织形态学分析显示，进行性红细胞增多和巨核细胞发育不良的细胞减少，细胞遗传学检测证实为单核。7年中进行的串行白血病基因组检测显示，在7岁时出现了多个白血病前克隆，随后出现了连续的突变事件。ETV6和RUNX1在9岁时引发急性髓细胞性白血病（AML），对28位先前报道的患者进行了全面的基因型-表型分析，发现MDS的存在不会影响整体存活率，但SAMD9的计算机变异致病性预测评分可区分预后差的患者。总体而言，我们的分析表明，可以通过追踪MIRAGE综合征患者白血病相关基因的突变演变来监测MDS向AML的进展，特定的SAMD9突变可能会影响疾病的严重程度和总体生存率。