Rentas Stefan, Pillai Vinodh, Wertheim Gerald B, Akgumus Gozde T, Nichols Kim E, Deardorff Matthew A, Conlin Laura K, Li Marilyn M, Olson Timothy S, Luo Minjie
Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Abramson Research Center, Room 716D, 3615 Civic Center Blvd., Philadelphia, PA 19104, United States.
Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Abramson Research Center, Room 716D, 3615 Civic Center Blvd., Philadelphia, PA 19104, United States; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States.
Cancer Genet. 2020 Jul;245:42-48. doi: 10.1016/j.cancergen.2020.06.002. Epub 2020 Jun 14.
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.
SAMD9功能获得性变异导致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综合征（MDS）、免疫反应差、生长受限、肾上腺功能不全、生殖器模糊、喂养困难，且通常会显著缩短寿命。在本研究中，我们描述了一名患有MIRAGE综合征且未经治疗的9年MDS患者连续骨髓检测中发生的组织形态学和基因变化。儿童期的组织形态学分析显示细胞减少逐渐加重，伴有红系和巨核系发育异常，细胞遗传学检测显示7号染色体单体。在七年期间进行的系列白血病基因panel检测显示，7岁时出现多个白血病前期克隆，随后在9岁时ETV6和RUNX1发生连续突变事件，导致急性髓系白血病（AML）。对28名先前报道的患者进行的综合基因型-表型分析发现，MDS的存在并不影响总生存期，但SAMD9的计算机变异致病性预测评分可区分预后不良的患者。总体而言，我们的分析表明，通过跟踪MIRAGE综合征患者白血病相关基因的突变演变，可以监测MDS向AML的进展，特定的SAMD9突变可能影响疾病严重程度和总生存期。
