The complex genetic landscape of familial MDS and AML reveals pathogenic germline variants
The complex genetic landscape of familial MDS and AML reveals pathogenic germline variants
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DOI：
10.1038/s41467-020-14829-5
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发表时间：
2020-02-25
影响因子：
16.6
通讯作者：
Dokal, Inderjeet
中科院分区：
文献类型：
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作者：
Rio-Machin, Ana;Vulliamy, Tom;Dokal, Inderjeet
将家族性骨髓性恶性肿瘤作为一个单独的疾病实体纳入修订后的WHO分类，重新努力提高对这组高危人群的认识和管理。在这里，我们报告了一个队列的86个急性髓性白血病（AML）和骨髓增生异常综合征（MDS）的家庭与49窝藏生殖系变异在16个先前定义的基因座（57%）。在另外37个未鉴定的家族（43%）中的全外显子组测序使我们能够合理化65个新的候选基因座，包括罕见血液病综合征中突变的基因（ADA、GP 6、IL 17 RA、PRF 1和SEC 23 B），在既往MDS/AML或遗传性骨髓衰竭系列中报告（DNAH 9、NAPRT 1和SH 2B 3）或在新基因座（DHX 34）的变体，其似乎对遗传形式的骨髓恶性肿瘤特异。总之，我们的MDS/AML家族系列为骨髓恶性肿瘤的病因学提供了新的见解，并提供了一个框架，以优先考虑纳入常规诊断和患者管理的变体。
The inclusion of familial myeloid malignancies as a separate disease entity in the revised WHO classification has renewed efforts to improve the recognition and management of this group of at risk individuals. Here we report a cohort of 86 acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) families with 49 harboring germline variants in 16 previously defined loci (57%). Whole exome sequencing in a further 37 uncharacterized families (43%) allowed us to rationalize 65 new candidate loci, including genes mutated in rare hematological syndromes (ADA, GP6, IL17RA, PRF1 and SEC23B), reported in prior MDS/AML or inherited bone marrow failure series (DNAH9, NAPRT1 and SH2B3) or variants at novel loci (DHX34) that appear specific to inherited forms of myeloid malignancies. Altogether, our series of MDS/AML families offer novel insights into the etiology of myeloid malignancies and provide a framework to prioritize variants for inclusion into routine diagnostics and patient management.