Further delineation of bone marrow failure syndrome caused by novel compound heterozygous variants of MYSM1
Further delineation of bone marrow failure syndrome caused by novel compound heterozygous variants of MYSM1
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MYSM1 新型复合杂合变体引起的骨髓衰竭综合征的进一步描述
DOI：
10.1016/j.gene.2020.144938
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发表时间：
2020-10-05
期刊：
影响因子：
3.5
通讯作者：
Wang, Jian
中科院分区：
文献类型：
--
作者：
Li, Niu;Xu, Yufei;Wang, Jian
Myb样SWB 1和MPN结构域（MYSM 1）是一种染色质结合的转录调节因子，介导组蛋白2A去泛素化，其在造血和淋巴细胞分化中起重要作用。MYSM 1中的双等位基因变体导致罕见的骨髓衰竭综合征（OMIM #618116）。迄今为止，在9名患者中仅报告了MYSM 1的3种致病性变体（E390*、R478* 和H656 R），并且所有变体都是纯合的。在这里，我们描述了一名中国女性患者，主要表现为白细胞减少症，粒细胞减少症，血小板减少症，严重贫血，外周血B细胞和自然杀伤细胞缺乏症，并被诊断为骨髓衰竭。三个全外显子组测序揭示了MYSM 1中的一种新的复合杂合变体（c.399G A，p.L133L和c.1467C > G，p.Y489*）。c.399G > A同义变体位于外显子6的3 '端，预计其影响MYSM 1 mRNA剪接。对从逆转录-聚合酶链反应获得的产物的分析显示，c.399G > A变体导致外显子6跳跃，导致提前终止密码子（c.321_399 del，p.V108Lfs*13）。cDNA测序表明，c.1467C > G变异体触发了无义介导的mRNA降解。此外，我们在人血细胞中鉴定了MYSM 1 mRNA（缺失外显子5和6）的新转录本。我们的研究结果扩大了MYSM 1的突变谱;此外，这是第一次报告的同义剪接变异体，诱导转录后跳过外显子6，导致骨髓衰竭综合征表型。
Myb-like SWIRM and MPN domains (MYSM1) is a chromatin-binding transcriptional regulator that mediates histone 2A deubiquitination, which plays a vital role in hematopoiesis and lymphocyte differentiation. Biallelic variants in MYSM1 cause a rare bone marrow failure syndrome (OMIM #618116). To date, only three pathogenic variants (E390*, R478*, and H656R) of MYSM1 have been reported in nine patients, and all variants are homozygous. Here, we describe a Chinese female patient who mainly presented with leukopenia, granulocytopenia, thrombocytopenia, severe anemia, and B-cell and natural killer cell deficiency in the peripheral blood, and was diagnosed with bone marrow failure. Trio whole-exome sequencing revealed a novel compound heterozygous variant in MYSM1 (c.399G A, p.L133L, and c.1467C > G, p.Y489*). The c.399G > A synonymous variant is located at the 3'-end of exon 6, which is predicted to affect MYSM1 mRNA splicing. Analysis of the products obtained from the reverse transcription-polymerase chain reaction revealed that the c.399G > A variant leads to exon 6 skipping, resulting in a premature termination codon (c.321_399 del, p.V108Lfs*13). cDNA sequencing suggested that the c.1467C > G variant triggered nonsense-mediated mRNA degradation. Moreover, we identified a novel transcript of MYSM1 mRNA (missing exons 5 and 6) in human blood cells. Our results expand the mutation spectrum of MYSM1; additionally, this is the first report of a synonymous splicing variant that induces post-transcriptional skipping of exon 6 leading to a bone marrow failure syndrome phenotype.