Two patients with MIRAGE syndrome lacking haematological features: role of somatic second-site reversion SAMD9 mutations
Two patients with MIRAGE syndrome lacking haematological features: role of somatic second-site reversion SAMD9 mutations
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DOI：
10.1136/jmedgenet-2017-105020
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发表时间：
2018-02-01
影响因子：
4
通讯作者：
Narumi, Satoshi
中科院分区：
文献类型：
--
作者：
Shima, Hirohito;Koehler, Katrin;Narumi, Satoshi
背景骨髓增生异常、感染、生长受限、肾上腺发育不全、生殖表型和肠病（MIPH）综合征是最近描述的由杂合SAMD 9突变引起的先天性疾病。该综合征的表型谱仍有待阐明。方法和结果我们描述了两个无关的患者谁表现出符合MIL-MS综合征的表现，除了血液学特征。用下一代测序和桑格测序分析白细胞基因组DNA样品，揭示患者在同一等位基因上具有两个新SAMD 9突变（患者1 p. [Gln 695 *; Ala 722 Glu]和患者2 p. [Gln39*; Asp769Gly]）。在患者1中，从毛囊提取的基因组DNA中不存在p.Gln695 *，这意味着无义突变是体细胞获得的。在患者2中，46，XX核型，在白细胞DNA中发现偏斜的X染色体失活模式，表明造血系统中细胞的单克隆性。体外表达实验证实了两个错义突变体SAMD 9蛋白的生长限制能力，这是MIRAGE相关SAMD 9 mutations.Conclusions的一个特征的体细胞无义SAMD 9突变在造血系统的细胞中的收购可能会恢复由生殖系SAMD 9突变（即，第二位点回复突变）引起的细胞生长抑制。这两名患者意外缺乏血液学特征可以用回复突变来解释。
Background Myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes and enteropathy (MIRAGE) syndrome is a recently described congenital disorder caused by heterozygous SAMD9 mutations. The phenotypic spectrum of the syndrome remains to be elucidated.Methods and results We describe two unrelated patients who showed manifestations compatible with MIRAGE syndrome, with the exception of haematological features. Leucocyte genomic DNA samples were analysed with next-generation sequencing and Sanger sequencing, revealing the patients to have two de novoSAMD9 mutations on the same allele (patient 1 p.[Gln695*; Ala722Glu] and patient 2 p.[Gln39*; Asp769Gly]). In patient 1, p. Gln695* was absent in genomic DNA extracted from hair follicles, implying that the non-sense mutation was acquired somatically. In patient 2, with the 46, XX karyotype, skewed X chromosome inactivation pattern was found in leucocyte DNA, suggesting monoclonality of cells in the haematopoietic system. In vitro expression experiments confirmed the growthrestricting capacity of the two missense mutant SAMD9 proteins that is a characteristic of MIRAGE-associated SAMD9 mutations.Conclusions Acquisition of a somatic nonsense SAMD9 mutation in the cells of the haematopoietic system might revert the cellular growth repression caused by the germline SAMD9 mutations (ie, second-site reversion mutations). Unexpected lack of haematological features in the two patients would be explained by the reversion mutations.