De novo mutations in CBL causing early-onset paediatric moyamoya angiopathy
De novo mutations in CBL causing early-onset paediatric moyamoya angiopathy
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DOI：
10.1136/jmedgenet-2016-104432
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发表时间：
2017-08-01
影响因子：
4
通讯作者：
Kossorotoff, Manoelle
中科院分区：
文献类型：
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作者：
Guey, Stephanie;Grangeon, Lou;Kossorotoff, Manoelle
背景烟雾病血管病（Moyamoya angiopathy，MMA）的特征是颈内动脉末端进行性狭窄和异常侧支深血管的发展。其病理生理学尚不清楚。MMA可以是该疾病的唯一表现（烟雾病）或与包括一些孟德尔疾病在内的各种病症（烟雾综合征）相关。我们的目的是使用全外显子组测序（WES）方法在没有任何明显症状提示已知孟德尔烟雾综合征的散发病例中进行研究烟雾病的遗传基础。方法对四例不相关的早发性烟雾病散发病例及其父母（三人组）进行WES。外显子组数据进行了分析显性从头，常染色体隐性和X连锁的假设。一个小组的17个额外的散发病例与早发烟雾病可用于突变复发analysis.Results，我们确定了两个生殖系从头突变CBL中的两个四个三重先证者，两个女孩提出了一个婴儿期发作的严重MMA。预测这两种突变都改变CBL蛋白的泛素连接酶活性，CBL蛋白充当RAS途径的负调节剂。这两个种系CBL突变先前已被描述与发育性努南样综合征和青少年粒单核细胞白血病（JMML）的易感性。值得注意的是，这两个突变的女孩从来没有开发JMML和RASopathy，并没有导致引起这种诊断在follow-up.Conclusions微妙的迹象，这些数据表明，CBL基因筛查应考虑在早发性烟雾病，即使在没有明显的迹象RASopathy。
Background Moyamoya angiopathy (MMA) is characterised by a progressive stenosis of the terminal part of the internal carotid arteries and the development of abnormal collateral deep vessels. Its pathophysiology is unknown. MMA can be the sole manifestation of the disease (moyamoya disease) or be associated with various conditions (moyamoya syndrome) including some Mendelian diseases. We aimed to investigate the genetic basis of moyamoya using a whole exome sequencing (WES) approach conducted in sporadic cases without any overt symptom suggestive of a known Mendelian moyamoya syndrome.Methods A WES was performed in four unrelated early-onset moyamoya sporadic cases and their parents (trios). Exome data were analysed under dominant de novo, autosomal recessive and X-linked hypotheses. A panel of 17 additional sporadic cases with early-onset moyamoya was available for mutation recurrence analysis.Results We identified two germline de novo mutations in CBL in two out of the four trio probands, two girls presenting with an infancy-onset severe MMA. Both mutations were predicted to alter the ubiquitin ligase activity of the CBL protein that acts as a negative regulator of the RAS pathway. These two germline CBL mutations have previously been described in association with a developmental Noonan-like syndrome and susceptibility to juvenile myelomonocytic leukaemia (JMML). Notably, the two mutated girls never developed JMML and presented only subtle signs of RASopathy that did not lead to evoke this diagnosis during follow-up.Conclusions These data suggest that CBL gene screening should be considered in early-onset moyamoya, even in the absence of obvious signs of RASopathy.