The array of clinical phenotypes of males with mutations in Methyl-CpG binding protein 2
The array of clinical phenotypes of males with mutations in Methyl-CpG binding protein 2
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DOI：
10.1002/ajmg.b.32707
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发表时间：
2019-01-01
影响因子：
2.8
通讯作者：
Percy, Alan K.
中科院分区：
文献类型：
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作者：
Neul, Jeffrey L.;Benke, Timothy A.;Percy, Alan K.
X连锁基因MECP2的突变与一种严重的神经发育障碍Rett综合征(RTT)有关，主要发生在女孩身上。曾有人怀疑甲基CpG结合蛋白2(MECP2)的突变会导致男性胚胎死亡，但已有报道称这种男性。为了加强对这些个体存在的表型谱的理解，我们在RTT自然历史研究数据库中确定了30名患有MECP2突变的男性。观察到了广泛的表型谱，从严重的新生儿脑病到认知障碍。两名在MECP2中有体细胞突变的男性患有典型的RTT。在剩余的28名受试者中，16人患有RTT引起的MECP2突变，9人携带女性RTT患者中未见但可能致病的突变，3人携带未知变异。两名携带RTT基因突变的受试者先前被诊断为非典型RTT；然而，仔细回顾临床病史发现，另有12/28名受试者符合非典型RTT的标准，但临床表现和病程比女性RTT更严重，RTT特征不那么明显，导致指定了一种新的诊断实体-男性RTT脑病。在有神经发育问题的男孩中，提高对临床谱系的认识和广泛的全面基因组测试将导致更好的识别。
Mutations in the X-linked gene MECP2 are associated with a severe neurodevelopmental disorder, Rett syndrome (RTT), primarily in girls. It had been suspected that mutations in Methyl-CpG-binding protein 2 (MECP2) led to embryonic lethality in males, however such males have been reported. To enhance understanding of the phenotypic spectrum present in these individuals, we identified 30 males with MECP2 mutations in the RTT Natural History Study databases. A wide phenotypic spectrum was observed, ranging from severe neonatal encephalopathy to cognitive impairment. Two males with a somatic mutation in MECP2 had classic RTT. Of the remaining 28 subjects, 16 had RTT-causing MECP2 mutations, 9 with mutations that are not seen in females with RTT but are likely pathogenic, and 3 with uncertain variants. Two subjects with RTT-causing mutations were previously diagnosed as having atypical RTT; however, careful review of the clinical history determined that an additional 12/28 subjects met criteria for atypical RTT, but with more severe clinical presentation and course, and less distinctive RTT features, than females with RTT, leading to the designation of a new diagnostic entity, male RTT encephalopathy. Increased awareness of the clinical spectrum and widespread comprehensive genomic testing in boys with neurodevelopmental problems will lead to improved identification.