BACKGROUND To date, at least 746 genes have been identified to cause intellectual disability (ID). Among them, mutations in the Methyl CpG binding protein 2 (MECP2) gene are the leading cause of Rett syndrome and associated ID. METHODS Considering the large number of ID-associated genes, we applied trio-based whole-exome sequencing (trio-WES) and in silico analysis for genetic diagnosis of 294 children with ID. RESULTS Three de novo heterozygous mutations [NM_004992.3: c.502C > T, p.(Arg168*), c.916C > T, p.(Arg306Cys), and c.879C > G, p.(Ile293Met)] in MECP2 were identified in three unrelated girls. The first two mutations were detected in two patients who were diagnosed as typical Rett syndrome, X-linked ID and psychomotor retardation. The third mutation (c.879C > G), a previously unreported, was found in a 6-year-old girl with ID, microcephaly, severe underweight and psychomotor retardation. Particularly, this extremely rare de novo mutation (DNM) is located in the transcriptional repression domain (TRD) of MECP2, where at least 62 different causal mutations are identified. CONCLUSIONS We identified three DNMs in MECP2 in a cohort of 294 individuals with ID. The novel c.879C > G mutation, as a likely pathogenic allele, may become a risk factor associated with X-linked ID, microcephaly and psychomotor retardation.

中文翻译：

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通过三重WES分析确定了MECP2中的三个与智力障碍相关的从头突变。

背景技术迄今为止，已经鉴定出至少746个基因导致智力障碍（ID）。其中，甲基CpG结合蛋白2（MECP2）基因的突变是Rett综合征和相关ID的主要原因。方法考虑到大量与ID相关的基因，我们应用了基于三重的全外显子组测序（trio-WES）和计算机模拟分析对294名ID患儿进行遗传诊断。结果在三个新的杂合突变[NM_004992.3：c.502C> T，p。（Arg168 *），c.916C> T，p。（Arg306Cys），c.879C> G，p。（Ile293Met）]在三个无关的女孩中发现了MECP2。在两名被诊断为典型Rett综合征，X连锁ID和精神运动发育迟缓的患者中检测到前两个突变。第三个突变（c.879C> G）是以前未报告的，是在一个ID为6岁的女孩中发现的，小头畸形，严重的体重不足和精神运动发育迟缓。尤其是，这种极为罕见的从头突变（DNM）位于MECP2的转录抑制域（TRD）中，其中至少鉴定出62种不同的因果突变。结论我们在294名ID为ID的人群中发现了MECP2中的三个DNM。作为可能的致病等位基因，新的c.879C> G突变可能成为与X连锁ID，小头畸形和精神运动发育迟缓相关的危险因素。