Yi Zhi, Pan Hong, Li Lin, Wu Hairong, Wang Songtao, Ma Yinan, Qi Yu
Department of Central Laboratory, Peking University First Hospital, Beijing, China.
Department of Central Laboratory, Peking University First Hospital, Beijing, China.
Eur J Med Genet. 2016 Jun;59(6-7):347-53. doi: 10.1016/j.ejmg.2016.05.004. Epub 2016 May 11.
Chromosome Xq28 duplications encompassing methyl-CpG-binding protein 2 gene (MECP2) are observed most in males with a severe neurodevelopmental disorder associated with hypotonia, spasticity, severe learning disability, delayed psychomotor development, and recurrent pulmonary infections. Most female carriers are asymptomatic due to extremely or completely skewed X-inactivation.
A retrospective clinical and molecular study was conducted to examine 16 patients and two fetuses from 10 families who were identified among patients with Xq28 duplications who presented at genetic clinics.
Of all 16 patients, 10 had a family history. Only one patient was female. All of the patients had no relevant pre-natal history. All of the patients exhibited severe psychomotor developmental delay, infantile hypotonia and recurrent infections. Some of the patients exhibited cardiac abnormalities, gastrointestinal mobility problems, hydrocele of tunica vaginalis, cryptorchidism, and autistic phenotypes. Additionally, neonatal kidney calculus, premature closure of the fontanel and pulmonary sequestration were found in the patients. Duplication sizes in these patients range from 0.21 to 14.391 Mb (most were smaller than 1 Mb), and all the duplications included host cell factor C1 (HCFC1), interleukin-1 receptor-associated kinase 1 (IRAK1), and MECP2. Bioinformatics analysis revealed that approximately half of the distal breakpoints were located within the low-copy repeats (LCRs), which may be involved in the recombination. The two fetuses were found to be healthy in the prenatal diagnosis.
This is the first large cohort of patients with MECP2 duplication syndrome, including a female, reported in China. Interestingly, neonatal kidney calculus, premature closure of the fontanel and pulmonary sequestration were first reported in this syndrome. However, it was difficult to distinguish if these patients represented unique cases or if these phenotypes can be considered as part of the syndrome. The correlation between the infrequent phenotypes and duplications/genes in the duplication region needs further systematic delineation. In conclusion, our study suggested that it is important to emphasize molecular genetic analysis in patients with developmental delay/intellectual disability and recurrent infections and that it is especially important for familial female carriers to accept prenatal diagnosis.
包含甲基化CpG结合蛋白2基因（MECP2）的X染色体q28重复在患有严重神经发育障碍的男性中最为常见，这些障碍与肌张力减退、痉挛、严重学习障碍、精神运动发育迟缓以及反复肺部感染有关。由于X染色体失活极度或完全偏向，大多数女性携带者无症状。
进行了一项回顾性临床和分子研究，以检查来自10个家庭的16例患者和2例胎儿，这些患者是在基因诊所就诊的Xq28重复患者中确定的。
在所有16例患者中，10例有家族病史。只有1例患者为女性。所有患者均无相关产前病史。所有患者均表现出严重的精神运动发育迟缓、婴儿期肌张力减退和反复感染。部分患者表现出心脏异常、胃肠蠕动问题、鞘膜积液、隐睾症和自闭症表型。此外，在患者中还发现了新生儿肾结石、囟门过早闭合和肺隔离症。这些患者的重复片段大小在0.21至14.391 Mb之间（大多数小于1 Mb），所有重复片段均包含宿主细胞因子C1（HCFC1）、白细胞介素-1受体相关激酶1（IRAK1）和MECP2。生物信息学分析显示，大约一半的远端断点位于低拷贝重复序列（LCRs）内，这可能与重组有关。在产前诊断中发现这2例胎儿健康。
这是中国报道的首个包括女性患者在内的MECP2重复综合征的大型队列。有趣的是，新生儿肾结石、囟门过早闭合和肺隔离症首次在该综合征中报道。然而，很难确定这些患者是独特病例，还是这些表型可被视为该综合征的一部分。罕见表型与重复区域内的重复片段/基因之间的相关性需要进一步系统地阐明。总之，我们的研究表明，对于发育迟缓/智力残疾和反复感染的患者，强调分子遗传学分析很重要，对于家族性女性携带者接受产前诊断尤为重要。
