背景:包含甲基-CpG结合蛋白2基因(MECP2)的染色体Xq28重复在患有与张力减退相关的严重神经发育障碍的男性中观察到最多,痉挛,严重的学习障碍,精神运动发育延迟,反复肺部感染.大多数女性携带者由于极度或完全偏斜的X失活而无症状。
方法: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名患者和2名胎儿,这些患者在遗传诊所就诊的Xq28重复患者中被鉴定。
结果:在所有16例患者中,10有家族史。只有一名患者是女性。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性发育迟缓,婴儿张力减退和反复感染。一些患者表现出心脏异常,胃肠道活动问题,阴道膜鞘膜积液,隐睾,和自闭症表型。此外,新生儿肾结石,患者发现fontanel过早闭合和肺隔离症。这些患者的重复尺寸范围为0.21至14.391Mb(大多数小于1Mb),所有重复包括宿主细胞因子C1(HCFC1),白细胞介素-1受体相关激酶1(IRAK1),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(LCR)内,这可能参与重组。在产前诊断中发现两个胎儿是健康的。
结论:这是第一个大型MECP2重复综合征患者队列,包括一个女性,在中国报道。有趣的是,新生儿肾结石,在该综合征中首次报道了fontanel的过早闭合和肺隔离症。然而,很难区分这些患者是否代表独特病例,或者这些表型是否可以被视为综合征的一部分.重复区域中不常见的表型与重复/基因之间的相关性需要进一步的系统描述。总之,我们的研究表明,对于患有发育迟缓/智力残疾和反复感染的患者,强调分子遗传学分析非常重要,对于家族性女性携带者来说,接受产前诊断尤为重要.
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.