Modeling Rett Syndrome Using TALEN-Edited MECP2 Mutant Cynomolgus Monkeys.

Gene-editing technologies have made it feasible to create nonhuman primate models for human genetic disorders. Here, we report detailed genotypes and phenotypes of TALEN-edited MECP2 mutant cynomolgus monkeys serving as a model for a neurodevelopmental disorder, Rett syndrome (RTT), which is caused by loss-of-function mutations in the human MECP2 gene. Male mutant monkeys were embryonic lethal, reiterating that RTT is a disease of females. Through a battery of behavioral analyses, including primate-unique eye-tracking tests, in combination with brain imaging via MRI, we found a series of physiological, behavioral, and structural abnormalities resembling clinical manifestations of RTT. Moreover, blood transcriptome profiling revealed that mutant monkeys resembled RTT patients in immune gene dysregulation. Taken together, the stark similarity in phenotype and/or endophenotype between monkeys and patients suggested that gene-edited RTT founder monkeys would be of value for disease mechanistic studies as well as development of potential therapeutic interventions for RTT.

Exploring the provision, efficiency and improvements of urban green spaces on accessibility at the metropolitan scale.

Accurately assessing urban green space (UGS) accessibility and proposing effective and specific proposals for UGS provision improvement accordingly is vital to urban development. Taking the metropolitan of Shanghai, China as the study site, this study first assessed its UGS provision by improved multiple step floating catchment area methods and multiple indexes, including UGS accessibility, theoretical capacity, potential demand, and traffic supply. Second, it investigated the impacts on citywide UGS accessibility justice for each UGS by comparing Gini index differences of citywide UGS accessibility between the conditions when exist and non-exist for each UGS. Third, it used ternary plots to explore the influence mechanism of the factors of UGS theoretical capacity, potential demand, and traffic supply on accessibility, and introduced an RGB color triangle to spatially and simultaneously display the effects of these three factors on accessibility for each UGS in Shanghai. Fourth, it assessed and classified the UGS provision efficiency for accessibility according to the relationships among the theoretical capacity, potential demand, and traffic supply factors by 3D scatter plot. Fifth, it proposed specific types and priorities of requirement for UGS improvement according to its impact on citywide UGS accessibility justice and the effect of its theoretical capacity factor on UGS accessibility. The findings showed that UGS accessibility and its three factors in Shanghai were correlative and had a spatial clustering trend in central city areas. The majority of UGSs showed positive impact on citywide accessibility justice, which went up with the values of accessibility and the three factors. Most UGSs were dominated by theoretical capacity power. The UGS provision efficiency was relatively good for most UGSs, which had relatively well-matched conditions and demands. The improvement requirements for UGSs on accessibility investigated in this study will improve UGS provision.

MECP2 germline mosaicism plays an important part in the inheritance of Rett syndrome: a study of MECP2 germline mosaicism in males.

BACKGROUND: Germline mosaicisms could be inherited to offspring, which considered as "de novo" in most cases. Paternal germline MECP2 mosaicism has been reported in fathers of girls with Rett syndrome (RTT) previously. For further study, we focused on MECP2 germline mosaicism in males, not only RTT fathers. METHODS: Thirty-two fathers of RTT girls with MECP2 pathogenic mutations and twenty-five healthy adult males without history and family history of RTT or other genetic disorders were recruited. Sperm samples were collected and ten MECP2 hotspot mutations were detected by micro-droplet digital PCR (mDDPCR). And routine semen test was performed at the same time if the sample was sufficient. Additionally, blood samples were also detected for those with sperm MECP2 mosaicisms. RESULTS: Nine fathers with RTT daughters (28.1%, 9/32) were found to have MECP2 mosaicism in their sperm samples, with the mutant allele fractions (MAFs) ranging from 0.05% to 7.55%. Only one father with MECP2 c.806delG germline mosaicism (MAF 7.55%) was found to have mosaicism in the blood sample, with the MAF was 0.28%. In the group of healthy adult males, MECP2 mosaicism was found in 7 sperm samples (28.0%, 7/25), with the MAFs ranging from 0.05% to 0.18%. None of the healthy adult males with MECP2 germline mosaicisms were found with MECP2 mosaicism in blood samples. There were no statistical differences in age, or the incidence of asthenospermia between fathers with RTT daughters and healthy adult males with MECP2 germline mosaicisms. Additionally, there was no linear correlation between MAFs of MECP2 mosaicisms and the age of males with germline MECP2 mosaicisms. CONCLUSIONS: Germline MECP2 mosaicism could be found not only in fathers with RTT daughters but also in healthy adult males without family history of RTT. As germline mosaic mutations may be passed on to offspring which commonly known as "de novo", more attention should be paid to germline mosaicism, especially in families with a proband diagnosed with genetic disorders.

The genetic and clinical characteristics of aromatic L-amino acid decarboxylase deficiency in mainland China.

Aromatic L-amino acid decarboxylase deficiency (AADCD) is a rare neurotransmitter metabolic disorder caused by DDC gene mutations, which leads to the metabolic disturbance of dopamine and serotonin. Most of the reported cases came from Taiwan China, but patients from mainland China were seldomly reported. The current study was the largest AADCD patient cohort from mainland China. Twenty-three patients with clinical features of AADCD and DDC gene variants were recruited. A total of 16 DDC variants were identified in this study, of which four variants (c.2T>C, c.277A>G, c.1021+1G>A, c.565G>T) were never reported previously. The intronic variant c.714+4A>T was the most common one, with an allele frequency of 45.7%. And patients carried this intronic variant presented with severe clinical manifestations, all of whom were bedridden. In this study, the average onset age was 3.61 ± 1.28 months and the average age of diagnosis was 12.91 ± 5.62 months. Early onset hypotonia, oculogyric crises, and autonomic symptoms such as excessive sweating, nasal congestion and profuse nasal, and oropharyngeal secretions, were common in our patients. Eighteen patients (78.3%) got various degree of improvement after using pyridoxine monotherapy or different combination of pyridoxine, dopamine agonists, and monoamine oxidase (MAO) inhibitors.

MECP2 mutation spectrum and its clinical characteristics in a Chinese cohort.

The dysfunction of methyl-CpG-binding protein 2 (MeCP2) is associated with several neurological disorders, of which Rett syndrome (RTT) is the most prominent. This study focused on a Chinese patient cohort with MECP2 mutations, and analyzed the characteristics of these mutations and their clinical manifestations. In total, 666 patients were identified with 126 different MECP2 mutations, including 22 novel mutations. Over 80% of patients carried an MECP2 mutation on exon 4. Nonsense and missense mutations were the most commonly reported types. Missense mutations were mainly located on methyl-CpG-binding domain (MBD), and nonsense mutations predominantly occurred on transcription repression domain (TRD) and inter domain. The predilection site of large deletion was exon 3 and/or exon 4. Patients with p.R133C, p.R294*, p.R306C, and C-terminal domain (CTD) deletions were less severely affected. Significant differences were found in ambulation ability, hand function, and language among different mutation groups. Three female patients with MECP2 mutations (1 with p.R306P and 2 with p.R309W) only presented with intellectual disability/developmental delay (ID/DD), and no obvious RTT symptoms were reported. Eight male individuals with MECP2 mutations were also identified in this study, including 2 diagnosed with typical RTT, 3 with atypical RTT and 3 with ID/DD.

Epstein-Barr virus-positive inflammatory follicular dendritic cell sarcoma presenting as a solitary colonic mass: two rare cases and a literature review.

AIMS: Follicular dendritic cell (FDC) sarcoma is a rare neoplasm originating from follicular dendritic cells in germinal centres. It is classified as conventional and Epstein-Barr virus (EBV)-positive inflammatory FDC sarcoma according to the 2019 World Health Organization classification of digestive system tumours; the latter is rarer. So in view of the rarity and difficulty in diagnosis, the aim of the manuscript is to share our experience of diagnosing EBV-positive inflammatory FDC sarcoma. METHODS AND RESULTS: Here, we describe the clinicopathological features, gross description, histomorphology, immunophenotype, EBV-encoded mRNA (EBER) in-situ hybridisation, gene rearrangement and clinical follow-up of two patients with EBV-positive inflammatory FDC sarcoma in the colon, and review the relevant literature. The tumours were found in two males, aged 53 and 48 years, respectively, with a tumour diameter between 10 and 45 mm. Both cases occurred in the colon and presented as pedunculated colonic masses. Microscopically, scanty atypical ovoid to spindle neoplastic cells were mixed in a background of florid lymphoplasmacytic infiltration. The nuclei of these atypical cells showed vesicular chromatin and small, distinct nucleoli. Immunohistochemistry demonstrated that the atypical stromal cells were positive for CD21, CD23, CD35, and D2-40. EBER in-situ hybridisation also gave positive results in two cases. There was a mean follow-up of 9 months (range, 7-11 months). CONCLUSION: EBV-positive inflammatory FDC sarcoma is an extremely rare tumour with a distinct morphology and phenotype. Therefore, it is very important to recognise it particularly for correct diagnosis and prevention of misdiagnosis and mistreatment.

First-Principles Study on Self-Activated Luminescence and 4f → 5d Transitions of Ce3+ in M5(PO4)3X (M = Sr, Ba; X = Cl, Br).

The origin of the self-activated luminescence in the apatite-type M5(PO4)3X (MPOX; M = Sr or Ba; X = Cl or Br) samples and the spectral assignment for cerium-doped Sr5(PO4)3Cl (SPOC) phosphors are determined from first-principles methods combined with hybrid density functional theory (DFT) calculations, using the standard PBE0 hybrid functional, with wave function-based embedded-cluster ab initio calculations (at the CASSCF/CASPT2/RASSI-SO level). Electronic structure calculations are performed in order to accurately derive the band gaps of the hosts, the locations of impurity states in the energy bands that are caused by native defects and doped Ce3+ ions, and the charge-compensation mechanisms of aliovalent doping. The calculations of defect formation energies under O-poor conditions demonstrate that the native defects are easily generated in the undoped MPOX samples prepared under reducing atmospheres, from which thermodynamic and optical transition energy levels, as well as the corresponding energies, are derived in order to interpret the luminescence mechanisms of the undoped MPOX as previously reported. Our calculations reveal that the self-activated luminescence is mainly attributed to the optical transitions of the excitons bound to the oxygen vacancies (VO), along with their transformation of the charge states 0 ↔ 1+. Furthermore, the eight excitation bands observed in the synchrotron radiation excitation spectra of SPOC: Ce3+, Na+ phosphors are successfully assigned according to the ab initio calculated energies and relative oscillator strengths of the 4f1 → 5d1-5 transitions for the Ce3+ ions at both the Sr(1) and Sr(2) sites in the host. It is hoped that the feasible first-principles approaches in this work are applied in order to explore the origins of the luminescence in undoped and lanthanide-doped phosphors, complementing the experiments from the perspective of chemical compositions and the microstructures of materials.

Epidemiological situation of leprosy in a province in China: a long time to diagnosis and a high rate of deformity.

BACKGROUND: This epidemiological study aimed to analyse both the distribution and characteristics of leprosy in an endemic province in Northwest China. METHODS: The medical records of leprosy patients in the province of Shaanxi, China, from 1998 to 2018 were collected from the Chinese Leprosy Management Information System (LEPMIS). Epidemiological variables were analysed in this study. RESULTS: A total of 477 new cases were diagnosed between 1998 and 2018 in this region. The average annual detection rate was 0.070/100,000 population, and the average annual prevalence was 0.305/100,000 population. The mean age of the newly diagnosed patients was 46.7 years, and the ratio of males to females was 2.5:1. There were 399 cases (83.6%) of multibacillary (MB) leprosy. One hundred forty-eight patients (31.0%) had grade 2 disability. The mean diagnosis time for new cases was 62.0 months. CONCLUSION: This epidemiological study showed that the characteristics of newly diagnosed leprosy cases in our province were a long time to diagnosis and a high rate of deformity, indicating the need for actions focusing on early diagnosis and treatment and strengthening the detection of leprosy in low-prevalence areas.

Clinical significance of CD133 and Nestin in astrocytic tumor: The correlation with pathological grade and survival.

BACKGROUND: We aimed to investigate the interaction between CD133 and Nestin and further assessed the correlation of CD133 and Nestin with clinicopathological characteristics and survival in patients with astrocytic tumor. METHODS: Totally 127 patients with astrocytic tumor underwent surgical resection were enrolled. Patients' age, gender, and World Health Organization (WHO) grade were recorded, and the survival data were extracted from the follow-up records. The expressions of CD133 and Nestin in astrocytic tumor tissues were analyzed by immunohistochemistry assay. The WHO grade I and II astrocytic tumors were defined as low-grade astrocytic tumors (LGA), the WHO grade III and IV astrocytic tumors were defined as high-grade astrocytic tumors (HGA). RESULTS: There were 79 (62.2%), 34 (26.8%), 14 (11.0%), and 0 (0.0%) patients with CD133 negative, low, moderate, and high expression, respectively; 7 (5.5%), 47 (37.0%), 20 (15.7%), 53 (41.7%) patients with Nestin negative, low, moderate, high expression, respectively. CD133 and Nestin were both correlated with advanced WHO grade but not with age or gender, and positive correlation was observed between CD133 and Nestin. For survival, both CD133 and Nestin were correlated with unfavorable overall survival (OS), and further analysis illustrated that Nestin but not CD133 independently predicted poor OS. Subgroup analysis also revealed that Nestin but not CD133 negatively associated with shorter OS in LGA patients, while both CD133 and Nestin were correlated with poor OS in HGA patients. CONCLUSION: CD133 and Nestin present as potential biomarkers for advanced pathological grade and poor survival in patients with astrocytic tumor.

Correction: Genomic mosaicism in the pathogenesis and inheritance of a Rett syndrome cohort.

The second author Jiarui Li is now listed as a co-first author according to her contribution to this paper. The list of authors who contributed equally now reads: Qingping Zhang, Xiaoxu Yang, Jiaping Wang, and Jiarui Li. This has now been corrected in both the PDF and HTML versions of the Article.

Genomic mosaicism in the pathogenesis and inheritance of a Rett syndrome cohort.

PURPOSE: To determine the role of mosaicism in the pathogenesis and inheritance of Rett and Rett-like disorders. METHODS: We recruited 471 Rett and Rett-like patients. Panel-sequencing targeting MECP2, CDKL5, and FOXG1 was performed. Mosaicism was quantified in 147 patients by a Bayesian genotyper. Candidates were validated by amplicon sequencing and digital PCR. Germline mosaicism of 21 fathers with daughters carrying pathogenic MECP2 variants was further quantified. RESULTS: Pathogenic variants of MECP2/CDKL5/FOXG1 were found in 324/471 (68.7%) patients. Somatic MECP2 mosaicism was confirmed in 5/471 (1.1%) patients, including 3/18 males (16.7%) and 2/453 females (0.4%). Three of the five patients with somatic MECP2 mosaicism had mosaicism at MECP2-Arg106. Germline MECP2 mosaicism was detected in 5/21 (23.8%) fathers. CONCLUSION: This is the first systematic screening of somatic and paternal germline MECP2 mosaicism at a cohort level. Our findings indicate that somatic MECP2 mosaicism contributes directly to the pathogenicity of Rett syndrome, especially in male patients. MECP2-Arg106 might be a mosaic hotspot. The high proportion of paternal germline MECP2 mosaicism indicates an underestimated mechanism underlying the paternal origin bias of MECP2 variants. Finally, this study provides an empirical foundation for future studies of genetic disorders caused by de novo variations of strong paternal origin.

Different effects of allergic rhinitis on nasal mucosa remodeling in chronic rhinosinusitis with and without nasal polyps.

BACKGROUND: Allergic rhinitis (AR) has been reported to be associated with chronic rhinosinusitis (CRS). The objective of this study was to investigate the effect of AR on nasal mucosa remodeling in CRS. METHODS: Patients were enrolled and divided into the following groups: CRS with nasal polyps (NP) with allergic rhinitis (AR)(CRSwNPwAR; n = 20), CRS with NP without AR (CRSwNPsAR; n = 20), CRS without NP with AR (CRSsNPwAR; n = 20), CRS without NP without AR (CRSsNPsAR; n = 20), AR without CRS (AR; n = 20) and controls (n = 14). Eosinophil infiltration, mucus production, and collagen deposition were examined by hematoxylin and eosin, periodic acid schiff and masson's trichrome staining, respectively. VEGF-A and microvessel density were detected by immunohistochemistry. The expression of remodeling markers, including TGF-ß1, MMP-7, MMP-9 and TIMP-1 were measured by Western blot. RESULTS: The expression of remodeling factors, including VEGF-A, CD31, CD34 and TIMP-1 were significantly increased in CRSwAR compared to CRSsAR. Goblet cell hyperplasia, as well as VEGF-A, CD31, CD34, and MMP-9 expression were significantly higher in CRSwNPwAR compared to CRSwNPsAR. However, the expression of collagen fibers, MMP-7 and TGF-ß1 were significantly higher in CRSsNPwAR compared to CRSsNPsAR. CONCLUSIONS: AR could enhance the remodeling process in CRS. Moreover, AR had different effects on CRSwNP and CRSsNP.

Novel MEF2C point mutations in Chinese patients with Rett (-like) syndrome or non-syndromic intellectual disability: insights into genotype-phenotype correlation.

BACKGROUND: MEF2C (Myocyte-specific enhancer factor 2C) has been associated with neurodevelopmental disorders. This study aimed at delineating the clinical profiles of MEF2C gene mutations. METHODS: In total, 112 Chinese patients with intellectual disability (ID) were recruited, including 44 patients presented with Rett syndrome (RTT) or RTT-like syndrome, and 68 patients with non-syndromic ID. Targeted next-generation sequencing (NGS) was performed. Detailed clinical information was collected. RESULTS: Five heterozygous MEF2C gene mutations were identified, of which three were novel. The MEF2C mutant rate was 4.5% (5/112) in total, and 6.8% (3/44) in the RTT (-like) cohort. All patients with MEF2C gene mutation presented with cognitive impairment, gross motor delay, speech disorder and autistic features. Four patients had epilepsy, which responded well to antiepileptic drugs. One female was diagnosed with classical RTT, two females with RTT-like syndrome, and two males with non-syndromic ID. Generally, the phenotype of two males with relatively downstream mutations (c.565C > T, p.Arg 189*; c.766C > T, p.Arg 256*) was milder than that of three females with upstream mutations (c.48C > G, p.Asn16Lys; c.334G > T, p.Glu112* and c.403-1G > T). CONCLUSIONS: Our findings expanded the current understanding of the consequences of MEF2C dysfunctions, especially MEF2C point mutations. MEF2C mutations are associated with a broad clinical spectrum, ranged from classical RTT to non-syndromic ID. Through our study, it can be inferred that there is correlation between the phenotype and MEF2C-genotype, the mutation site. Overall, the MEF2C gene mutational analysis should be performed in ID cohort, especially in patients with features overlapped with RTT.

[Clinical and genetic features of five patients with Allan-Herndon-Dudley syndrome].

OBJECTIVE: To delineate the clinical and genetic characteristics of patients with Allan-Herndon-Dudley syndrome (AHDS). METHODS: Genetic testing was carried out by next generation sequencing on 117 patients featuring intellectual disability and developmental delay. Clinical information including clinical manifestation, brain magnetic resonance imaging(MRI）, thyroid hormone levels, and electrocardiogram was collected for those with SLC16A2 mutations. RESULTS: Five male patients with SLC16A2 gene mutations were identified, including 2 affected brothers and 3 sporadic cases. The ages of the patients ranged from 8 months to 8 years. All patients presented with severe intellectual disability and developmental delay including poor head control, inability to sit independently, no speech, and poor response to external stimuli. All patients presented with hypotonia, dystonia, and positive pyramidal signs. Three patients had sinus tachycardia. All patients had abnormal thyroid hormone levels with elevated free triiodothyronine (FT3), decreased free tetraiodothyronine(FT4), and normal thyroid stimulating hormone (TSH). Brain MRI on 3 patients showed delayed myelination. Among the 3 sporadic patients, 2 carried de novo mutations including c.61G to T(p.E21X) and c.695_699delATGGT(p.N232SfsX7), respectively, 1 carried a c.42delC(p.W15GfsX69)mutation, which was inherited from his heterozygous mother. A nonsense mutation (c.916C to T, p.Q306X) was discovered in the two brothers, for which their mother was heterozygous. CONCLUSION: AHDS is characterized by severe psychomotor developmental delay as well as congenital hypotonia, dystonia and positive pyramidal signs. Affected males may present with distinctive thyroid hormone abnormalities including increased FT3 and low FT4 accompanied by normal TSH. Delayed meylination of white matter is common. It is an X-linked mental retardation caused by SLC16A2 gene mutations.

SCN8A mutations in Chinese patients with early onset epileptic encephalopathy and benign infantile seizures.

BACKGROUND: SCN8A mutations have recently been associated with epilepsy and neurodevelopmental disorders. This study aimed to broaden the phenotypic-spectrum of disease related with SCN8A mutations. METHODS: To identify the pathogenic gene of a Chinese family, in which six members suffered from epilepsy, whole-exome sequencing was performed. In addition, target next-generation sequencing (NGS) was performed on 178 sporadic patients, who had epilepsy of unknown etiology within 6 months after birth. A detailed clinical history was obtained. RESULTS: A heterozygous missense mutation of SCN8A was identified in the Chinese family. Six de novo mutations of SCN8A were detected in 6 sporadic patients with epilepsy. In the family, six members developed seizures within a few years after birth. Five of them had milder clinical performance, that they had normal cognition and developmental milestones, and seizure-free was achieved by mono-therapy. The other one affected member presented with refractory epilepsy and developmental regression. She died from sudden unexpected death in epilepsy (SUDEP) at 17-year-old. Clinical features of six sporadic patients with SCN8A mutations were diverse, ranging from severe epileptic encephalopathy to benign epilepsy with normal cognition. Seizures started at the mean age of 3.9 months (from 2 months to 6 months). Seizure-free was achieved in four of them by mono- or multi-antiepileptic drugs. Five of them demonstrated mild or severe psychomotor retardation, whereas the other one was normal in development and intelligence. CONCLUSIONS: Our findings extend the spectrum of SCN8A mutations and the clinical features of patients with SCN8A mutations. The majority of SCN8A mutations were de novo, inherited mutations from the heterozygous parents can also occur. The phenotypic spectrum of SCN8A mutation varied largely. Most affected patients manifested as refractory epilepsy and severe intellectual disability, only a small number of patients presented with milder clinical patterns. Additionally, our study confirmed that the same mutation can lead to different phenotypes.

Novel FOXG1 mutations in Chinese patients with Rett syndrome or Rett-like mental retardation.

BACKGROUND: We aimed to delineate clinical phenotypes associated with FOXG1 mutations in Chinese patients with Rett syndrome (RTT) or RTT-like mental retardation (MR). METHODS: Four hundred and fifty-one patients were recruited, including 418 with RTT and 33 with RTT-like MR. Gene mutations were identified by a target capture method and verified by Sanger sequencing. RESULTS: Four FOXG1 mutations were detected in four patients (three with RTT and one with RTT-like MR), including one previously described mutation and three novel mutations. These mutations included one missense and three micro-insertion mutations. Overall, 0.7% (3/418) of patients who had RTT in our cohort had FOXG1 mutations. All patients had early global developmental delays followed later by severe mental retardation. None of the patients acquired speech or purposeful hand movements, and all of them presented with severe hypotonia, epilepsy, and hypoplasia of the corpus callosum. CONCLUSIONS: Our findings extend the spectrum of FOXG1 mutations and the clinical features of RTT in Chinese patients. We recommend that patients with congenital RTT and Rett-like MR, especially those with brain malformations, such as hypoplasia of the corpus callosum, should be tested for FOXG1 mutations.

Familial cases and male cases with MECP2 mutations.

This is the first report of Chinese familial cases with Rett syndrome (RTT) or X-linked mental retardation (XLMR). RTT is a neurodevelopmental disorder that almost exclusively affects females. Most RTT cases are sporadic. We have studied eight cases with MECP2 mutations in six Chinese families, including three females and five males with RTT or XLMR. All shared identical MECP2 mutations with their mothers. The three females fulfilled the diagnostic criteria for RTT, while the five males were XLMR. A random X-chromosome inactive (XCI) pattern was seen in all the three female patients and two mothers while a skewed XCI in the rest four mothers. The clinical manifestations and pathogenic gene spectrum between male and female patients were different. The different MECP2 mutations and different XCI pattern may be the determinants of the phenotypic heterogeneity between the family members.

[Correction: Advance in research on MRCP2 duplication syndrome. Zhonghua Yi Xue Yi Chuan Xue Za Zhi, 2015, 32(3): 426-429].

The English Title for the above article, as appeared in our June 2015 issue, should be corrected as "Advance in research on MECP2 duplication syndrome".

MECP2 duplication syndrome in a Chinese family.

BACKGROUND: Methyl-CpG-binding protein 2 (MeCP2) is a key transcriptional regulator of gene expression in the maintenance and development of the central nervous system. Loss- or gain-function of this gene may contribute to neurodevelopmental disorders. The aim of this study is to delineate the clinical characteristics of MECP2 duplication syndrome and the hereditary mechanism in a Chinese family. CASE PRESENTATION: We identified a Chinese family with three persons carry MECP2 gene duplication: a boy, his mother and his grandmother. The duplication segment which was detected by multiplex ligation-dependent probe amplification (MLPA) included gene MECP2, interleukin-1 receptor-associated kinase 1 (IRAK1), filamin A (FLNA), and L1 cell adhesion molecule (L1CAM). Furthermore, array comparative genomic hybridization (aCGH) was performed on the mother, showed that MECP2 containing duplication was 510 Kb (153,113,885-153,624,154), including 16 other genes except MECP2. The boy showed most symptoms of MECP2 duplication syndrome. His mother and maternal grandmother were asymptomatic. Both female carriers had a skewed X chromosome inactivation (XCI), which were 80:20 and 74:26 respectively. CONCLUSION: To our knowledge, this is the second reported Chinese Han family with MECP2-containing duplications. And this patient had recurrent respiratory infections which was different from the first two Chinese-brother cases. MECP2 is the core gene responsible for MECP2 duplication syndrome. XCI may play an important role in modulating the clinical manifestation.

[Advance in research on MECP2 [corrected] duplication syndrome].

Methyl-CpG-binding protein 2 gene (MECP2; OMIM 300005) is located at chromosome Xq28. Mutations of the gene including point mutation, duplication and deletion can lead to severe neurodevelopmental disorders. The disease caused by duplication of the entire MECP2 gene, named as MECP2 duplication syndrome, is mostly seen in males. The clinical manifestation of this syndrome include mental retardation, hypotonia, poor speech development, recurrent infection, progressive spasticity, epilepsy, autism or autistic features with or without midface hypoplasia. Most patients have inherited the duplication from their unaffected mothers, with only a few cases having de novo mutation. Females with duplicated MECP2 gene are typically asymptomatic because of a skewed X chromosome inactivation (XCI) pattern. Proposed mechanisms of this genomic rearrangement include fork stalling and template switching (FoSTeS) and microhomology mediated break-induced replication (MMBIR). Since no effective treatment is available for this disease, proper genetic counseling and prenatal diagnosis for the high risk families are crucial.