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1.
Am J Hum Genet ; 105(5): 996-1004, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31587869

RESUMO

Mechanically activated (MA) ion channels convert physical forces into electrical signals. Despite the importance of this function, the involvement of mechanosensitive ion channels in human disease is poorly understood. Here we report heterozygous missense mutations in the gene encoding the MA ion channel TMEM63A that result in an infantile disorder resembling a hypomyelinating leukodystrophy. Four unrelated individuals presented with congenital nystagmus, motor delay, and deficient myelination on serial scans in infancy, prompting the diagnosis of Pelizaeus-Merzbacher (like) disease. Genomic sequencing revealed that all four individuals carry heterozygous missense variants in the pore-forming domain of TMEM63A. These variants were confirmed to have arisen de novo in three of the four individuals. While the physiological role of TMEM63A is incompletely understood, it is highly expressed in oligodendrocytes and it has recently been shown to be a MA ion channel. Using patch clamp electrophysiology, we demonstrated that each of the modeled variants result in strongly attenuated stretch-activated currents when expressed in naive cells. Unexpectedly, the clinical evolution of all four individuals has been surprisingly favorable, with substantial improvements in neurological signs and developmental progression. In the three individuals with follow-up scans after 4 years of age, the myelin deficit had almost completely resolved. Our results suggest a previously unappreciated role for mechanosensitive ion channels in myelin development.

2.
Inorg Chem ; 58(19): 13394-13402, 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31556604

RESUMO

Carbon dots (CDs), as an effective bioimaging agent, have aroused widespread interest. With the increasing number of CDs used in photodynamic therapy (PDT), developing efficient CDs with multiple functions such as imaging and phototherapy has become a new challenge. Herein, a new type of copper-doped CDs (Cu-CDs) with a high fluorescence quantum yield of 24.4% was synthesized from a copper complex of poly(acrylic acid) through coordination between the carboxyl group and copper ions. Owing to their good solubility, bright fluorescence, and low cytotoxicity, the Cu-CDs can be used for fluorescence imaging in both the HeLa (human cervical cancer) cell line and SH-SY5Y (human neuroblastoma cells) multicellular spheroids (3D MCs). More importantly, the Cu-CDs show a high quantum yield of singlet oxygen (1O2; 36%), good photoinduced cytotoxicity, and effective inhibition of 3D MC growth. Therefore, the Cu-CDs can be used as a promising imaging-guided PDT agent. This study provides a new carbon-based nanomaterial for multifunctional photodiagnostic and therapeutic agents for biological applications.

3.
Environ Sci Pollut Res Int ; 26(28): 28884-28897, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31385246

RESUMO

Industrialization and urbanization process has brought both economic development and a series of environmental problems. Hebei Province is a high haze area and one of the key areas of China's "Blue Sky Defense" policy. As carbon emission is one of the most important factors causing haze, it is necessary to screen the influencing factors effectively to make quantitative analysis and predict carbon emissions in different degrees of coordination. Faced with the new situation of Beijing-Tianjin-Hebei coordinated development and more environmental constraints, this paper designs a system for predicting carbon emissions in Hebei Province innovatively using the data during 1990-2016. In the first step, 7 influence factors are determined by "graded screening." Then, this paper improved the traditional support vector machine (SVM) by improved gray wolf optimizer (IGWO), and established IGWO-SVM model. Finally, the carbon emissions in Hebei Province from 2017 to 2025 are predicted under three stages of different cooperative development speed of 7 influence factors by the improved intelligent algorithm model. Based on the forecasting results, this paper put forward some pertinent opinions to provide theoretical basis for formulating relevant policies on carbon emissions in Hebei Province to effectively control carbon emissions from the source.

4.
World J Pediatr ; 15(5): 454-464, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31372844

RESUMO

BACKGROUND: Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare neurological degenerative disorder caused by the mutations of MLC1 or GLIALCAM with autosomal recessive or autosomal dominant inheritance and a different prognosis, characterized by macrocephaly, delayed motor and cognitive development, and bilateral abnormal signals in cerebral white matter (WM) with or without cysts on magnetic resonance imaging (MRI). This study aimed to reveal the clinical and genetic features of MLC patients with GLIALCAM mutations and to explore the brain pathological characteristics and prognosis of mouse models with different modes of inheritance. METHODS: Clinical information and peripheral venous blood were collected from six families. Genetic analysis was performed by Sanger sequencing of GLIALCAM. GlialcamArg92Trp/+ and GlialcamLys68Met/Thr132Asn mouse models were generated based on mutations from patients (c.274C>T(p.Arg92Trp) (c.203A>T(p.Lys68Met), and c.395C>A (p.Thr132Asn))). Brain pathologies of the mouse models at different time points were analyzed. RESULTS: Six patients were clinically diagnosed with MLC. Of the six patients, five (Pt1-Pt5) presented with a heterozygous mutation in GLIALCAM (c.274C>T(p.Arg92Trp) or c.275G>C(p.Arg92Pro)) and were diagnosed with MLC2B; the remaining patient (Pt6) with two compound heterozygous mutations in GLIALCAM (c.203A>T (p.Lys68Met) and c.395C>A (p.Thr132Asn)) was diagnosed with MLC2A. The mutation c.275C>G (p.Arg92Pro) has not been reported before. Clinical manifestations of the patient with MLC2A (Pt6) progressed with regression, whereas the course of the five MLC2B patients remained stable or improved. The GlialcamArg92Trp/+ and GlialcamLys68Met/ Thr132Asn mouse models showed vacuolization in the anterior commissural WM at 1 month of age and vacuolization in the cerebellar WM at 3 and 6 months, respectively. At 9 months, the vacuolization of the GlialcamLys68Met/ Thr132Asn mouse model was heavier than that of the GlialcamArg92Trp/+ mouse model. Decreased expression of Glialcam in GlialcamArg92Trp/+ and GlialcamLys68Met/ Thr132Asn mice may contribute to the vacuolization. CONCLUSIONS: Clinical and genetic characterization of patients with MLC and GLIALCAM mutations revealed a novel mutation, expanding the spectrum of GLIALCAM mutations. The first Glialcam mouse model with autosomal recessive inheritance and a new Glialcam mouse model with autosomal dominant inheritance were generated. The two mouse models with different modes of inheritance showed different degrees of brain pathological features, which were consistent with the patients' phenotype and further confirmed the pathogenicity of the corresponding mutations.

5.
Inflammation ; 42(5): 1857-1868, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31332661

RESUMO

Pseudoginsenoside-F11 (PF11), an ocotillol-type saponin, has been reported to have anti-inflammatory properties, but the effects of PF11 on acute lung inflammation were unknown. The present study aimed to investigate the protective effects and potential mechanisms of PF11 on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in male BALB/c mice. After being treated with PF11 (3, 10, and 30 mg/kg, intravenous) once a day for 3 consecutive days, the mice were challenged by intratracheal instillation of LPS, and then their lung tissues and bronchoalveolar lavage fluid (BALF) were collected for further analysis. The results showed that PF11 attenuated LPS-induced ALI, with alleviated histopathological damage, decreased lung wet/dry weight ratio, and reduced protein concentration and inflammatory cells number in BALF. Moreover, PF11 reversed the LPS-induced increases of mRNA expression and protein levels of interleukin-6, tumor necrosis factor-α, and interleukin-1ß. Meanwhile, PF11 decreased LPS-induced myeloperoxidase activity and neutrophil infiltration in lung tissue by reducing the expression of macrophage inflammatory protein-2 and intercellular adhesion molecule-1, as well as enhanced neutrophil clearance by accelerating neutrophils apoptosis and their phagocytosis by alveolar macrophages. In conclusion, these results indicated that PF11 significantly attenuated LPS-induced ALI through suppressing neutrophil infiltration and accelerating neutrophil clearance, suggesting its potential in the treatment of ALI.

6.
BMC Med Genet ; 20(1): 76, 2019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-31064337

RESUMO

BACKGROUND: Brown-Vialetto-Van Laere Syndrome (BVVLS), a rare neurological disorder characterized by motor, sensory, and cranial neuronopathies, is mainly associated with defective riboflavin transporters encoded by SLC52A2 and SLC52A3 genes. Clinical outcomes have been shown to be improved significantly by high-dose riboflavin supplementation. The aim of this study was to identify genetic causes and further evaluate the clinical course and response to riboflavin in a Chinese pedigree with BVVLS. CASE PRESENTATION: We report the novel compound heterozygous variants c.1328G>A p.(Cys443Tyr) and c.1022_1023insC p. (Leu341Profs*103) of SLC52A2 gene in a female proband who presented in our out-patient clinic at the age of one-year-old with progressive mental and motor regression, breath holding, and brain stem dysfunction including facial weakness, hearing loss, dysphagia. Following high-dose riboflavin supplementation, the respiratory insufficiency and mental, motor, and bulbar function improved. However, sensorineural hearing loss was not improved. The missense variant site was highly conserved. Both variants were not found in the population database gnomAD. The two variants were inherited from her mother and father, respectively. Both variants were predicted to be deleterious by Polyphen2, Mutation taster, and SIFT and were classified as likely pathogenic according to the ACMG guideline. CONCLUSIONS: Two novel pathogenic variations of SLC52A2 gene were firstly found from a Chinese pedigree with BVVLS. Clinical outcomes could be improved by early diagnosis and riboflavin supplementation.


Assuntos
Paralisia Bulbar Progressiva/genética , Perda Auditiva Neurossensorial/genética , Mutação , Receptores Acoplados a Proteínas-G/genética , Sequência de Aminoácidos , China , Feminino , Humanos , Lactente , Masculino , Linhagem , Receptores Acoplados a Proteínas-G/química , Homologia de Sequência de Aminoácidos
7.
BMC Med Genet ; 20(1): 80, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088393

RESUMO

BACKGROUND: Intellectual disability/developmental delay is a complex condition with extraordinary heterogeneity. A large proportion of patients lacks a specific diagnosis. Next generation sequencing, enabling identification of genetic variations in multiple genes, has become an efficient strategy for genetic analysis in intellectual disability/developmental delay. METHODS: Clinical data of 112 Chinese families with unexplained intellectual disability/developmental delay was collected. Targeted next generation sequencing of 454 genes related to intellectual disability/developmental delay was performed for all 112 index patients. Patients with promising variants and their other family members underwent Sanger sequencing to validate the authenticity and segregation of the variants. RESULTS: Fourteen promising variants in genes EFNB1, MECP2, ATRX, NAA10, ANKRD11, DHCR7, LAMA1, NFIX, UBE3A, ARID1B and PTPRD were identified in 11 of 112 patients (11/112, 9.82%). Of 14 variants, eight arose de novo, and 13 are novel. Nine patients (9/112, 8.03%) got definite molecular diagnoses. It is the first time to report variants in EFNB1, NAA10, DHCR7, LAMA1 and NFIX in Chinese intellectual disability/developmental delay patients and first report about variants in NAA10 and LAMA1 in affected individuals of Asian ancestry. CONCLUSIONS: Targeted next generation sequencing of 454 genes is an effective test strategy for patients with unexplained intellectual disability/developmental delay. Genetic heterogenicity is significant in this Chinese cohort and de novo variants play an important role in the diagnosis. Findings of this study further delineate the corresponding phenotypes, expand the mutation spectrum and support the involvement of PTPRD in the disease.


Assuntos
Deficiências do Desenvolvimento/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Deficiência Intelectual/genética , Mutação , Adolescente , Criança , Pré-Escolar , China , Cromossomos Humanos X , Feminino , Genes Dominantes , Genes Recessivos , Heterogeneidade Genética , Humanos , Lactente , Masculino , Linhagem , Fenótipo
8.
Clin Genet ; 96(3): 207-215, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31066047

RESUMO

Congenital muscular dystrophies (CMDs) are clinically and genetically heterogeneous conditions. We launched a nationwide study to determine the frequency of CMD in the Chinese population and assess the status of diagnosis and disease management for CMD in China. Cases were chosen from databases in 34 tertiary academic hospitals from 29 first-level administrative divisions (provinces, municipalities, autonomous regions, and special administrative regions), and medical records were reviewed to confirm the diagnoses. The study included 409 patients, of those patients who consented to genetic testing (n = 340), mutations were identified in 286 of them. The most common forms identified were LAMA2-related CMD (36.4%), followed by COL6-related CMD (23.2%) and α-dystroglycanopathy (21.0%). The forms of CMD related to mutations in LMNA and SEPN1 were less frequent (12.5% and 2.4%, respectively). We also recorded a significant difference in the diagnostic capabilities and disease management of CMD, with this being relatively backward in research centers from less developed regions. We provide, for the first time, comprehensive epidemiologic information of CMD in a large cohort of Chinese people. To our knowledge, this is the largest sample size of its kind so far highlighting the prevalence of CMD in China.

9.
ACS Appl Mater Interfaces ; 11(20): 18203-18212, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31026133

RESUMO

Commercial gadolinium-based materials have been widely used as contrast agents for magnetic resonance imaging (MRI), but the high toxicity of leaking free Gd3+ ions still raises biosafety concerns. Here, we develop a novel, safe, and efficient MRI contrast agent based on a stable Fe(III) complex of fluorine and nitrogen co-doped carbon dots (F,N-CDs) that was prepared from glucose and levofloxacin by a simple microwave-assisted thermal decomposition method. The obtained Fe3+@F,N-CD complex exhibits higher longitudinal relaxivity ( r1 = 5.79 mM-1·s-1) than that of the control samples of the Fe3+@CD complex ( r1 = 4.23 mM-1 s-1) and free Fe3+ ( r1 = 1.59 mM-1 s-1) in aqueous solution, as assessed by a 1.5 T NMR analyzer. More importantly, the Fe3+@F,N-CD complex is very stable with a large coordination constant of 1.06 × 107 in aqueous medium. While incubated with HeLa cells, the Fe3+@F,N-CD complex shows clear MR images, demonstrating that it has potential to be an excellent MRI contrast agent. Furthermore, in vivo MRI experiments indicate that the Fe3+@F,N-CD complex provides high-resolution MRI pictures of 4T1 tumor bearing BALB/c mice 15 min after injection and can be completely excreted 2 h after administration. No cytotoxicity was observed with F,N-CDs and Fe concentration up to 0.2 mg/mL and 0.3 mM in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell proliferation assay, respectively. The possible mechanism of the enhanced MRI effect of the Fe3+@F,N-CD complex is therefore proposed. The extremely low toxicity, high r1 relaxivity, strong photoluminescence, and low synthetic cost enable the Fe3+@F,N-CD complex to be a safe and promising T1-weighted MRI contrast agent for clinical applications.

10.
Gene ; 700: 168-175, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-30904718

RESUMO

To evaluate the additional diagnostic yield of whole exome sequencing (WES) reanalysis in patients with epilepsy and intellectual disability/mental retardation, we reanalyzed raw WES data and clinical information for 76 patient trios whose initial reports returned negative results. Eight patients (10.5%, 8/76) had positive genetic diagnoses finally, including six novel mutations in five genes. The reasons for the previous false-negative reports were divided into four categories: specific gene-disease associations had not been established at the time of the initial report; the disease database of the genetic test center had not been updated in a timely manner; the patient's clinical phenotype had not been carefully or correctly collected, submitted and reviewed when applicating genetic test and analyzing the variants; and the first round of data analysis missed a synonymous variant that affected splicing. Therefore, physicians should not give up the discovery of disease-causing mutations before re-examining the WES data and clinical phenotype by themselves or by collaborating with bioinformatic experts in the genetic test centers, especially for patients with strongly suspected genetic disease whose initial WES result was "negative". The suitable time points for reanalysis might be the 6-12 months after initial report.


Assuntos
Epilepsia/genética , Testes Genéticos/métodos , Deficiência Intelectual/genética , Sequenciamento Completo do Exoma/métodos , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Masculino , Mutação , Fenótipo
11.
CNS Neurosci Ther ; 25(6): 759-771, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30720246

RESUMO

AIMS: Vanishing white matter disease (VWM) is an inherited leukoencephalopathy in children attributed to mutations in EIF2B1-5, encoding five subunits of eukaryotic translation initiation factor 2B (eIF2B). Although the defects are in the housekeeping genes, glial cells are selectively involved in VWM. Several studies have suggested that astrocytes are central in the pathogenesis of VWM. However, the exact pathomechanism remains unknown, and no model for VWM induced pluripotent stem cells (iPSCs) has been established. METHODS: Fibroblasts from two VWM children were reprogrammed into iPSCs by using a virus-free nonintegrating episomal vector system. Control and VWM iPSCs were sequentially differentiated into neural stem cells (NSCs) and then into neural cells, including neurons, oligodendrocytes (OLs), and astrocytes. RESULTS: Vanishing white matter disease iPSC-derived NSCs can normally differentiate into neurons, oligodendrocytes precursor cells (OPCs), and oligodendrocytes in vitro. By contrast, VWM astrocytes were dysmorphic and characterized by shorter processes. Moreover, δ-GFAP and αB-Crystalline were significantly increased in addition to increased early and total apoptosis. CONCLUSION: The results provided further evidence supporting the central role of astrocytic dysfunction. The establishment of VWM-specific iPSC models provides a platform for exploring the pathogenesis of VWM and future drug screening.

12.
Pediatr Neurol ; 94: 38-47, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30770271

RESUMO

BACKGROUND: We aimed to delineate the pattern of natural course, neuroimaging features, and the genotypic spectrum of cavitating leukoencephalopathies. METHODS: Children (age of onset ≤16 years) who met the criteria for cavitating leukoencephalopathies from January 2009 to October 2018 were identified. Whole-exome sequencing and prospective follow-up study of the natural history and brain magnetic resonance imaging (MRI) were performed. RESULTS: Thirty-seven children were clinically diagnosed with cavitating leukoencephalopathies. Pathogenic or likely pathogenic mutations in eight genes were identified in 31 individuals (83.78%): IBA57 (17/37), NDUFS1 (5/37), NDUFV1 (2/37), NDUFV2 (3/37), NDUFAF5 (1/37), LYRM7 (1/37), NDUFB8 (1/37), and GLRX5 (1/37). All genes were engaged in mitochondrial function. IBA57 was identified in half of children. Mutations in NDUFV2, NDUFAF5, NDUFB8, or GLRX5 were first found to be related to cavitating leukoencephalopathies. Follow-up with a median of 23.5 months (four to 107 months) was available. The median age at disease onset was 11 months. All cases presented acute or subacute onset, and the initial presentation was rapid motor regression in 35 cases. Thirty-five children (35/37) exhibited a stabilized or improved pattern. Cavities and high-intensity diffusion-weighted imaging signals were the common MRI features during the acute stage. Although clinically stable, 21 children had reserved high diffusion-weighted imaging signals for a long time. Patients with different gene mutations show different MRI patterns. CONCLUSIONS: The study expands the number of genes involved in cavitating leukoencephalopathies to 22. IBA57 is the most common candidate gene. Most cases showed a stabilized or improved pattern after an acute or subacute onset, which is different from most other inherited metabolic diseases or leukodystrophies. More cases and a longer follow-up period are needed.

13.
J Clin Invest ; 129(3): 1240-1256, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30620337

RESUMO

Sphingolipid imbalance is the culprit in a variety of neurological diseases, some affecting the myelin sheath. We have used whole-exome sequencing in patients with undetermined leukoencephalopathies to uncover the endoplasmic reticulum lipid desaturase DEGS1 as the causative gene in 19 patients from 13 unrelated families. Shared features among the cases include severe motor arrest, early nystagmus, dystonia, spasticity, and profound failure to thrive. MRI showed hypomyelination, thinning of the corpus callosum, and progressive thalamic and cerebellar atrophy, suggesting a critical role of DEGS1 in myelin development and maintenance. This enzyme converts dihydroceramide (DhCer) into ceramide (Cer) in the final step of the de novo biosynthesis pathway. We detected a marked increase of the substrate DhCer and DhCer/Cer ratios in patients' fibroblasts and muscle. Further, we used a knockdown approach for disease modeling in Danio rerio, followed by a preclinical test with the first-line treatment for multiple sclerosis, fingolimod (FTY720, Gilenya). The enzymatic inhibition of Cer synthase by fingolimod, 1 step prior to DEGS1 in the pathway, reduced the critical DhCer/Cer imbalance and the severe locomotor disability, increasing the number of myelinating oligodendrocytes in a zebrafish model. These proof-of-concept results pave the way to clinical translation.

14.
Nat Nanotechnol ; 14(2): 131-136, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30617308

RESUMO

Spintronic devices based on antiferromagnetic (AFM) materials hold the promise of fast switching speeds and robustness against magnetic fields1-3. Different device concepts have been predicted4,5 and experimentally demonstrated, such as low-temperature AFM tunnel junctions that operate as spin-valves6, or room-temperature AFM memory, for which either thermal heating in combination with magnetic fields7 or Néel spin-orbit torque8 is used for the information writing process. On the other hand, piezoelectric materials were employed to control magnetism by electric fields in multiferroic heterostructures9-12, which suppresses Joule heating caused by switching currents and may enable low-energy-consuming electronic devices. Here, we combine the two material classes to explore changes in the resistance of the high-Néel-temperature antiferromagnet MnPt induced by piezoelectric strain. We find two non-volatile resistance states at room temperature and zero electric field that are stable in magnetic fields up to 60 T. Furthermore, the strain-induced resistance switching process is insensitive to magnetic fields. Integration in a tunnel junction can further amplify the electroresistance. The tunnelling anisotropic magnetoresistance reaches ~11.2% at room temperature. Overall, we demonstrate a piezoelectric, strain-controlled AFM memory that is fully operational in strong magnetic fields and has the potential for low-energy and high-density memory applications.

15.
Environ Sci Pollut Res Int ; 26(4): 4041-4055, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30554316

RESUMO

Understanding the intrinsic mechanism behind changes on energy intensity provides insights about reducing carbon emissions and promoting the sustainable development of Beijing-Tianjin-Hebei (BTH) region. Although various studies have found a causal relationship between energy intensity and energy-related carbon emissions, the internal mechanisms are still unclear. This paper presents a comprehensive analysis of the impact of energy intensity on carbon emissions from 2005 to 2015. With an association established between logarithmic mean Divisia index (LMDI) and generalized Fisher index (GFI), two-layer factor decomposition model is proposed to explore the factor analysis in-depth. (1) LMDI method proves that energy intensity is the main contributor that reduces carbon emissions in BTH. (2) GFI model further decomposes energy intensity into five effects, namely energy substitution, technology progress, labor productivity, capital substitution, and labor-capital resources allocation. (3) The results reveal that the effect of capital-energy substitution in declining energy intensity surpasses technology progress. (4) Energy-labor substitution has increased energy intensity, while energy-energy substitution is negligible. For the coordinate development of BTH, the government should aim at energy intensity and attach importance to encouraging entrepreneurship, accelerating the construction of carbon trading market, allocating resources rationally, and guiding the capital flow into energy-efficient direction.


Assuntos
Carbono/análise , Fontes Geradoras de Energia , Gases de Efeito Estufa/análise , Pequim , China , Cidades , Fontes Geradoras de Energia/estatística & dados numéricos , Modelos Teóricos
16.
Adv Neurobiol ; 21: 247-266, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30334225

RESUMO

Epilepsy is one of the most common complex neurological diseases. It is frequently associated with intellectual and developmental disabilities (ID/DD). In recent years, copy number variation (CNV), especially microdeletion, was proven to be a potential key factor of genetic epilepsy. In this paper, the authors tested the hypothesis that the large de novo rare CNV is an important cause of epilepsy with ID/DD. We performed a custom array comparative genomic hybridization (aCGH) to detect the CNVs of 96 Chinese epileptic patients with ID/DD. The aCGH was designed with a higher density probe coverage of 320 genes known to be involved in epilepsy and ID/DD with lower density whole-genome backbone coverage. We detected 9 large de novo rare microdeletions from 8 patients. These CNVs are located on 2q24.1, 2q33.1-q34, 5q13.2 (2 similar CNVs), 5q33.1-q34, 17p13.2, 22q11.21-q11.22 (2 identical CNVs) and Xp22.31. We also found that only a few genes in the CNVs are known epilepsy related genes. By analysis with systems biology, we found most of the genes are interacting genes known to be epilepsy related genes. We also found a gene motif "BGNADP", constructed by BTD, GALNT10, NMUR2, AUTS2, DLG2 and PTPRD, would be a key motif in epilepsy and ID/DD. These findings strongly indicate that some large de novo rare microdeletion is an important pathological cause of epilepsy with ID/DD. Our study also found a gene motif "BGNADP" should be a key small network in epilepsy with ID/DD.

17.
Am J Hum Genet ; 103(3): 448-455, 2018 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-30122539

RESUMO

Neurodevelopment is a transcriptionally orchestrated process. Cyclin K, a regulator of transcription encoded by CCNK, is thought to play a critical role in the RNA polymerase II-mediated activities. However, dysfunction of CCNK has not been linked to genetic disorders. In this study, we identified three unrelated individuals harboring de novo heterozygous copy number loss of CCNK in an overlapping 14q32.3 region and one individual harboring a de novo nonsynonymous variant c.331A>G (p.Lys111Glu) in CCNK. These four individuals, though from different ethnic backgrounds, shared a common phenotype of developmental delay and intellectual disability (DD/ID), language defects, and distinctive facial dysmorphism including high hairline, hypertelorism, thin eyebrows, dysmorphic ears, broad nasal bridge and tip, and narrow jaw. Functional assay in zebrafish larvae showed that Ccnk knockdown resulted in defective brain development, small eyes, and curly spinal cord. These defects were partially rescued by wild-type mRNA coding CCNK but not the mRNA with the identified likely pathogenic variant c.331A>G, supporting a causal role of CCNK variants in neurodevelopmental disorders. Taken together, we reported a syndromic neurodevelopmental disorder with DD/ID and facial characteristics caused by CCNK variations, possibly through a mechanism of haploinsufficiency.

18.
Zhongguo Dang Dai Er Ke Za Zhi ; 20(8): 652-657, 2018 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-30111475

RESUMO

Supernumerary marker chromosome 15 is a rare chromosome abnormality. This paper reports the clinical diagnosis and treatment, as well as genetic defects, of a child with supernumerary marker chromosome 15. The patient was a 9.5-year-old girl who had mental and motor retardation since infancy, breast development at the age of 7 years, and seizures at the age of 8.5 years. Seizures occurred with various features and could not be controlled by a variety of antiepileptic drugs. No abnormalities were found by brain magnetic resonance imaging. Electroencephalogram showed frequent epileptiform discharges. G-banding karyotype analysis, fluorescence in situ hybridization, methylation-specific multiplex ligation-dependent probe amplification, and array comparative genomic hybridization identified a de novo 15q duplication in the patient. The maternal copy number increased in the 15q11-13 region. The form of genome rearrangement was 47,XX,+inv dup(15)(pter to q13:q13 to pter). The increased copy number in the 15q11-13 region is closely related to mental retardation, intractable epilepsy, and central precocious puberty. High-resolution karyotype analysis is recommended for children with unexplained mental retardation and epilepsy.

19.
Int J Genomics ; 2018: 2361068, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30057904

RESUMO

Objective: Metachromatic leukodystrophy (MLD) is an inherited disease caused by a deficiency of the enzyme arylsulfatase A (ARSA) that leads to severe physiologic and developmental problems. Our study is aimed at elucidating the clinical and genetic characteristics of Chinese MLD patients. Methods: Clinical data of 21 MLD patients was collected. All coding exons of ARSA and their flanking intronic sequences were amplified by polymerase chain reaction and subjected to direct sequencing. Results: All 21 patients were diagnosed with MLD clinically and genetically, out of which 17 patients were late infantile and 4 were juvenile types. A total of 34 ARSA mutations, including 28 novel mutations (22 missense, 1 splicing, 1 nonsense, 3 small insertions, and 1 small deletion mutation) and 6 known mutations (5 missense and 1 small insertion mutation), were identified. Prenatal diagnosis was performed for four pedigrees. One fetus was a patient, two fetuses were carriers, and two were wild type. Conclusions: The present study discovered 28 novel ARSA mutations and widely expanded the mutation spectrum of ARSA. Four successful prenatal diagnoses provided critical information for MLD families.

20.
BMC Med Genomics ; 11(1): 49, 2018 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-29793483

RESUMO

BACKGROUND: Developmental delay (DD) and intellectual disability (ID) are frequently associated with a broad spectrum of additional phenotypes. Chromosomal microarray analysis (CMA) has been recommended as a first-tier test for DD/ID in general, whereas the diagnostic yield differs significantly among DD/ID patients with different comorbid conditions. METHODS: To investigate the genotype-phenotype correlation, we examined the characteristics of identified pathogenic copy number variations (pCNVs) and compared the diagnostic yields among patient subgroups with different co-occurring conditions. RESULTS: This study is a retrospective review of CMA results generated from a mixed cohort of 710 Chinese patients with DD/ID. A total of 247 pCNVs were identified in 201 patients (28%). A large portion of these pCNVs were copy number losses, and the size of copy number losses was generally smaller than gains. The diagnostic yields were significantly higher in subgroups with co-occurring congenital heart defects (55%), facial dysmorphism (39%), microcephaly (34%) or hypotonia (35%), whereas co-occurring conditions of skeletal malformation (26%), brain malformation (24%) or epilepsy (24%) did not alter the yield. In addition, the diagnostic yield nominally correlated with ID severity. CONCLUSION: Varied yields exist in DD/ID patients with different phenotypic presentation. The presence of comorbid conditions can be among factors to consider when planning CMA.

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