Small-molecule-induced epigenetic rejuvenation promotes SREBP condensation and overcomes barriers to CNS myelin regeneration.

Remyelination failure in diseases like multiple sclerosis (MS) was thought to involve suppressed maturation of oligodendrocyte precursors; however, oligodendrocytes are present in MS lesions yet lack myelin production. We found that oligodendrocytes in the lesions are epigenetically silenced. Developing a transgenic reporter labeling differentiated oligodendrocytes for phenotypic screening, we identified a small-molecule epigenetic-silencing-inhibitor (ESI1) that enhances myelin production and ensheathment. ESI1 promotes remyelination in animal models of demyelination and enables de novo myelinogenesis on regenerated CNS axons. ESI1 treatment lengthened myelin sheaths in human iPSC-derived organoids and augmented (re)myelination in aged mice while reversing age-related cognitive decline. Multi-omics revealed that ESI1 induces an active chromatin landscape that activates myelinogenic pathways and reprograms metabolism. Notably, ESI1 triggered nuclear condensate formation of master lipid-metabolic regulators SREBP1/2, concentrating transcriptional co-activators to drive lipid/cholesterol biosynthesis. Our study highlights the potential of targeting epigenetic silencing to enable CNS myelin regeneration in demyelinating diseases and aging.

Olig2 targets chromatin remodelers to enhancers to initiate oligodendrocyte differentiation.

Establishment of oligodendrocyte identity is crucial for subsequent events of myelination in the CNS. Here, we demonstrate that activation of ATP-dependent SWI/SNF chromatin-remodeling enzyme Smarca4/Brg1 at the differentiation onset is necessary and sufficient to initiate and promote oligodendrocyte lineage progression and maturation. Genome-wide multistage studies by ChIP-seq reveal that oligodendrocyte-lineage determination factor Olig2 functions as a prepatterning factor to direct Smarca4/Brg1 to oligodendrocyte-specific enhancers. Recruitment of Smarca4/Brg1 to distinct subsets of myelination regulatory genes is developmentally regulated. Functional analyses of Smarca4/Brg1 and Olig2 co-occupancy relative to chromatin epigenetic marking uncover stage-specific cis-regulatory elements that predict sets of transcriptional regulators controlling oligodendrocyte differentiation. Together, our results demonstrate that regulation of the functional specificity and activity of a Smarca4/Brg1-dependent chromatin-remodeling complex by Olig2, coupled with transcriptionally linked chromatin modifications, is critical to precisely initiate and establish the transcriptional program that promotes oligodendrocyte differentiation and subsequent myelination of the CNS.

Microglia-organized scar-free spinal cord repair in neonatal mice.

Spinal cord injury in mammals is thought to trigger scar formation with little regeneration of axons1-4. Here we show that a crush injury to the spinal cord in neonatal mice leads to scar-free healing that permits the growth of long projecting axons through the lesion. Depletion of microglia in neonatal mice disrupts this healing process and stalls the regrowth of axons, suggesting that microglia are critical for orchestrating the injury response. Using single-cell RNA sequencing and functional analyses, we find that neonatal microglia are transiently activated and have at least two key roles in scar-free healing. First, they transiently secrete fibronectin and its binding proteins to form bridges of extracellular matrix that ligate the severed ends of the spinal cord. Second, neonatal-but not adult-microglia express several extracellular and intracellular peptidase inhibitors, as well as other molecules that are involved in resolving inflammation. We transplanted either neonatal microglia or adult microglia treated with peptidase inhibitors into spinal cord lesions of adult mice, and found that both types of microglia significantly improved healing and axon regrowth. Together, our results reveal the cellular and molecular basis of the nearly complete recovery of neonatal mice after spinal cord injury, and suggest strategies that could be used to facilitate scar-free healing in the adult mammalian nervous system.

Effects of nitrate- and ammonium- nitrogen on anatomical and physiological responses of Catalpa bungei under full and partial root-zone drought.

Catalpa bungei is a precious timber species distributed in North China where drought often occurs. To clarify adaptive responses of C. bungei to partial- and full- root-zone drought under the influence of nitrogen forms, a two-factor experiment was conducted in which well-watered (WW), partial root-zone drought in horizontal direction (H-PRD) and in vertical direction (V-PRD), and full root-zone drought (FRD) were combined with nitrate-nitrogen (NN) and ammonium-nitrogen (AN) treatments. C. bungei responded to FRD by sharply closing stomata, decreasing gas exchange rate and increasing leaf instantaneous water use efficiency (WUEi). Under FRD condition, the growth of seedlings was severely inhibited and the effect of N forms was covered up by the drastic drought effect. In comparison, stomata conductance and gas exchanges were moderately inhibited by PRDs. WUEi in V-PRD treatment was superior to H-PRD due to the active stomata regulation resulting from a higher ABA level and active transcription of genes in abscisic acid (ABA) signaling pathway under V-PRD. Under both PRDs and FRD, nitrate benefited antioxidant defense, stomata regulation and leaf WUEi. Under V-PRD, WUEi in nitrate treatment was superior to that in ammonium treatment due to active stomata regulation by signaling network of nitric oxide (NO), Ca2+ and ABA. Under FRD, WUEi was higher in nitrate treatment due to the favoring photosynthetic efficiency resulting from active NO signal and antioxidant defense. The interactive effect of water and N forms was significant on wood xylem development. Superoxide dismutase (SOD) and catalase (CAT) largely contributes to stress tolerance and xylem development.

Variants in BSN gene associated with epilepsy with favourable outcome.

BACKGROUND: BSN gene encodes Bassoon, an essential protein to assemble the cytomatrix at the active zone of neurotransmitter release. This study aims to explore the relationship between BSN variants and epilepsy. METHODS: Whole-exome sequencing was performed in a cohort of 313 cases (trios) with epilepsies of unknown causes. Additional cases with BSN variants were collected from China Epilepsy Gene V.1.0 Matching Platform. The Clinical Validity Framework of ClinGen was used to evaluate the relationship between BSN variants and epilepsy. RESULTS: Four pairs of compound heterozygous variants and one cosegregating heterozygous missense variant in BSN were identified in five unrelated families. These variants presented statistically higher frequency in the case cohort than in controls. Additional two de novo heterozygous nonsense variants and one cosegregating heterozygous missense variant were identified in three unrelated cases from the gene matching platform, which were not present in the Genome Aggregation Database. The missense variants tended to be located in C-terminus, including the two monoallelic missense variants. Protein modelling showed that at least one missense variant in each pair of compound heterozygous variants had hydrogen bond alterations. Clinically, two cases were diagnosed as idiopathic generalised epilepsy, two as focal epilepsy and the remaining four as epilepsy with febrile seizures plus. Seven out of eight probands showed infancy or childhood-onset epilepsy. Eight out of 10 affected individuals had a history of febrile convulsions. All the cases were seizure-free. The cases with monoallelic variants achieved seizure-free without treatment or under monotherapy, while cases with biallelic missense variants mostly required combined therapy. The evidence from ClinGen Framework suggested an association between BSN variants and epilepsy. CONCLUSION: The BSN gene was potentially a novel candidate gene for epilepsy. The phenotypical severity was associated with the genotypes and the molecular subregional effects of the variants.

Clinical features of CNOT3-associated neurodevelopmental disorder in three Chinese patients.

CNOT3 is the central component of the CCR4-NOT protein complex, which is a global regulator of RNA polymerase II transcription. Loss of function mutations in CNOT3 lead to intellectual developmental disorder with speech delay, autism, and dysmorphic facies (IDDSADF), which is very rare. Herein, we reported two novel heterozygous frameshift mutations (c.1058_1059insT and c.724delT) and one novel splice site variant (c.387 + 2 T > C) in CNOT3 (NM_014516.3) gene in three Chinese patients with dysmorphic features, developmental delay, and behavior anomalies. The functional study showed that the CNOT3 mRNA levels were significantly decreased in the peripheral blood of two patients with c.1058_1059insT and c.387 + 2 T > C variants, respectively, and minigene assay demonstrated that the splice variant (c.387 + 2 T > C) resulted in exon skipping. We also found that CNOT3 deficiency was linked to alterations of expression levels of other CCR4-NOT complex subunits in mRNA level in the peripheral blood. By analyzing the clinical manifestations of all these patients with CNOT3 variants, including our three cases and 22 patients previously reported, we did not observe a correlation between genotypes and phenotypes. In summary, this is the first time to report cases with IDDSADF in the Chinese population, and three novel CNOT3 variants in these patients expand its mutational spectrum.

Combined effects of high-fat diet and polystyrene microplastic exposure on microplastic bioaccumulation and lipid metabolism in zebrafish.

Extensive use of microplastics (MPs) threatens the safety of aquatic environments and hydrobionts. Increasing the weight of economic fish through high-fat diet (HFD) to increase production is common in aquaculture. However, little is known about the combined effects of MPs and HFD in fish. The aim of this study was to investigate the relationship between adiposity and MP bioaccumulation in fish. Using zebrafish as a vertebrate model, the content of polystyrene (PS) MPs in zebrafish tissues exposed to 5 and 50 µm of 1000 µg/L PS MPs was detected via confocal Raman spectroscopy in normal diet (ND) and HFD. The content of PS MPs in HFD group was significantly higher than that in ND group. The levels of hepatic lipids were significantly elevated in zebrafish subjected to HFD treatment, and this effect was aggravated by exposure to 5 µm PS MPs, and even caused liver injury. Transcriptomic analysis revealed that exposure to PS MPs interferes with hepatic lipid metabolism and energy homeostasis in zebrafish. These results suggests that in addition to controlling the use and performing proper recycling of plastic products in our daily life, we should not blindly increase the weight of fish through HFD. This aids protect the quality of economic fish and prevent MPs from being consumed by humans through the food chain. This study explored the interaction between fish feed culture and environmental pollutants to provide important reference for fish culture.

Unraveling the influential mechanism of short-chain branching on the crystallization of trimodal polyethylene by molecular dynamics simulation.

Trimodal polyethylene (PE) has become the focus of research in recent years due to its excellent performance. By means of molecular dynamics simulations, we aim to expound the molecular mechanism of short-chain branching (SCB) in the nucleation process, crystallization process and chain entanglement of trimodal PE. In this study, a series of polyethylene models including different short-chain branching concentrations (SCBCs), short-chain branching lengths (SCBLs), and short-chain branching distributions (SCBDs) were considered. The increase of SCBCs greatly reduces the ability of flipping and movement of PE chains, resulting in more time for nucleation and crystallization and a significant reduction of crystallinity. In contrast, an increase in the SCBL only slightly slows down the diffusion rate of the chain, which leads to a little increase in crystallization time. Most important of all, in the study of SCBD, we find that the distribution of SCBs on a high molecular weight chain, which is the characteristic of trimodal PE, is conducive to the chain entanglement and prevents the occurrence of micro phase separation compared with the case where the SCBs are distributed on a medium molecular weight chain. The mechanism of chain entanglement is proposed to explain the effect of SCBs on tie chain entanglement.

Ruthenium red attenuates acute pancreatitis by inhibiting MCU and improving mitochondrial function.

Acute pancreatitis (AP) is a common inflammatory disease of the digestive system. Mitochondrial calcium uniporter (MCU) mediates mitochondrial uptake of Ca2+ and plays an important role in calcium homeostasis. However, it is undefined whether AP can be relieved by inhibiting MCU. This study aimed to study the therapeutic potential of Ruthenium red (RuR), a MCU inhibitor, in AP mice model and primary acinar cells. Cell injury and AP mice model was induced by caerulein. RuR alleviated CER-AP evidenced by reduced serum lipase, TNF-α, and pancreatic MPO levels, less severe pancreatic pathology damage, and decreased inflammatory cell infiltration. In freshly isolated pancreatic acinar cells, RuR diminished cell necrosis with effect on suppressing the expression of MCU. RuR also decreased levels of cytosolic calcium and ROS, preventing mitochondrial membrane potential loss, ATP depletion and MPTP opening. The present findings indicate that inhibit MCU by RuR has a beneficial effect in AP by preventing calcium overload, mitochondrial dysfunction, and cell necrosis.

Genetic testing enables a precision medicine approach for nephrolithiasis and nephrocalcinosis in pediatrics: a single-center cohort.

OBJECTIVE: Hereditary factors are the main cause of pediatric nephrolithiasis (NL)/nephrocalcinosis (NC). We summarized the genotype-phenotype correlation of hereditary NL/NC in our center, to evaluate the role of genetic testing in early diagnosis. METHODS: The clinical data of 32 NL/NC cases, which were suspected to have an inherited basis, were retrospectively analyzed from May 2017 to August 2020. The trio-whole exome sequencing was used as the main approach for genetic testing, variants were confirmed by Sanger sequencing, and pathogenicity analysis according to protein function was predicted with custom-developed software. RESULTS: Causative monogenic mutations were detected in 24 of 32 NL/NC patients, and copy number variation was detected in one patient. A summary of manifestations in patients with inherited diseases revealed a significant degree of growth retardation, increased urinary excretion of the low-molecular weight protein, hypercalciuria, electrolyte imbalances, and young age of onset to be common in heredity disease. In addition, some patients had abnormal renal function (3 ppm 25). The most frequent pathology identified was distal renal tubular acidosis (with inclusion of SLC4A1, ATP6V1B1, and ATP6VOA4 genes), followed by Dent disease (CLCN5 and OCRL1 genes), primary hyperoxaluria (PH) (AGXT and HOGA1 genes) and Kabuki syndrome (KMT2D gene), which was more likely to present as NC or recurrent stone and having a higher correlation with a specific biochemical phenotype and extrarenal phenotype. CONCLUSION: The etiology of NL/NC is heterogeneous. This study explored in depth the relationship between phenotype and genotype in 32 patients, and confirmed that genetic testing and clinical phenotype evaluation enable the precision medicine approach to treating patients.

Molecular dynamics simulation of extension-induced crystallization of branched bimodal HDPE: Unraveling the effects of short-chain branches.

Bimodal HDPE models were designed for extension-induced crystallization imitating the architecture of industrial bimodal HDPE copolymerized with ethylene and 1-butene, 1-hexene, or 1-octene. Crystallites of bimodal HDPE experienced the emergence of precursors, shish nuclei, and lamellae. The compact conformation of branched polymers impeded the rolling-over, deposition, and folding of chains on the substrate, and thus the formation of nuclei and lamella. Moreover, this retardation was intensified with the rising branch density and length, causing a depression of crystallinity and an increment of tie-chains concentration. Besides, when branches were all located on long chains, the compact conformation enlarged the resistance to the disentanglement of main chains, thus relatively fewer branched long chains were involved in the precursors or nuclei, resulting in the attenuation of lamella formation. Furthermore, for ethyl branched polymers, the coexistent orthorhombic and monoclinic crystallites were built up, and a few expanded monoclinic cells occurred for butyl branches because of the larger butyl reeling into lamella, while hexagonal crystals were created for ethyl/1-hexyl copolymers because of cocrystallization. Additionally, relative to ethyl, larger butyl and hexyl were preferential to be repelled outside crystals to form tie-chains, and hexyl branched polymers acquired relatively fewer tie-chains because of hexagonal eutectoid.

Identification and characterization of novel mutations in MOGS in a Chinese patient with infantile spams.

Congenital disorders of glycosylation (CDGs) are a genetically heterogeneous group of disorders caused by the defects in the synthesis and processing of glycoproteins. CDG is caused by mannosyl-oligosaccharide glucosidase (MOGS) deficiency, and is an extremely rare type, and only six patients have been reported. Here, we report a patient from China with facial dysmorphism, infantile spams, developmental delay, low vison, and abnormal liver function and low immunoglobulin. Brain MRI showed hypoplasia of the corpus callosum and slightly wide sulci at bilateral frontal parietal lobes. Compound heterozygous mutations of (c.1694G>A: R565Q and c.1619G>A: R540H) in exon 4 of MOGS gene (NM_006302.2) were identified by whole exome sequencing. Further investigation showed that the gene expression of MOGS in patients' peripheral blood was decreased. We observed that two mutations were associated with lower protein expression of MOGS, cell growth, and cell cycle in transiently transfected Hela cells. We also noticed that cell cycle-related proteins, ß-catenin, cyclin D1, and C-myc, were decreased in mutant cells. In conclusion, our study suggested whole exome sequencing, and genes associated with CDGs should be analyzed in patients with infantile spams and multiple system involvement, and mutant MOGS-impaired cell cycle progression. Our work broadens the mutation spectrum of MOGS gene.

A novel delins (c.773_819+47delinsAA) mutation of the PCCA gene associated with neonatal-onset propionic acidemia: a case report.

BACKGROUND: Propionic acidemia (PA)(OMIM#606054) is an inborn error of branched-chain amino acid metabolism, caused by defects in the propionyl-CoA carboxylase (PCC) enzyme which encoded by the PCCA and PCCB genes. CASE PRESENTATION: Here we report a Chinese neonate diagnosed with suspected PA based on the clinical symptoms, gas chromatography-mass spectrometry (GC/MS), and brain imaging tests. Targeted next-generation sequencing (NGS) was performed on the proband. We detected only one heterozygous recurrent nonsense variant (c.937C > T, p.Arg313Ter) in the PCCA gene. When we manually checked the binary alignment map (BAM) diagram of PCCA gene, we found a heterozygous deletion chr13:100915039-100915132delinsAA (c.773_819 + 47delinsAA) (GRCh37.p13) inside the exon 10 in the PCCA gene. The results were validated by Sanger sequencing and qPCR method in the family: the variant (c.937C > T, p.Arg313Ter) was in the maternal allele, and the delins was in the paternal allele. When the mother was pregnant again, prenatal diagnosis was carried out through amniocentesis at 18 weeks gestation, the fetus carried neither of the two mutations. After birth, newborn screening was undertaken, the result was negative. CONCLUSIONS: We identified a recurrent c.937C > T and a novel c.773_819 + 47delinsAA mutations in the PCCA gene, which may be the genetic cause of the phenotype of this patient. Our findings expanded the spectrum of causative genotype-phenotype of the PCCA gene. For the cases, the NGS results revealed only a heterozygous mutation in autosomal recessive disease when the gene is associated with phenotypes, it is necessary to manually check the BAM diagram to improve the detection rate. Targeted NGS is an effective technique to detect the various genetic lesions responsible for the PA in one step. Genetic testing is essential for genetic counselling and prenatal diagnosis in the family to avoid birth defects.

cDNA Library for Mining Functional Genes in Sedum alfredii Hance Related to Cadmium Tolerance and Characterization of the Roles of a Novel SaCTP2 Gene in Enhancing Cadmium Hyperaccumulation.

Heavy metal contamination presents serious threats to living organisms. Functional genes related to cadmium (Cd) hypertolerance or hyperaccumulation must be explored to enhance phytoremediation. Sedum alfredii Hance is a Zn/Cd cohyperaccumulator exhibiting abundant genes associated with Cd hypertolerance. Here, we developed a method for screening genes related to Cd tolerance by expressing a cDNA-library for S. alfredii Hance. Yeast functional complementation validated 42 of 48 full-length genes involved in Cd tolerance, and the majority of them were strongly induced in roots and exhibited diverse expression profiles across tissues. Coexpression network analysis suggested that 15 hub genes were connected with genes involved in metabolic processes, response to stimuli, and metal transporter and antioxidant activity. The functions of a novel SaCTP2 gene were validated by heterologous expression in Arabidopsis, responsible for retarding chlorophyll content decrease, maintaining membrane integrity, promoting reactive oxygen species (ROS) scavenger activities, and reducing ROS levels. Our findings suggest a highly complex network of genes related to Cd hypertolerance in S. alfredii Hance, accomplished via the antioxidant system, defense genes induction, and the calcium signaling pathway. The proposed cDNA-library method is an effective approach for mining candidate genes associated with Cd hypertolerance to develop genetically engineered plants for use in phytoremediation.

Molecular dynamics simulation of shish-kebab crystallization of polyethylene: Unraveling the effects of molecular weight distribution.

By means of molecular dynamics simulations, extensional flow was performed on five polyethylene models with different molecular weight distributions (MWDs) precisely designed in view of Grubbs, metallocene, Ziegler-Natta, and chromium-based catalysts, while ignoring the sequence distributions of short branches to shed light on the molecular mechanism of MWD on shish-kebab formation. The formation of shish-kebab crystallites can be divided into three stages: the emergence of precursors, evolution from precursors to shish nuclei, and the formation of lamellar crystallites. The results demonstrated that the precursors initiated from trans-rich segments with local order and minor crystallinity grew into large shish nuclei and eventually evolved into lamellae. There were more inconsecutively trans-state bonds occurring in long chains rather than in short chains, which promoted an easier transformation from precursors to shish nuclei. Therefore, broader MWDs make positive contributions to the formation of shish nuclei, increase the crystallization speed, and the generation of a more regular, compact, and thicker lamella with less tie molecule fractions, while the final crystallinity is independent of MWD.

Identification and comprehensive analysis of the characteristics and roles of leucine-rich repeat receptor-like protein kinase (LRR-RLK) genes in Sedum alfredii Hance responding to cadmium stress.

Sedum alfredii Hance is a Zn/Cd co-hyperaccumulator and its underlying molecular mechanism of Cd tolerance is worthy to be elucidated. Although numerous studies have reported the uptake, sequestration and detoxification of Cd in S. alfredii Hance, how it senses Cd-stress stimuli and transfers signals within tissues remains unclear. Leucine-rich repeat receptor-like protein kinases (LRR-RLKs) are vital for plant growth, development, immunity and signal transduction. Till now, there is lack of comprehensive studies addressing their functions in S. alfredii Hance responding to Cd stress. In the present study, we identified 60 LRR-RLK genes in S. alfredii Hance based on transcriptome analysis under Cd stress. They were categorized into 11 subfamilies and most of them had highly conserved protein structures and motif compositions. The inter-family diversity provided evidence for their functional divergence, supported by their expression level and profile in tissues under Cd stress. Co-expression network analysis revealed that the most highly connected hubs, Sa0F.522, Sa0F.1036, Sa28F.115 and Sa1F.472, were closely related with other genes involved in metal transport, stimulus response and transcription regulations. Of the ten hub genes exhibiting differential expression dynamics under the short-term Cd stress (Sa0F.522, Sa0F.1036 and Sa28F.115) were dramatically induced in the whole plant. Among them, Sa0F.522 gene was heterologously expressed in a Cd-sensitive yeast cell line and its function in Cd signal perception was confirmed. For the first time, our findings performed a comprehensive analysis of LRR-RLKs in S. alfredii Hance, mapped their expression patterns under Cd stress, and identified the key roles of Sa0F.522, Sa0F.1036 and Sa28F.115 in Cd signal transduction.

[Phenotypic and genotypic analysis of a girl carrying a 2q22.3 microduplication encompassing the MBD5 gene].

OBJECTIVE: To carry out single nucleotide polymorphism (SNP)-based chromosome microarray analysis (CMA) for a boy featuring global developmental delay. METHODS: The SNP array was conducted for the child, and real-time PCR was used to validate its result and identify the origin of pathological copy number variants. RESULTS: SNP array revealed that the patient has carried a de novo 2.5 Mb duplication at 2q22.3q23.3, which encompassed ACVR2A, KIF5C, MBD5, EPC2, LYPD6, LYPD6, MMADHC and ORC4 genes. Literature review suggested that the MBD5 gene from the duplicated region may have predisposed to the global developmental delay shown by the girl. CONCLUSION: The patient's clinical phenotype was consistent to that of 2q23 duplication, for which the MBD5 gene may play a key role. CMA has provided an important tool for the diagnosis of patients with global developmental delay.

[Genome-wide copy number microarray analysis for a boy with autism].

OBJECTIVE: To carry out genome-wide copy number variations (CNVs) analysis for a boy with autism by using single nucleotide polymorphism array (SNP array). METHODS: SNP array analysis was conducted for the boy and his parents, and the data was validated by real-time PCR. Correlation between the deleted genes and the phenotype was analyzed by reviewing the literature. RESULTS: The patient was found to carry a terminal deletion of 18q22.3q23 (7.1 Mb), which involved FBXO15, ZNF407, ZADH2, TSHZ1, MBP and ADNP2 genes. No pathogenic CNVs were found in the parents. Comparison of the patient with cases reported in the literature suggested that the ZNF407 gene probably accounts for the autistic phenotype in these patients. CONCLUSION: The autistic phenotype of the patient may be attributed to the 18q deletion, for which ZNF407 may be a critical candidate. SNP array has provided an useful tool for the study of molecular mechanism underlying autism.

[Clinical features and genetic analysis of a case with Coffin-Siris syndrome].

OBJECTIVE: To explore the clinical features and genomic abnormality of a patient with Coffin-Siris syndrome. METHODS: Microdeletion and microduplication were detected with chromosomal microarray analysis (CMA) and verified with real-time quantitative PCR. RESULTS: The patient, a 6-month-old boy, featured global development delay, thick eyebrows, low frontal hairline, long eyelash, flat nasal bridge, hypotonia, difficulty in turning over, over stretching of head, and hypoplatic nails. He could not stand stability or actively grasp. He also has characteristics of rickets. Chromosome karyotype of the patient was normal. Genomic analysis has detected a 1.3 Mb deletion in 6q25.3 region encompassing the ARID1B gene. Neither of his parents was found to harbor the same deletion. CONCLUSION: The 6q25.3 microdeletion probably underlies the Coffin-Siris syndrome in this patient, and rickets may be part of its clinical spectrum.

Severe congenital microcephaly with 16p13.11 microdeletion combined with NDE1 mutation, a case report and literature review.

BACKGROUND: Microcephaly is a disorder characterized by severe impairment in brain development, reduced brain and head size. Congenital severe microcephaly is very rare, and NDE1 deletion and genetic mutations are important contributors. CASE PRESENTATION: Single nucleotide polymorphism (SNP) chromosomal microarray analysis (CMA) and muation screening of NDE1 gene were performed in an 8-month patient with severe congenital microcephaly, and/or his parents. Genetic studies found a 16p13.11 deletion containing NDE1 gene, and a novel NDE1 mutation c.555_556GC > CT on the non-deleted homolog, inherited from his phenotypically normal parents, respectively. The 2 bp nucleotide change results in a missense mutation p.K185 N and a nonsense mutation p.Q186X. We also conducted literaturte review to compare the clinical phenotypes of our patient to those of cases previously reported with NDE1 mutations, and found all patients had mental retardation, severe microcephaly, and corpus callosum agenesis. CONCLUSION: This is the first Chinese reported with microcephaly caused by NDE1 mutations. NDE1 is a critical pathogenetic gene in severe congenital microcephaly. Sequencing NDE1 and CMA in patients with severe congenital microcephaly may be warranted.