Hereditary spastic paraplegia (HSP) comprises a group of neurodegenerative disorders characterized by progressive spasticity of the lower limbs. Troyer syndrome (MIM #275900), an autosomal recessive form of complicated HSP, was initially described in the Old Order Amish population. The syndrome is associated with a spectrum of clinical manifestations, including spastic paraplegia, muscle atrophy, dysarthria, intellectual disability, and abnormal white matter on neuroimaging. The causative gene for Troyer syndrome has been identified as SPG20, which encodes the spartin protein. Spartin plays a pivotal role in lipid droplet degradation and mitochondrial function. Here, we report the clinical and molecular features of the second documented case of Troyer syndrome in China. The patient, a 5-year-8-month-old Han Chinese girl, presented with delayed psychomotor development, abnormal gait, and a history of febrile seizures. Whole-exome sequencing revealed a novel homozygous pathogenic variant, c.1734-1G>C, in SPG20, leading to a frameshift and the expression of a truncated protein. This variant was absent from multiple population databases of healthy individuals, and both parents were heterozygous carriers without clinical manifestations. Functional studies in cells transfected with SPG20 constructs demonstrated that the variant spartin protein failed to localize to lipid droplets, leading to their accumulation. This functional impairment may contribute to the pathogenesis of Troyer syndrome. Our findings expand the variant spectrum of SPG20 and provide further insight into the genotype–phenotype relationship in Troyer syndrome, highlighting the critical role of spartin in lipid metabolism and neuronal function.

Spinal muscular atrophy(SMA)is a progressive autosomal recessive motor neuron disease caused by a deficiency of survival motor neuron(SMN)protein due to biallelic dele-tion or a pathogenic variant of the SMN1 gene[1],which is classified into five types on the basis of onset age and severity,and the severity generally correlates inversely with the copy number of SMN2,a homologous gene on chromo-some 5q13[2].

Four patients with infantile-onset Pompe's disease received a single intravenous injection of an adeno-associated virus serotype 9 vector carrying codon-optimized complementary DNA encoding human acid α-glucosidase (GAA) (dose, 1.2 × 1014 vector genomes per kilogram of body weight). One patient was withdrawn from the study and subsequently died. The other patients had improvement in cardiac outcomes and motor function over a 52-week observation period. Anti-GAA antibodies were not detected in any of the patients during the observation period. Respiratory tract infections were the most common adverse events. (Funded by the National Natural Science Foundation of China and National High Level Hospital Clinical Research Funding; Chinese Clinical Trial Registry number, ChiCTR2200063229.).

BACKGROUND:Six-transmembrane epithelial antigen of prostate 3 (STEAP3), an essential constituent of the STEAP family protein, plays a notable role in promoting cancer proliferation and metastasis. Despite the importance of the STEAP gene family in tumor progression, the function of STEAP3 in cervical cancer (CC) remains unclear. MATERIALS AND METHODS:The expression of STEAP3 protein in CC tissues and cell lines was identified using immunohistochemistry. The Reduced Representation Bisulfite Sequencing (RRBS) was used to detect global gene DNA methylation in CC tissues and paracancerous tissues. Cell viability, proliferation, migration, and invasion, were evaluated using the Cell Counting Kit-8 (CCK8), 5-ethynyl-2'-deoxyuridine (EdU), wound repair assay, and transwell assay, respectively. RNA sequencing was applied to explore STEAP3-related signaling pathways. Western blotting was performed to detect the expression of related proteins, including epithelial-mesenchymal transition (EMT) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling markers. RESULTS:Herein, STEAP3 was strongly expressed in CC tissues and associated with poor prognosis. CC samples exhibited lower levels of STEAP3 methylation than normal samples, and the methylation levels of CpG islands in STEAP3 were association with prognosis. In contrast to control group, STEAP3 knockdown suppressed the proliferation and invasion of CC cells and enhanced sensitivity to oxaliplatin. Silencing of STEAP3 led to reduced N-cadherin and vimentin levels and increased E-cadherin expression. RNA sequencing analysis suggested that STEAP3 mediated the activation of the JAK STAT3 signaling pathway. Additionally, inhibition of STEAP3 decreased the phosphorylation of JAK2 and STAT3. Interestingly, colivelin (a STAT3 activator) modified STEAP3-induced cell proliferation, invasion, and expression of related proteins in the EMT and JAK/STAT3 signaling pathway. CONCLUSION:STEAP3 was significantly associated with CC progression mediated via the JAK/STAT3 signaling pathway and may serve as an effective therapeutic target.

AbstractDevelopmental delay (DD), or intellectual disability (ID) is a very large group of early onset disorders that affects 1–2% of children worldwide, which have diverse genetic causes that should be identified. Genetic studies can elucidate the pathogenesis underlying DD/ID. In this study, whole-exome sequencing (WES) was performed on 225 Chinese DD/ID children (208 cases were sequenced as proband-parent trio) who were classified into seven phenotype subgroups. The phenotype and genomic data of patients with DD/ID were further retrospectively analyzed. There were 96/225 (42.67%; 95% confidence interval [CI] 36.15–49.18%) patients were found to have causative single nucleotide variants (SNVs) and small insertions/deletions (Indels) associated with DD/ID based on WES data. The diagnostic yields among the seven subgroups ranged from 31.25 to 71.43%. Three specific clinical features, hearing loss, visual loss, and facial dysmorphism, can significantly increase the diagnostic yield of WES in patients with DD/ID (P = 0.005, P = 0.005, and P = 0.039, respectively). Of note, hearing loss (odds ratio [OR] = 1.86%; 95% CI = 1.00-3.46, P = 0.046) or abnormal brainstem auditory evoked potential (BAEP) (OR = 1.91, 95% CI = 1.02–3.50, P = 0.042) was independently associated with causative genetic variants in DD/ID children. Our findings enrich the variation spectrums of SNVs/Indels associated with DD/ID, highlight the value genetic testing for DD/ID children, stress the importance of BAEP screen in DD/ID children, and help to facilitate early diagnose, clinical management and reproductive decisions, improve therapeutic response to medical treatment.

Spinal muscular atrophy (SMA), a neurodegenerative disorder caused by mutations in survival motor neuron 1 (SMN1) resulting in reduced expression of the survival motor neuron (SMN) protein, is inherited in an autosomal recessive manner. SMA type 1 is the most frequent subtype of SMA characterized by onset before 6 months of life, inability to achieve independent sitting, and rapidly progressive respiratory and bulbar deterioration, causing a mortality of >90% before 2 years of age.[1] Currently, there have been two lifelong splice-modifying therapies (nusinersen and risdiplam), and a single-dose gene replacement therapy via intravenous onasemnogene abeparvovec for SMA type 1 patients, approved by the US Food and Drug Administration (FDA).[2] Here, we developed recombinant adeno-associated virus serotype 9 (AAV9) containing codon-optimized human SMN1 (co-SMN1) complementary DNA (GC101) driven by cytomegalovirus (CMV) enhancer and chicken β-actin promoter with the attributes of high titer, low endotoxin, low aggregation, and a low empty capsid rate. Knowing that the degeneration and death of α-motor neurons in the spinal cord and brainstem are major manifestations of the disease, and that the AAV9 vector would not only reach the motor neurons directly but could also pass the blood–brain barrier[3] before reaching the peripheral tissues, it seems possible that intrathecal injection of GC101[1] could have a favorable benefit-risk profile. The aim of this trial was to investigate the safety and efficacy of GC101 via intrathecal injection in SMA type 1 patients. This open-label, single-arm, phase 1 clinical trial of gene-replacement therapy was conducted in the Department of Pediatrics, the Seventh Medical Center of PLA General Hospital (Beijing, China). The study was done in accordance with the Declaration of Helsinki, International Council for Harmonisation and Good Clinical Practice guidelines. The study protocol and informed consent forms were reviewed and approved by the Ethics Committee of the Hospital (S2021-003). Written informed consent was obtained from all parents or guardians of the patients before study participation. The redacted study protocol is available at Chictr.org.cn (ChiCTR2200056833). GC101 was administered as a one-time intrathecal injection of 2.4 × 1014 vector genomes [vg] per infant. The details of the inclusion and exclusion criteria, treatments, outcomes, and statistical analysis are listed in the Supplementary file, https://links.lww.com/CM9/C76 (Supplemental methods, Supplemental table 1). Briefly, patients should be diagnosed as SMA type 1 with age ≤12 months. The patients were recruited in the study and received GC101 treatment between January 25, 2022 and April 12, 2022 at the Seventh Medical Center of PLA General Hospital (Beijing, China) [Figure 1A]. The demographics and baseline clinical characteristics are shown in Supplementary Table 2, Supplementary Figure 1, https://links.lww.com/CM9/C76. P2 and P3 survived without administration of supplemental oxygen, ventilation, and tube feeding during the 12-month observation period. The pharmacokinetic parameters were shown in Supplementary file, https://links.lww.com/CM9/C76 [Supplemental Figure 2, Table 3].Figure 1: Enrollment, motor function changes, timeline of treatments and motor milestones achievements of 3 SMA type 1 patients injected with GC101. (A) Trial profile. (B) Changes in the score for motor function on the CHOP INTEND (Three patients who received gene therapy with GC101 adeno-associated viral vector containing DNA coding for SMN). The scale ranges from 0 to 64, with higher scores indicating better motor function; the dashed lines on the curves indicate a missed assessment in that month. Due to the coronavirus disease 2019 (COVID-19) pandemic, P1 failed to attend the subsequent follow-up visits after week 4, and P2 and P3 failed to attend the follow-up visit at weeks 12 and 28 after injection with GC101, respectively. P1 withdrew from the trial because of respiratory failure (Grade III) due to severe pneumonia caused by infection, considered unrelated to GC101 at home at the 28th week (+6 days) after injection of GC101. (C) Timeline of treatments and motor milestones achievements. The motor milestone achievements of three patients were assessed by the six gross motor milestones of WHO criteria. Two patients received nusinersen treatment prior to GC101. Patient 2 received once on day 19 and Patient 3 received three times on day 83, 63, and 21 before intrathecal delivery of GC101. Termination in patient 1 means the time of withdrawal from the trial. CHOP-INTEND: Children's Hospital of Philadelphia-Infant Test of Neuromuscular Disorders; WHO: World Health Organization. SMN: Survival motor neuron. All adverse events (AEs) were Grade I or Grade II, except one serious adverse event (SAE) that occurred in P1 by the end of the observation period [Supplementary Table 4, https://links.lww.com/CM9/C76]. The SAE was respiratory failure (Grade III) due to severe pneumonia caused by infection, which was considered unrelated to GC101 because it occurred 28 weeks after injection. Most AEs occurred in the respiratory system which were considered not related to GC101. Transient fever (Day 1), diarrhea (Day 1–5), and loss of appetite (Day 6) occurred in P2, which were considered related with the GC101 treatment. The other systematic AEs, including anemia (P2), the increased heart rate and rapid breath (P1), and papular urticaria (P2), had no temporal association to the day of GC101 injection [Supplementary Table 4, https://links.lww.com/CM9/C76]. Of the biochemical indicators, elevation of total cholesterol (TC) and low density lipoprotein (LDL) cholesterol in all three patients was considered due to the treatment of prednisolone.[4,5] Atorvastatin was used in P2 (5th–6th weeks) because of the consistently high level of LDL cholesterol and it was considered to be related to the elevated levels of AST (6th week) and ALT (6th week) [Supplementary Figure 3, https://links.lww.com/CM9/C76]. Hypoglycemia in P3 was considered associated with the natural history of SMA [Supplementary Table 4, https://links.lww.com/CM9/C76]. The other laboratory test indicators [Supplementary Table 4, https://links.lww.com/CM9/C76] were not considered associated with GC101, for there was no temporal association to the day of GC101 treatment. No clinically significant abnormal indicator of coagulation function and D-dimer was observed. Early and sustained improvement in Children's Hospital of Philadelphia-Infant Test of Neuromuscular Disorders (CHOP-INTEND) assessments are shown in Figure 1B. One month after the GC101 injection, the CHOP-INTEND score increased 8 (P1), 9 (P2) and 10 (P3), which could be considered to be clinically meaningful.[6] The CHOP-INTEND scores reached the points of 53 and 57 at the end of the trial (52nd week). For P2 and P3, 10 of the 16 items reached the highest point 4 during the observation period. [Supplementary Figure 4, https://links.lww.com/CM9/C76]. P2 and P3 achieved two motor milestones according to the WHO scales during the observation period after GC101 injection [Figure 1C]. After injection of GC101, P2 and P3 could sit unassisted in the 28th week. At the last follow-up visit in the 50th week, P2 and P3 could stand with assistance for about 120 s and 30 s, respectively. Unfortunately, P1 did not attain any new milestones before withdrawal from the trial at the 28th week after GC101 injection. Our study showed that AAV9-mediated gene therapy via intrathecal injection was safe and effective for SMA type 1 infants. All AEs were Grade I or Grade II, except one SAE (respiratory failure) occurring in P1, which was not considered to be associated with the GC101 therapy. No associated event suggestive of dorsal root ganglia cell inflammation was observed. Laboratory test results did not reveal a specific pattern among infants who received GC101. P1 withdrew from the trial because of the serious AE. Both P2 and P3 achieved the motor milestone of "stand with assistance" 52 weeks after intrathecal injection with GC101, and survived without using oxygen supplementation, ventilation, and tube feeding at any time during the 12-month observation period. These results are comparable with the report given by Mendell et al[7], illustrating the feasibility and effectiveness of intrathecal injection with less dosing of GC101 as compared with intravenous injection with onasemnogene abeparvovec. Although it was confounded by treatment with nusinersen before GC101 treatment for P2 and P3, considering that nusinersen is needed successively (4 doses at Week 0, 2, 4, and 9, followed by dosing every 4 months), in addition to that fact that P2 and P3 did not receive any of the nusinersen or the other gene therapies during the observation period, the effectiveness of the one-dose GC101 therapy via intrathecal injection in the observation period could not be ignored and is considered important for the improvement of the infants. It is valuable and feasible for scaling up clinical trials to further validate the safety and therapeutic efficacy of GC101. In conclusion, our single-dose AAV9-mediated gene therapy of GC101 by intrathecal delivery for SMA type 1 patients proved to be safe and could extend survival time and improve motor function than in natural history of SMA patients. Limitation existed due to the relatively small sample size, however, the inspiring results of our study indicated that it is valuable for scaling up clinical trials to further assess the safety and efficacy of GC101. Acknowledgments We would like to thank all the parents or guardians for their participation in this study. We appreciate the hard work and dedication of many people who contributed to this study at the Seventh Medical Center of PLA General Hospital and Genecradle Therapeutic Inc. We would like to thank Richard D. Leapman of National Institute of Biomedical Imaging & Bioengineering (National Institutes of Health, Bethesda, MD, USA) for editing our manuscript. Funding This project was supported by the E-Town Cooperation & Development Foundation (No.YCXJ-JZ-2022-007). Conflicts of interest Wenhao Ma, Xiaodong Wang, Ying Du, Zhiming Zhu, Yingqian Zhang are employees of Genecradle Therapeutics Inc. during the conduct of the study. Xiaoyan Dong is co-founder of Genecradle Therapeutics Inc. during the conduct of the study. Xiaobing Wu is founder of Genecradle Therapeutics Inc. during the conduct of the study. Wenhao Ma, Xiaobing Wu, and Xiaoyan Dong has a patent. All the other authors declare no competing interests. Data sharing After publication, the data will be made available to others on reasonable requests to the corresponding authors. A proposal with detailed description of study objectives and statistical analysis plan will be needed for the evaluation of the reasonability of requests. Additional materials might also be required during the process of evaluation. Deidentified participant data will be provided after approval from the corresponding authors and Seventh Medical Centre of the Chinese PLA general hospital.

Bone marrow-derived mesenchymal stem cells (BMSCs) have been extensively studied for potential clinical use. Recently, increasing attention is being paid to the relationship between p53 and BMSCs differentiation. In this study, we investigated the effects of p53 on the alveolar epithelial differentiation of BMSCs. Rat BMSCs (rBMSCs) were cultured with and without hyperoxia-damaged lung tissue to observe their differentiation process in vitro. Furthermore, p53 expression was inhibited by pifithrin-alpha during rBMSCs differentiation. Transmission electron microscopy, immunofluorescence, luciferase assay, and an analysis of cell proliferation and apoptosis levels were performed to examine the changes in rBMSCs. We found that rBMSCs in vitro exhibited alveolar epithelial differentiation when co-cultured with damaged lung tissue, and cell apoptosis, cell proliferation, and p53 levels of rBMSCs were significantly altered during the differentiation process. Furthermore, when p53 was inhibited in rBMSCs by pifithrin-alpha (a specific p53 inhibitor), apoptosis was alleviated, cell proliferation was promoted, and the potential alveolar epithelial differentiation of rBMSCs was blocked. Our results suggest that p53 can effectively regulate alveolar epithelial differentiation of rBMSCs. These results provide the basis for developing more effective cellular clinical therapies for lung diseases in further research.

出生缺陷的概念及分类 出生缺陷又称发育缺陷,也称先天性异常,是指在出生时就存在的、非分娩损伤所致的、人类胚胎在外形或体内有可识别的结构或功能上的异常.胎儿在母体的子宫内发育异常,出生后表现为肉眼可见或通过辅助诊断技术检查出的器质性和功能、代谢、行为、精神等方面的异常,既包括染色体综合征和基因病,也包括环境致畸因素造成的缺陷.

Background: Genetic causes in most affected children with intellectual disability and/or development delay remain unknown. Methods: To identify potential variants responsible for these disorders, we recruited 161 affected families and performed whole-exome sequencing and associated bioinformatics analysis. Results: In the present study, we report the identification of variants in the ALG13 gene in two of the families. In family 1, a known pathogenic missense variant (c.23T > C; p.V8A) of ALG13 was identified in a boy and his mother. In family 2, a novel missense variant (c.862C > G; p.L288V) of the same gene was identified in the affected boy and his phenotypically normal mother. Genotype–phenotype correlation analysis by comparing reported 28 different variants (HGMD) showed that three major phenotypes, including various seizures/epilepsy, intellectual disability, and development delay (such as growth, speech, motor, etc.), are present in most affected individuals. However, other phenotypes, such as strabismus and absence of seizure in our second patient, are not reported if any, which may represent a unique case of X-linked recessive nonsyndromic disorder caused by a mutation in ALG13. Conclusion: We identified two missense variants in ALG13 in a cohort of 161 families with affected individuals diagnosed as intellectual disability and/or development delay. A novel c.862C > G mutation may represent a case of X-linked recessive.

Pathogenic variants in CHD2 have been reported to have a wide range of phenotypic variability in neurodevelopmental disorders, such as early-onset epileptic encephalopathy, developmental delay, and behavior problems. So far, there is no clear correlation between genotypes and phenotypes. This study reports a Chinese patient with a novel heterozygous CHD2 mutation (c.4318C>T, pArg1440*). Her main clinical manifestations include developmental delay, myoclonic epilepsy, and hypothyroidism. Then, we reviewed a total of 144 individuals carrying CHD2 variants with epileptic encephalopathy. In terms of clinical manifestations, these patients are usually described with variable epilepsy phenotypes, including idiopathic photosensitive occipital epilepsy, Dravet syndrome, Jeavons syndrome, Lennox-Gastaut syndrome, juvenile myoclonic epilepsy, and non-specific epileptic encephalopathy. Among them, myoclonic seizures and generalized tonic-clonic seizures are the main seizure types in all patients hosting CHD2 single-nucleotide or indel variants (non-CNVs). At the molecular level, there are 102 types of CHD2 non-CNVs in 126 patients, almost one mutational type corresponding to one person, and there is no difference in the incidence ratio of each position. Furthermore, we summarized that a small proportion of patients inherited CHD2 variants, and not all patients with CHD2 variants had seizures. Importantly, the phenotypes, especially seizures control and fever sensitivity, and genotypes had a relative association. These results enriched the database of CHD2-relative neurodevelopmental disorders and provided a theoretical foundation for researching the relationship between genotypes and phenotypes.

Background The classic infantile-onset Pompe disease (IOPD) is characterized by cardiac hypertrophy, respiratory insufficiency, and rapidly progressive muscle weakness due to the acid alpha-glucosidase (GAA) deficiency. Enzyme replacement therapy (ERT) is the current approach for IOPD, but it entails several limitations. Aiming to overcome the limited efficiency of ERT, we developed adeno-associated virus (AAV) gene therapy for IOPD patients.Method One IOPD patient received a single intravenous dose of GC301, a recombinant adeno-associated virus 9 (rAAV9) expressing the human GAA (rAAV-hGAA). During the follow-up, safety was accessed by the physical examinations, cardiac and laboratory evaluations. GAA activity, the titers of serum antibodies to AAV9 and GAA, and motor development were monitored regularly.Result The infant showed significant improvements in motor milestones. The GAA enzyme activity increased to the normal range. The cardiac function improved notably.Conclusion In patient with IOPD, a single intravenous AAV9-hGAA gene therapy improved the clinical outcomes remarkably. The trial is still ongoing, the safety of this gene therapy and the long-term clinical benefit remain to be monitored for months and years to come.### Competing Interest StatementThe authors have declared no competing interest.### Clinical TrialNCT05567627### Funding Statementthe Natural Science Foundation of China Youth Fund （32100640）### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This trial was approved by the ethics committee of the seventh medical center of PLA General Hospital (S2022-004-01)I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data produced in the present study are available upon reasonable request to the authors.

目的:探索Kaufman眼脑面综合征(KOS)的临床特征。方法:回顾中国人民解放军总医院第七医学中心儿科医学部儿内二病区确诊的1例KOS患儿的临床资料及检查结果。在PubMed、中国知网数据库检索KOS的相关文献，描述1例新病例的临床特点和基因型，并系统性回顾既往已报道的34例病例，总结KOS的临床特点。结果:既往已报道的34例KOS患儿的特征为：新生儿期喂养困难(90%)、呼吸困难(84%)，生长发育缓慢(85%)，智力障碍，颅面部畸形，包括：小头畸形(91%)、睑裂狭小/上睑下垂(91%)、短/前倾的鼻子(94%)、特殊的眉型(87%)等。本例患儿主要临床表现为：生长发育迟缓、喂养困难和面容异常，异常面容表现：小头畸形、右眼上睑缺损、睑裂狭小/上睑下垂、睑裂上斜、眼距宽、耳位低、低鼻梁、鼻孔前倾、小嘴、小下颌。1岁9个月时全外显子测序发现泛素蛋白质连接酶E3B基因( UBE3B基因)Exon25纯合突变c.2737C>T(p.R913X)，Sanger测序验证父母均携带此突变，诊断KOS。随访患儿至4岁8个月，精神、运动及体格发育均明显落后。 结论:新生儿期的呼吸困难和喂养困难、生长发育迟缓、智力障碍、颅面部异常是KOS患儿的常见表现，颅面部异常包括：小头畸形、睑裂狭小、短/前倾的鼻子、特殊的眉型等，诊断依靠基因检测。

目的:探讨脑胶质瘤及急性播散性脑脊髓炎(acute disseminated encephalomyelitis，ADEM)的临床与头颅MRI特点，分析误诊原因，减少早期误诊率。方法:回顾性分析我院一例脑胶质瘤患儿误诊为ADEM的临床表现及头颅MRI特点并进行文献复习。结果:患儿，10岁，以头痛、呕吐和精神差为主要临床表现。头颅MRI提示左侧顶叶、颞叶、海马、后联合、胼胝体、双侧基底节及脑室旁、桥脑延髓、双侧小脑齿状核肿胀，可见多发片状稍长T2稍长T1异常信号影，诊断为ADEM。经过丙种球蛋白(2 g/kg)、甲泼尼龙琥珀酸钠[20 mg/(kg·d)]冲击治疗3个疗程，随后口服醋酸泼尼松片，头疼、呕吐症状完全缓解，激素总疗程3个月。复查头颅MRI提示左侧顶叶、颞叶、海马、后联合、胼胝体、双侧基底节及脑室旁、桥脑延髓、双侧小脑齿状核肿胀，可见多发片状稍长T2稍长T1异常信号影。激素停用后1个月，患儿再次出现头疼、呕吐，行脑组织病理学检查，确诊为脑胶质瘤(星形细胞瘤，WHO Ⅱ级)，行手术治疗、联合化疗和放疗，症状缓解，随访1年无复发。结论:脑胶质瘤在颅内呈弥漫性、多发性病变，头颅MRI及临床表现不典型，极易误诊，应与ADEM、多发性硬化、中枢神经系统感染等疾病相鉴别。

目的 分析多发先天畸形-肌张力低下-癫痫综合征1(MCAHS1)的临床及遗传学特征.方法 回顾2018年4月确诊的1例MCAHS 1患儿的临床资料;应用全外显子测序及Sanger验证行基因检测;采用流式细胞术分析患儿外周血粒细胞表面糖基磷脂酰肌醇(GPI)锚定蛋白FLAER、CD16、CD24、CD58、CD59表达量.结果 男性患儿,4月龄,因阵发性双眼上翻,发育落后就诊;患儿有特殊面容、肌张力低下.全外显子测序发现患儿PIGN基因存在2个杂合变异,c.343 G>C和c.1694 G>T,分别来自于临床表型正常的母亲和父亲,为复合杂合变异.该变异尚未见报道,经美国医学遗传学与基因组学学会(ACMG)指南评级为疑似致病性变异.该复合杂合变异导致粒细胞表面GPI锚定蛋白的表达量下降.随访发现患儿10月龄出现发热抽搐,15月龄出现癫痫,口服丙戊酸钠后发作控制.经康复治疗患儿仍发育缓慢.文献检索已经报道MCAHS 1患者18例,基因变异以错义变异最常见,多数患儿预后不佳.结论 该MCAHS1患儿的基因测序扩充了MCAHS1基因变异谱.

The broad spectrum of intellectual disability (ID) patients' clinical manifestations, the heterogeneity of ID genetic variation, and the diversity of the phenotypic variation represent major challenges for ID diagnosis. By exploiting a manually curated systematic phenotyping cohort of 3803 patients harboring ID, we identified 704 pathogenic genes, 3848 pathogenic sites, and 2075 standard phenotypes for underlying molecular perturbations and their phenotypic impact. We found the positive correlation between the number of phenotypes and that of patients that revealed their extreme heterogeneities, and the relative contribution of multiple determinants to the heterogeneity of ID phenotypes. Nevertheless, despite the extreme heterogeneity in phenotypes, the ID genes had a specific bias of mutation types, and the top 44 genes that ranked by the number of patients accounted for 39.9% of total patients. More interesting, enriched co-occurrent phenotypes and co-occurrent phenotype networks for each gene had the potential for prioritizing ID genes, further exhibited the convergences of ID phenotypes. Then we established a predictor called IDpred using machine learning methods for ID pathogenic genes prediction. Using10-fold cross-validation, our evaluation shows remarkable AUC values for IDpred (auc = 0.978), demonstrating the robustness and reliability of our tool. Besides, we built the most comprehensive database of ID phenotyped cohort to date: IDminer http://218.4.234.74:3100/IDminer/, which included the curated ID data and integrated IDpred tool for both clinical and experimental researchers. The IDminer serves as an important resource and user-friendly interface to help researchers investigate ID data, and provide important implications for the diagnosis and pathogenesis of developmental disorders of cognition.

Background To date, at least 746 genes have been identified to cause intellectual disability (ID). Among them, mutations in the Methyl CpG binding protein 2 ( MECP2 ) gene are the leading cause of Rett syndrome and associated ID. Methods Considering the large number of ID-associated genes, we applied trio-based whole-exome sequencing (trio-WES) and in silico analysis for genetic diagnosis of 294 children with ID. Results Three de novo heterozygous mutations [NM_004992.3: c.502C > T, p.(Arg168*), c.916C > T, p.(Arg306Cys), and c.879C > G, p.(Ile293Met)] in MECP2 were identified in three unrelated girls. The first two mutations were detected in two patients who were diagnosed as typical Rett syndrome, X-linked ID and psychomotor retardation. The third mutation (c.879C > G), a previously unreported, was found in a 6-year-old girl with ID, microcephaly, severe underweight and psychomotor retardation. Particularly, this extremely rare de novo mutation (DNM) is located in the transcriptional repression domain (TRD) of MECP2 , where at least 62 different causal mutations are identified. Conclusions We identified three DNMs in MECP2 in a cohort of 294 individuals with ID. The novel c.879C > G mutation, as a likely pathogenic allele, may become a risk factor associated with X-linked ID, microcephaly and psychomotor retardation.

[Objective] To explore the correlation between the genetic polymorphism at the T-819C locus of IL-10 gene and susceptibility to spontaneous preterm birth (SPTB).[Methods] There were 569 SPTB neonates in the case group and 673 term neonates in the control group.The single nucleotide polymorphism was genotyped at the T-819C locus of IL-10 gene by Sequenom MassARRAY(R)SNP.[Results] Compared with the TT genotype,the IL-10T-819C C-positive genotype (TC + CC genotype) was significantly associated with an increased susceptibility to extreme preterm birth.[Conclusion] Among the Chinese population,IL-10T-819C polymorphism is significantly associated with genetic susceptibility to extreme preterm birth.

OBJECTIVE:To investigate the association between the genetic polymorphism of IL-6 C-572G and susceptibility to spontaneous preterm birth (SPTB). METHODS:The subjects were from Beijing and the surrounding areas of Beijing. This case-control study enrolled 569 SPTB infants, including 56 extremely preterm (<28 weeks of gestation), 166 very preterm (28-31+6 weeks of gestation) and 347 moderate to late preterm infants (32 to 36+6 weeks of gestation). A total of 673 term infants were enrolled as the control group. The latest Sequenom MassARRAY®SNP detection technique was used for the typing of single nucleotide polymorphism of IL-6 C-572G. RESULTS:Compared with the CC genotypes, the IL-6 C-572G G-positive genotype (CG+GG genotype) was significantly associated with an increased susceptibility to moderate to late SPTB (OR=1.35, 95%CI: 1.01-1.80, P=0.04). CONCLUSIONS:Among the Chinese population, IL-6 C-572G polymorphism is associated with susceptibility to moderate to late SPTB.

OBJECTIVE To study the association between interleukin-1β (IL-1β) C+3953T and genetic susceptibility to spontaneous preterm birth (SPTB). METHODS In this case-control study, 753 SPTB neonates were enrolled in the case group and 681 full-term neonates were enrolled in the control group. The latest Sequenom MassARRAY®SNP detection technique was used for the typing of single nucleotide polymorphisms (SNP) of IL-1β C+3953T. RESULTS Compared with those carrying CC genotype of IL-1β C+3953T, the neonates who carried at least one T allele (CT+TT genotype) had significantly increased risks of SPTB, SPTB complicated by premature rupture of membranes, and mild preterm birth. CONCLUSIONS In the Chinese population, IL-1β C+3953T has significant genetic association with an increased risk of SPTB. The identification of this SNP helps to prevent SPTB and clarify the causes and pathogenesis of SPTB.

OBJECTIVE:To study the association between tumor necrosis factor-α (TNF-α) G-308A polymorphisms and genetic susceptibility to spontaneous preterm birth (SPTB).METHODS:The case group enrolled 753 SPTB infants and the control group included 681 term infants. TNF-α G-308A polymorphisms were genotyped using Sequenom MassARRAY®SNP.RESULTS:The frequencies of the allele (G and A) in the case and control groups were not significantly different (P=0.35). The frequencies of the genotypes (GG, GA and AA) in the case and control groups were not significantly different (P=0.64). The logistic regression analysis found that TNF-α G-308A was not associated with genetic susceptibility to SPTB (OR=0.85; 95%CI: 0.61-1.19; P=0.35).CONCLUSIONS:There is no association between the polymorphisms of TNF-α G-308A and the genetic susceptibility to SPTB.