Exploring the barriers and facilitators of palliative care in the adult intensive care unit from nurses' perspectives in China: A qualitative study.

BACKGROUND: Intensive care units (ICUs) in China primarily focus on active rescue efforts, and it is not common to provide palliative care services within the ICU. As nurses play a primary role as caregivers for end-of-life patients in the ICU, it is necessary to explore the factors that impede or facilitate palliative care from their perspective. AIM: To explore the barriers and facilitators associated with implementing palliative care in Chinese adult ICUs from nurses' perspectives. STUDY DESIGN: This study utilized a descriptive phenomenological research approach and purposive sampling to conduct face-to-face semi-structured interviews with nurses working in adult ICUs from three comprehensive hospitals in China during the period between February and May 2023. A total of 17 nurses were interviewed, and the collected data were transcribed, coded, and synthesized thematically. RESULTS: Two themes of barriers and facilitators of palliative care in the Chinese adult ICU were extracted. The three sub-themes of hindering factors are as follows: (1) The influence of Chinese traditional culture. (2) The specificity of the ICU context. (3) Lacking sufficient attention in the ICU. The three sub-themes of the promoting factors are as follows: (1) Government and society value palliative care. (2) Patients and their families have palliative care needs. (3) Nurses view palliative care positively. CONCLUSION: Currently, integrating palliative care into the ICU may face challenges such as cultural factors, the specificity of the ICU context, and insufficient attention. However, it is worth noting that as the government and society place more emphasis on palliative care, more and more people are gradually paying attention to the palliative care needs of critically ill patients and their families. RELEVANCE TO CLINICAL PRACTICE: This study serves as a reference for exploring an ICU palliative care service model that is suitable for China's national conditions, such as education and training, resource allocation, service processes, and the palliative care environment, among others.

Comprehensive assessment of the genetic characteristics of small for gestational age newborns in NICU: from diagnosis of genetic disorders to prediction of prognosis.

BACKGROUND: In China, ~1,072,100 small for gestational age (SGA) births occur annually. These SGA newborns are a high-risk population of developmental delay. Our study aimed to evaluate the genetic profile of SGA newborns in the newborn intensive care unit (NICU) and establish a prognosis prediction model by combining clinical and genetic factors. METHODS: A cohort of 723 SGA and 1317 appropriate for gestational age (AGA) newborns were recruited between June 2018 and June 2020. Clinical exome sequencing was performed for each newborn. The gene-based rare-variant collapsing analyses and the gene burden test were applied to identify the risk genes for SGA and SGA with poor prognosis. The Gradient Boosting Machine framework was used to generate two models to predict the prognosis of SGA. The performance of two models were validated with an independent cohort of 115 SGA newborns without genetic diagnosis from July 2020 to April 2022. All newborns in this study were recruited through the China Neonatal Genomes Project (CNGP) and were hospitalized in NICU, Children's Hospital of Fudan University, Shanghai, China. RESULTS: Among the 723 SGA newborns, 88(12.2%) received genetic diagnosis, including 42(47.7%) with monogenic diseases and 46(52.3%) with chromosomal abnormalities. SGA with genetic diagnosis showed higher rates in severe SGA(54.5% vs. 41.9%, P=0.0025) than SGA without genetic diagnosis. SGA with chromosomal abnormalities showed higher incidences of physical and neurodevelopmental delay compared to those with monogenic diseases (45.7% vs. 19.0%, P=0.012). We filtered out 3 genes (ITGB4, TXNRD2, RRM2B) as potential causative genes for SGA and 1 gene (ADIPOQ) as potential causative gene for SGA with poor prognosis. The model integrating clinical and genetic factors demonstrated a higher area under the receiver operating characteristic curve (AUC) over the model based solely on clinical factors in both the SGA-model generation dataset (AUC=0.9[95% confidence interval 0.84-0.96] vs. AUC=0.74 [0.64-0.84]; P=0.00196) and the independent SGA-validation dataset (AUC=0.76 [0.6-0.93] vs. AUC=0.53[0.29-0.76]; P=0.0117). CONCLUSION: SGA newborns in NICU presented with roughly equal proportions of monogenic and chromosomal abnormalities. Chromosomal disorders were associated with poorer prognosis. The rare-variant collapsing analyses studies have the ability to identify potential causative factors associated with growth and development. The SGA prognosis prediction model integrating genetic and clinical factors outperformed that relying solely on clinical factors. The application of genetic sequencing in hospitalized SGA newborns may improve early genetic diagnosis and prognosis prediction.

Genetic background and clinical characteristics of infantile hyperammonemia.

Background: This study was conducted to analyze the genetic spectrum and clinical characteristics of infantile hyperammonemia. Methods: Between January 2016 and June 2020, we retrospectively enrolled infantile hyperammonemia patients with definitive genetic diagnosis at the Children's Hospital of Fudan University. Based on the age of hyperammonemia onset, patients were grouped into neonatal and post-neonatal subgroups to compare their genetic and clinical features. Results: Collectively, 136 pathogenic or likely pathogenic variants of the 33 genes were identified. Fourteen genes were reported with hyperammonemia (42%, 14/33), with SLC25A13 and MUT being the top two detected genes. In contrast, 19 genes, which have not been previously reported with hyperammonemia, were detected (58%, 19/33), in which JAG1 and ABCC8 were the most frequently mutated genes. Compared with post-neonatal hyperammonemia, neonatal patients with hyperammonemia presented with higher rates of organic acidemia (P=0.001) and fatty acid oxidation disorder (P=0.006), but a lower rate of cholestasis (P<0.001). Patients with neonatal hyperammonemia had a higher ratio of peak plasma ammonia level ≥500 µmol/L (P=0.003) and were more likely to receive precision medicine (P=0.027); however, they had a refractory clinical course (P=0.001) and poorer prognosis than the infantile group. Conclusions: There were significant differences in the genetic spectrum, clinical features, clinical course, and outcomes between infants with different hyperammonemia onset ages.

Risk stratification of hemodynamically significant patent ductus arteriosus by clinical and genetic factors.

BACKGROUND: Hemodynamically significant patent ductus arteriosus (hsPDA) is associated with increased comorbidities in neonates. Early evaluation of hsPDA risk is critical to implement individualized intervention. The aim of the study was to provide a powerful reference for the early identification of high-risk hsPDA population and early treatment decisions. METHODS: We enrolled infants who were diagnosed with PDA and performed exome sequencing. The collapsing analyses were used to find the risk gene set (RGS) of hsPDA for model construction. The credibility of RGS was proven by RNA sequencing. Multivariate logistic regression was performed to establish models combining clinical and genetic features. The models were evaluated by area under the receiver operating curve (AUC) and decision curve analysis (DCA). RESULTS: In this retrospective cohort study of 2199 PDA patients, 549 (25.0%) infants were diagnosed with hsPDA. The model [all clinical characteristics selected by least absolute shrinkage and selection operator regression (all CCs)] based on six clinical variables was acquired within three days of life, including gestational age (GA), respiratory distress syndrome (RDS), the lowest platelet count, invasive mechanical ventilation, and positive inotropic and vasoactive drugs. It has an AUC of 0.790 [95% confidence interval (CI) = 0.749-0.832], while the simplified model (basic clinical characteristic model) including GA and RDS has an AUC of 0.753 (95% CI = 0.706-0.799). There was a certain consistency between RGS and differentially expressed genes of the ductus arteriosus in mice. The AUC of the models was improved by RGS, and the improvement was significant (all CCs vs. all CCs + RGS: 0.790 vs. 0.817, P < 0.001). DCA demonstrated that all models were clinically useful. CONCLUSIONS: Models based on clinical factors were developed to accurately stratify the risk of hsPDA in the first three days of life. Genetic features might further improve the model performance. Video Abstract (MP4 86834 kb).

Genetic background of idiopathic neurodevelopmental delay patients with significant brain deviation volume.

BACKGROUND: Significant brain volume deviation is an essential phenotype in children with neurodevelopmental delay (NDD), but its genetic basis has not been fully characterized. This study attempted to analyze the genetic factors associated with significant whole-brain deviation volume (WBDV). METHODS: We established a reference curve based on 4222 subjects ranging in age from the first postnatal day to 18 years. We recruited only NDD patients without acquired etiologies or positive genetic results. Cranial magnetic resonance imaging (MRI) and clinical exome sequencing (2742 genes) data were acquired. A genetic burden test was performed, and the results were compared between patients with and without significant WBDV. Literature review analyses and BrainSpan analysis based on the human brain developmental transcriptome were performed to detect the potential role of genetic risk factors in human brain development. RESULTS: We recruited a total of 253 NDD patients. Among them, 26 had significantly decreased WBDV (<-2 standard deviations [SDs]), and 14 had significantly increased WBDV (>+2 SDs). NDD patients with significant WBDV had higher rates of motor development delay (49.8% [106/213] vs . 75.0% [30/40], P  = 0.003) than patients without significant WBDV. Genetic burden analyses found 30 genes with an increased allele frequency of rare variants in patients with significant WBDV. Analyses of the literature further demonstrated that these genes were not randomly identified: burden genes were more related to the brain development than background genes ( P  = 1.656e -9 ). In seven human brain regions related to motor development, we observed burden genes had higher expression before 37-week gestational age than postnatal stages. Functional analyses found that burden genes were enriched in embryonic brain development, with positive regulation of synaptic growth at the neuromuscular junction, positive regulation of deoxyribonucleic acid templated transcription, and response to hormone, and these genes were shown to be expressed in neural progenitors. Based on single cell sequencing analyses, we found TUBB2B gene had elevated expression levels in neural progenitor cells, interneuron, and excitatory neuron and SOX15 had high expression in interneuron and excitatory neuron. CONCLUSION: Idiopathic NDD patients with significant brain volume changes detected by MRI had an increased prevalence of motor development delay, which could be explained by the genetic differences characterized herein.

Genetic architecture in neonatal intensive care unit patients with congenital heart defects: a retrospective study from the China Neonatal Genomes Project.

BACKGROUND: Congenital heart defects (CHDs) are the most common type of birth defects. The genetic aetiology of CHD is complex and incompletely understood. The overall distribution of genetic causes in patients with CHD from neonatal intensive care units (NICUs) needs to be studied. METHODS: CHD cases were extracted from the China Neonatal Genomes Project (2016-2021). Next-generation sequencing results and medical records were retrospectively evaluated to note the frequency of genetic diagnosis and the respective patient outcomes. RESULTS: In total, 1795 patients were included. The human phenotype ontology term of atrial septal defect, patent ductus arteriosus and ventricular septal defect account for a large portion of the CHD subtype. Co-occurring extracardiac anomalies were observed in 35.1% of patients. 269 of the cases received genetic diagnoses that could explain the phenotype of CHDs, including 172 copy number variations and 97 pathogenic variants. The detection rate of trio-whole-exome sequencing was higher than clinical exome sequencing (21.8% vs 14.5%, p<0.05). Further follow-up analysis showed the genetic diagnostic rate was higher in the deceased group than in the surviving group (29.0% vs 11.9%, p<0.05). CONCLUSION: This is the largest cohort study to explore the genetic spectrum of patients with CHD in the NICU in China. Our findings may benefit future work on improving genetic screening and counselling for NICU patients with CHD.

In the developing cerebral cortex: axonogenesis, synapse formation, and synaptic plasticity are regulated by SATB2 target genes.

BACKGROUND: Special AT-rich sequence-binding protein 2 is essential for the development of cerebral cortex and key molecular node for the establishment of proper neural circuitry and function. Mutations in the SATB2 gene lead to SATB2-associated syndrome, which is characterized by abnormal development of skeleton and central nervous systems. METHODS: We generated Satb2 knockout mouse model through CRISPR-Cas9 technology and performed RNA-seq and ChIP-seq of embryonic cerebral cortex. We conducted RT-qPCR, western blot, immunofluorescence staining, luciferase reporter assay and behavioral analysis for experimental verification. RESULTS: We identified 1363 downstream effector genes of Satb2 and correlation analysis of Satb2-targeted genes and neurological disease genes showed that Satb2 contribute to cognitive and mental disorders from the early developmental stage. We found that Satb2 directly regulate the expression of Ntng1, Cdh13, Kitl, genes important for axon guidance, synaptic formation, neuron migration, and Satb2 directly activates the expression of Mef2c. We also showed that Satb2 heterozygous knockout mice showed impaired spatial learning and memory. CONCLUSIONS: Taken together, our study supportsroles of Satb2 in the regulation of axonogenesis and synaptic formation at the early developmental stage and provides new insights into the complicated regulatory mechanism of Satb2 and new evidence to elucidate the pathogen of SATB2-associated syndrome. IMPACT: 1363 downstream effector genes of Satb2 were classified into 5 clusters with different temporal expression patterns. We identified Plxnd1, Ntng1, Efnb2, Ephb1, Plxna2, Epha3, Plxna4, Unc5c, and Flrt2 as axon guidance molecules to regulate axonogenesis. 168 targeted genes of Satb2 were found to regulate synaptic formation in the early development of the cerebral cortex. Transcription factor Mef2c is positively regulated by Satb2, and 28 Mef2c-targeted genes can be directly regulated by Satb2. In the Morris water maze test, Satb2+/- mice showed impaired spatial learning and memory, further strengthening that Satb2 can regulate synaptic functions.

PRMT3 drives glioblastoma progression by enhancing HIF1A and glycolytic metabolism.

Glioblastoma (GBM) is the most common and aggressive primary brain tumor, but the mechanisms underlying tumor growth and progression remain unclear. The protein arginine methyltransferases (PRMTs) regulate a variety of biological processes, however, their roles in GBM growth and progression are not fully understood. In this study, our functional analysis of gene expression networks revealed that among the PRMT family expression of PRMT3 was most significantly enriched in both GBM and low-grade gliomas. Higher PRMT3 expression predicted poorer overall survival rate in patients with gliomas. Knockdown of PRMT3 markedly reduced the proliferation and migration of GBM cell lines and patient-derived glioblastoma stem cells (GSC) in cell culture, while its over-expression increased the proliferative capacity of GSC cells by promoting cell cycle progression. Consistently, stable PRMT3 knockdown strongly inhibited tumor growth in xenograft mouse models, along with a significant decrease in cell proliferation as well as an increase in apoptosis. We further found that PRMT3 reprogrammed metabolic pathways to promote GSC growth via increasing glycolysis and its critical transcriptional regulator HIF1α. In addition, pharmacological inhibition of PRMT3 with a PRMT3-specific inhibitor SGC707 impaired the growth of GBM cells. Thus, our study demonstrates that PRMT3 promotes GBM progression by enhancing HIF1A-mediated glycolysis and metabolic rewiring, presenting a point of metabolic vulnerability for therapeutic targeting in malignant gliomas.

Case report: A novel truncating variant of BCL11B associated with rare feature of craniosynostosis and global developmental delay.

Craniosynostosis is a premature fusion of cranial sutures, resulting in abnormally shaped skull and brain development disorder. The description of craniosynostosis in patients with BCL11B mutations is rare. Here, we firstly report a 25-month-old Chinese boy with a novel frameshift variant in BCL11B gene. The patient was identified c.2346_2361del by whole-exome sequencing and was confirmed to be de novo by parental Sanger sequencing. This patient presented clinical phenotype of craniosynostosis as well as global developmental delay. He had a small mouth, thin upper lip, arched eyebrows, a long philtrum, midfacial hypoplasia and craniosynostosis. Brain MRI showed brain extracerebral interval and myelination changes, and brain CT with 3D reconstruction showed multi-craniosynostosis. Our study expands the clinical phenotypes of patients with BCL11B gene mutation, and our findings may help guide clinical treatment and family genetic counseling.

Rare-variant collapsing analyses identified risk genes for neonatal acute respiratory distress syndrome.

Background: Acute respiratory distress syndrome (ARDS) could account for a considerable proportion of neonatal death, while the genetic etiology and pathophysiology of neonatal ARDS remain elusive. In this case-control study, 515 neonates were enrolled in the China Neonatal Genomes Project (CNGP, NCT03931707) from August 2016 to June 2021, including 196 ARDS and 319 non-ARDS matched by sex, gestational age, birth weight, perinatal asphyxia, pneumonia, sepsis, and necrotizing enterocolitis. Clinical exome sequencing was used to detect genetic variants. Collapsing analyses together with permutation tests were used to identify ARDS risk genes enriched for rare variants in ARDS samples. In silico functional interaction analysis and expression pattern studies at different stages of lung development were used to investigate the biological functions of the risk genes. Results: Collapsing analyses identified that rare variants were significantly abundant in the genes associated with the precursor of the lamellar body and there were eight predicted risk genes with strong confidence (P < 0.01). Among them, the expression of EDNRB increased significantly in lung development and was up-regulated in ARDS (P < 0.05). In addition, 151 predicted transcriptional target proteins of EDNRB were highly enriched in the lamellar body responsible for pulmonary surfactant storage and secretion. Conclusions: In our study, the genes associated with pulmonary surfactant storage and release were highly enriched with rare variants. A novel neonatal ARDS risk gene EDNRB may be a key gene for neonatal lung development and pulmonary surfactant homeostasis. Additional validation in independent patient populations and further exploration of underlying molecular mechanisms are warranted.

A multi-omic approach reveals utility of CD45 expression in prognosis and novel target discovery.

CD45, the leukocyte common antigen, is expressed on almost all cells of the immunological and hematological systems. CD45 expression is related to a variety of diseases, including leukemia and lymphoma. In this study, we analyzed the expression level of CD45 across cancers and evaluated the relationship between its expression and patient prognosis. We further integrated methylation data to explore the differences in CD45 across cancers from a multi-omics perspective. We also analyzed the relationship between CD45 expression and levels of immune cell infiltrates and immune modifiers. Our results revealed the distinct expression characteristics and prognostic value of CD45 across multiple tumors. In addition, we screened drug targets based on the immune index defined by CD45 expression and identified that GPR84 affected the proliferation of tumor cells and was associated with the inflammation caused by immunotherapy. In summary, our findings provide a comprehensive understanding of the role of CD45 in oncogenesis and its prognostic significance across cancers.

Molecular Genetic Analysis of Newborns with Congenital Microcephaly.

INTRODUCTION: Data on the genetic landscape of congenital microcephaly (CM) in China are scarce, and the incidence of CM caused by the most commonly mutated gene ASPM in China remains unknown. METHODS: Sixty-one neonates with CM who were hospitalized in the Children's Hospital of Fudan University between August 1, 2016, and August 31, 2020, were enrolled, and the clinical data and clinical exome-sequencing data were analyzed. An additional 18,103 parental data entries from the Chinese Children's Genetic Testing Clinical Collaboration System database were collected to estimate the incidence of ASPM-related congenital microcephaly (ASPM-CM) in East China by analyzing the carrier frequency of ASPM mutations. RESULTS: Among the 61 neonates with CM, 35 (57.4%) patients were identified with genetic findings, including 24 patients with single nucleotide variants (SNVs) and 11 patients with copy number variations (CNVs). ASPM was the most common gene with detrimental SNVs detected in 3 patients. Patients with genetic findings showed a significantly higher incidence of developmental delay (91.3%, 21/23) than those without genetic findings (60%, 9/15) (p = 0.04). All the 3 decreased patients had genetic findings. The estimated ASPM-CM incidence in East China was 1/1,295,044. CONCLUSION: Comprehensive genetic testing, detecting both SNVs and CNVs, is recommended for newborns with CM. Patients with genetic findings should be aware of the potential for developmental delay. ASPM gene defect was the most common genetic cause of CM in this study. The estimation of the incidence of ASPM-CM in East China might provide a reference for analyzing overall incidence.

Clinical Study of 30 Novel KCNQ2 Variants/Deletions in KCNQ2-Related Disorders.

Background: KCNQ2-related disorder is typically characterized as neonatal onset seizure and epileptic encephalopathy. The relationship between its phenotype and genotype is still elusive. This study aims to provide clinical features, management, and prognosis of patients with novel candidate variants of the KCNQ2 gene. Methods: We enrolled patients with novel variants in the KCNQ2 gene from the China Neonatal Genomes Project between January 2018 and January 2021. All patients underwent next-generation sequencing tests and genetic data were analyzed by an in-house pipeline. The pathogenicity of variants was classified according to the guideline of the American College of Medical Genetics. Each case was evaluated by two geneticists back to back. Patients' information was acquired from clinical records. Results: A total of 30 unrelated patients with novel variants in the KCNQ2 gene were identified, including 19 patients with single-nucleotide variants (SNVs) and 11 patients with copy number variants (CNVs). For the 19 SNVs, 12 missense variants and 7 truncating variants were identified. Of them, 36.8% (7/19) of the KCNQ2 variants were located in C-terminal regions, 15.7% (3/19) in segment S2, and 15.7% (3/19) in segment S4. Among them, 18 of 19 patients experienced seizures in the early neonatal period. However, one patient presented neurodevelopmental delay (NDD) as initial phenotype when he was 2 months old, and he had severe NDD when he was 3 years old. This patient did not present seizure but had abnormal electrographic background activity and brain imaging. Moreover, for the 11 patients with CNVs, 20q13.3 deletions involving EEF1A2, KCNQ2, and CHRNA4 genes were detected. All of them presented neonatal-onset seizures, responded to antiepileptic drugs, and had normal neurological development. Conclusion: In this study, patients with novel KCNQ2 variants have variable phenotypes, whereas patients with 20q13.3 deletion involving EEF1A2, KCNQ2, and CHRNA4 genes tend to have normal neurological development.

Deletion of CHD8 in cerebellar granule neuron progenitors leads to severe cerebellar hypoplasia, ataxia, and psychiatric behavior in mice.

CHD8 is a candidate gene for autism spectrum disorders and neurological development delay. It has been reported to be essential for neurogenesis in the cerebral cortex, but the function of CHD8 in cerebellum has not been comprehensively investigated. The potential relationship of cerebellum dysplasia with psychiatric disorders in patients with CHD8 mutations is still not clear. In this study, we establish different conditional knockout mouse models to investigate the roles of CHD8 in cerebellar development. Mice with neural stem cell-specific Chd8 deletion exhibit significant reduction of cerebellum volume and no layering structure is detected. Genetic deletion of Chd8 in cerebellar granule neuron progenitors (GNPs) leads to cerebellar hypoplasia, absent of proliferation layer and ectopic of Purkinje neuron. However, no substantial cerebellar dysplasia is detected in mice with Purkinje neuron- or oligodendrocyte-specific Chd8 ablation. Single-cell RNA sequencing indicates that ribosome-related genes and pathways are most significantly disrupted in GNPs, indicating the potential mechanism. Importantly, in addition to the ataxia phenotype, mice with GNP-specific Chd8 ablation present a neuropsychiatric phenotype in three-chamber and light/dark tests. Taken together, our results provide insights not only into the function of CHD8 in cerebellar development, but also the pathogenesis of neuropsychiatric disorders in patients with CHD8 mutations.

mTOR pathway repressing expression of FoxO3 is a potential mechanism involved in neonatal white matter dysplasia.

Neonatal white matter dysplasia (NWMD) is characterized by developmental abnormity of CNS white matter, including abnormal myelination. Besides environmental factors such as suffocation at birth, genetic factors are also main causes. Signaling pathway is an important part of gene function and several signaling pathways play important roles in myelination. Here, we performed genetic analysis on a cohort of 138 patients with NWMD and found that 20% (5/25) cause genes which referred to 28.57% (8/28) patients enriched in mammalian target of rapamycin (mTOR) signaling pathway. Depletion of mTOR reduced genesis and proliferation of oligodendrocyte progenitor cells (OPC) during embryonic stage and reduced myelination in corpus callosum besides cerebellum and spinal cord during early postnatal stages which is related to not only differentiation but also proliferation of oligodendrocyte (OL). Transcriptomic analyses indicated that depletion of mTOR in OLs upregulated expression of forkhead box O3 (FoxO3), which is a repressor of expression of myelin basic protein, and downregulating expression of FoxO3 by short interfering RNA promoted OPCs develop into MBP+ OLs. Thus, our findings suggested that mTOR signaling pathway is NWMD-related pathway and mTOR is important for myelination of the entire CNS during early developmental stages through regulating expression of FoxO3 at least partially.

KIF5C deficiency causes abnormal cortical neuronal migration, dendritic branching, and spine morphology in mice.

BACKGROUND: Malformation of cortical development (MCD) includes a variety of developmental disorders that are common causes of neurodevelopmental delay and epilepsy. Most recently, clinical studies found that patients carrying KIF5C mutations present early-onset MCD; however, the underlying mechanisms remain elusive. METHODS: KIF5C expression level was examined in mouse primary cortical neurons and human ips-derived forebrain organoids. We studied the cortical neuronal migration, dendritic branching, and dendritic spine growth after knocking down the KIF5C gene by electroporation in vitro and in vivo. Then, we studied the transcriptome differences between the knockdown and control groups through RNA sequencing. RESULTS: We observed high KIF5C expression in neurons during the early developmental stage in mice and the human brain. Kif5c deficiency results in disturbed cortical neuronal migration, dendritic, and spine growth. Finally, we found that Kif5c knockdown affected several genes associated with cortical neuronal development in vitro. CONCLUSIONS: These results suggested a critical role for Kif5c in cortical development, providing insights into underlying pathogenic factors of kinesins in MCD. IMPACT: KIF5C mutation-related MCD might be caused by abnormal early cortical neuronal development. Kif5c deficiency led to abnormal cortical neuronal dendritic and spine growth and neuronal migration. Our findings explain how Kif5c deficiency is involved in the aberrant development of cortical neurons and provide a new perspective for the pathology of MCD.

Novel Variants of the SMARCA4 Gene Associated with Autistic Features Rather Than Typical Coffin-Siris Syndrome in Eight Chinese Pediatric Patients.

Autism spectrum disorders (ASDs) are a group of neurodevelopmental-related disorders with a high genetic risk. Recently, chromatin remodeling factors have been found to be related to ASDs. SMARCA4 is such a catalytic subunit of the chromatin-remodeling complex. In this report, we identified seven novel missense variants in the SMARCA4 gene from eight pediatric patients. All eight patients had moderate to severe intellectual disability, and seven showed autistic/likely autistic features. Compared with the patients reported in the literature, our patients were less likely to show craniofacial or finger/toe anomalies. Our findings further supported that SMARCA4 is associated with ASDs. We suggest that individuals with the abovementioned phenotypes should consider genetic testing.

Transcriptional Networks Identify BRPF1 as a Potential Drug Target Based on Inflammatory Signature in Primary Lower-Grade Gliomas.

Gliomas are the most common tumors of the central nervous system and are classified into grades I-IV based on their histological characteristics. Lower-grade gliomas (LGG) can be divided into grade II diffuse low-grade gliomas and grade III moderate gliomas and have a relatively good prognosis. However, LGG often develops into high-grade glioma within a few years. This study aimed to construct and identify the prognostic value of an inflammatory signature and discover potential drug targets for primary LGG. We first screened differentially expressed genes in primary LGG (TCGA) compared with normal brain tissue (GTEx) that overlapped with inflammation-related genes from MSigDB. After survival analysis, nine genes were selected to construct an inflammatory signature. LGG patients with a high inflammatory signature score had a poor prognosis, and the inflammatory signature was a strong independent prognostic factor in both the training cohort (TCGA) and validation cohort (CGGA). Compared with the low-inflammatory signature group, differentially expressed genes in the high-inflammatory signature group were mainly enriched in immune-related signaling pathways, which is consistent with the distribution of immune cells in the high- and low-inflammatory signature groups. Integrating driver genes, upregulated genes and drug targets data, bromodomain and PHD finger-containing protein 1 (BRPF1) was selected as a potential drug target. Inhibition of BRPF1 function or knockdown of BRPF1 expression attenuated glioma cell proliferation and colony formation.

Bronchopulmonary Dysplasia Predicted by Developing a Machine Learning Model of Genetic and Clinical Information.

BACKGROUND: An early and accurate evaluation of the risk of bronchopulmonary dysplasia (BPD) in premature infants is pivotal in implementing preventive strategies. The risk prediction models nowadays for BPD risk that included only clinical factors but without genetic factors are either too complex without practicability or provide poor-to-moderate discrimination. We aim to identify the role of genetic factors in BPD risk prediction early and accurately. METHODS: Exome sequencing was performed in a cohort of 245 premature infants (gestational age <32 weeks), with 131 BPD infants and 114 infants without BPD as controls. A gene burden test was performed to find risk genes with loss-of-function mutations or missense mutations over-represented in BPD and severe BPD (sBPD) patients, with risk gene sets (RGS) defined as BPD-RGS and sBPD-RGS, respectively. We then developed two predictive models for the risk of BPD and sBPD by integrating patient clinical and genetic features. The performance of the models was evaluated using the area under the receiver operating characteristic curve (AUROC). RESULTS: Thirty and 21 genes were included in BPD-RGS and sBPD-RGS, respectively. The predictive model for BPD, which combined the BPD-RGS and basic clinical risk factors, showed better discrimination than the model that was only based on basic clinical features (AUROC, 0.915 vs. AUROC, 0.814, P = 0.013, respectively) in the independent testing dataset. The same was observed in the predictive model for sBPD (AUROC, 0.907 vs. AUROC, 0.826; P = 0.016). CONCLUSION: This study suggests that genetic information contributes to susceptibility to BPD. The predictive model in this study, which combined BPD-RGS with basic clinical risk factors, can thus accurately stratify BPD risk in premature infants.