Efficacy of urokinase in maintaining patency of hemodialysis catheters: A meta-analysis.

BACKGROUND: Catheter malfunctions are associated with reduced blood flow and interrupted dialysis during hemodialysis. AIM: This meta-analysis aimed to determine whether the use of urokinase to lock hemodialysis catheters can maintain their patency and prevent catheter-related bloodstream infections (CRBSIs). MATERIALS AND METHODS: The PubMed, Cochrane Library, Web of Science, Embase, and Chinese medical databases were searched for controlled trials of hemodialysis catheter locking using urokinase from database inception until July 15, 2021. The primary outcome was catheter malfunction, and the secondary outcomes were the peak catheter blood flow rate (Qb) and CRBSIs. RESULTS: Across 16 trials, 1,041 patients were randomized to receive either urokinase/urokinase mixture (treated) or heparin (control) locks once or thrice a week. Locking with urokinase alone or in combination with another substance significantly prevented catheter malfunction. The effect on Qb was significant, with that in the treated group being better than in the control group. Similarly, the incidence of CRBSIs in the treated group was lower. CONCLUSION: Urokinase locking maintains catheter patency more effectively than heparin. Prophylactic locking with urokinase or urokinase mixtures reduces incidences of catheter malfunction, which ensures the smooth progression of hemodialysis and reduces patient medical costs. The results of this study have important clinical implications and will provide guidance to medical practitioners globally.

Structure-activity relationship, bioactivities, molecular mechanisms, and clinical application of nuciferine on inflammation-related diseases.

Nuciferine aporphine alkaloid mainly exists in Nelumbo nucifera Gaertn and is a beneficial to human health, such as anti-obesity, lowering blood lipid, prevention of diabetes and cancer, closely associated with inflammation. Importantly, nuciferine may contribute to its bioactivities by exerting intense anti-inflammatory activities in multiple models. However, no review has summarized the anti-inflammatory effect of nuciferine. This review critically summarized the information regarding the structure-activity relationships of dietary nuciferine. Moreover, biological activities and clinical application on inflammation-related diseases, such as obesity, diabetes, liver, cardiovascular diseases, and cancer, as well as their potential mechanisms, involving oxidative stress, metabolic signaling, and gut microbiota has been reviewed. The current work provides a better understanding of the anti-inflammation properties of nuciferine against multiple diseases, thereby improving the utilization and application of nuciferine-containing plants across functional food and medicine.

Chromosomal abnormalities in recurrent pregnancy loss and its association with clinical characteristics.

OBJECTIVE: To evaluate the distribution of chromosomal abnormalities in a recurrent pregnancy loss (RPL) cohort and explore the associations between chromosomal abnormalities and clinical characteristics. METHOD: Over a 5-year period, fresh products of conception (POC) from women with RPL were analyzed by single-nucleotide polymorphism (SNP) array at our hospital. After obtaining the information on clinical characteristics, we investigated the associations between the causative chromosomal abnormalities and clinical characteristics by the chi-squared test or Fisher's exact test and logistic regression. RESULTS: A total of 2383 cases were enrolled. Overall, 56.9% (1355/2383) were identified with causative chromosomal abnormalities, of which 92.1% (1248/1355) were numerical abnormalities, 7.5% (102/1355) were structural variants, and 0.4% (5/1355) were loss of heterozygosity (LOH). The risk of numerical abnormalities was increased in women with maternal age ≥ 35 years (OR, 1.71; 95% CI, 1.41-2.07), gestational age at pregnancy loss ≤ 12 weeks (OR, 2.78; 95% CI, 1.79-4.33), less number of previous pregnancy losses (twice: OR, 2.32; 95% CI, 1.84-2.94; 3 times: OR, 1.59; 95% CI, 1.23-2.05, respectively), and pregnancy with a female fetus (OR, 1.37; 95% CI, 1.15-1.62). The OR of pregnancy loss with recurrent abnormal CMA was 4.00 (95% CI: 1.87-8.58, P < 0.001) and the adjusted OR was 5.05 (95% CI: 2.00-12.72, P = 0.001). However, the mode of conception was not associated with the incidence of numerical abnormality. No association was noted between structural variants and clinical characteristics. CONCLUSION: Chromosomal abnormality was the leading cause of RPL. Numerical chromosome abnormality was more likely to occur in cases with advanced maternal age, an earlier gestational age, fewer previous pregnancy losses, and pregnancy with a female fetus.

The Value of Exome Sequencing in Thoracoamniotic Shunt for Severe Pleural Effusion with Fetal Hydrops: A Retrospective Clinical Study.

OBJECTIVE: We aimed to study the value of exome sequencing (ES) in severe pleural effusion with nonimmune hydrops fetalis (NIHF) that underwent thoracoamniotic shunt (TAS). METHODS: It was a retrospective study of NIHF that underwent TAS between 2012 and 2020 at Shanghai First Maternity and Infant Hospital. After a detailed assessment, NIHF cases with aneuploidies, infections, and structural anomalies were excluded, and TAS was offered to cases with severe pleural effusion. Quantitative fluorescence polymerase chain reaction (QF-PCR) was conducted to exclude Trisomy 21, 18, and 13 before fetal therapy, and chromosomal microarray analysis (CMA) was offered to all the cases. Before 2019, ES was retrospectively performed using stored fetal DNA extracted from prenatal samples; from 2019 onward, ES was discussed and offered before intrauterine therapies. RESULTS: A total of 18 NIHF cases underwent TAS with negative CMA and continuing pregnancy were included. Fetal hydrops was relieved in 16 cases (88.9%). The median gestational ages at intervention and at delivery were 31.2 (22.0-33.1) weeks and 34.3 (29.7-38.6) weeks, respectively. The neonatal survival rate was 72.2% (13/18), and no causative gene variants were identified from ES in any survivors. Pathogenic or likely pathogenic variants were detected in 3 out of 5 neonatal deaths. If rapid ES could have been available to guide fetal therapy, the neonatal survival rate after TAS would have increased from 72.2% to 86.7%. CONCLUSIONS: Single-gene disorders were one of the major causes of perinatal death in NIHF cases that underwent fetal therapy. Prenatal rapid ES may be of good promise in NIHF to explore precise etiology and guide fetal therapy.

[Prenatal diagnosis for a pedigree affected with Wolf-Hirschhorn syndrome due to a subtle chromosomal translocation].

OBJECTIVE: To make molecular diagnosis of an infant affected with severe developmental delay and multiple birth defects, assisting prenatal diagnosis for the second pregnancy. METHODS: Standard G-banded karyotyping was performed for the fetus and his parents. Single nucleotide polymorphism array (SNP array) was used to detect submicroscopic chromosomal aberration. Fluorescence in situ hybridization (FISH) was employed to determine the parental origin of the aberration. RESULTS: Both the proband and the fetus harbored a 5.4 Mb distal 4p deletion and a 6.9 Mb distal 6q duplication. FISH confirmed that the mother has carried a balanced translocation involving 4p and 6q. CONCLUSION: The unbalanced chromosomal aberration in the proband and the fetus were both derived from the mother. Both patients showed a Wolf-Hirschhorn syndrom phenotype and partial phenotype of 6q trisomy. SNP array combined with FISH are essential for the detection of cryptic chromosomal aberrations which may be missed by coventional karyotyping analysis.

A novel TSC2 missense variant associated with a variable phenotype of tuberous sclerosis complex: case report of a Chinese family.

BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder characterized by the development of hamartomas in multiple organs, including the brain, heart, skin, kidney, lung and retina. A diagnosis of TSC is established with a recently revised clinical/radiological set of criteria and/or a causative mutation in TSC1 or TSC2 gene. CASE PRESENTATION: We report a Chinese TSC family with two siblings presenting with multiple hypomelanotic macules, cardiac rhabdomyomas and cortical tubers associated with a small subependymal nodule. The older child had seizures. A novel heterozygous missense variant in the TSC2 gene (c.899G > T, p.G300 V) was identified and shown to be inherited from their father as well as paternal grandfather, both of whom presented with variable TSC-associated signs and symptoms. CONCLUSION: We identified a novel heterozygous TSC2 variant c.899G > T as the causative mutation in a Chinese family with TSC, resulting in wide intrafamilial phenotypic variability. Our study illustrates the importance of clinical evaluation and genetic testing for family members of the patient affected with TSC.

In vitro digestion and fermentation behaviors of polysaccharides from Choerospondias axillaris fruit and its effect on human gut microbiota.

Choerospondias axillaris fruit has attracted more and more attention due to its various pharmacological activities, which are rich in polysaccharides. This study investigated the in vitro saliva-gastrointestinal digestion and fecal fermentation behaviors of polysaccharides from Choerospondias axillaris fruit (CAP), as well as its impact on human gut microbiota. The results showed that CAP could be partially degraded during the gastrointestinal digestion. The FT-IR spectra of the digested CAP didn't change significantly, however, the morphological feature of SEM changed to disordered flocculent and rod-like structures. 16S rRNA sequencing analysis found that after in vitro fermentation, CAP could increase the relative abundances of beneficial bacteria including Megasphaera, Megamonas and Bifidobacterium to produce short-chain fatty acids (SCFAs), while it can also reduce the abundances of harmful bacteria of Collinsella, Gemmiger, Klebsiella and Citrobacter, suggesting that CAP could modulate the composition and abundance of gut microbiota. These results implied that CAP can be developed as a potential prebiotic in the future.

Long-term polystyrene nanoparticles exposure reduces electroretinal responses and exacerbates retinal degeneration induced by light exposure.

The impact of plastic pollution on living organisms have gained significant research attention. However, the effects of nanoplastics (NPs) on retina remain unclear. This study aimed to investigate the effect of long-term polystyrene nanoparticles (PS-NPs) exposure on mouse retina. Eight weeks old C57BL/6 J mice were exposed to PS-NPs at the diameter of 100 nm and concentration of 10 mg/L in drinking water for 3 months. PS-NPs were able to penetrate the blood-retina barrier, accumulated at retinal tissue, caused increased oxidative stress level and reduced scotopic electroretinal responses without remarkable structural damage. PS-NPs exposure caused cytotoxicity and reactive oxygen species accumulation in cultured photoreceptor cell. PS-NPs exposure increased oxidative stress level in retinal pigment epithelial (RPE) cells, leading to changes of gene and protein expression indicative of compromised phagocytic activity and cell junction formation. Long-term PS-NPs exposure also aggravated light-induced photoreceptor cell degeneration and retinal inflammation. The transcriptomic profile of PS-NPs-exposed, light-challenged retinal tissue shared similar features with those of age-related macular degeneration (AMD) patients in the activation of complement-mediated phagocytic and proinflammatory responses. Collectively, these findings demonstrated the oxidative stress- and inflammation-mediated detrimental effect of PS-NPs on retinal function, suggested that long-term PS-NPs exposure could be an environmental risk factor contributing to retinal degeneration.

Lumbar Epidural versus Caudal Epidural for Postoperative Analgesia After Lower Extremity Osteotomy Surgery in Pediatric Patients with Osteogenesis Imperfecta: A Propensity-Matched Cohort Analysis in a Single-Center Over 9 Years.

Purpose: Although pediatric epidural analgesia is a well-established technique used perioperatively. It is unclear whether a lumbar or caudal epidural is suitable for osteogenesis imperfecta (OI) patients, which may be associated with brittle bones and spine deformity. We conducted a retrospective study to investigate and compare the efficacy of the two continuous epidural techniques in pediatric patients undergoing lower extremity osteotomy surgery using a propensity score-matched analysis (PSMA). Patients and Methods: A total of 274 patients were included. Patients' age, weight, and height were adjusted using PSMA. 90 patients were matched for further analysis, with 45 patients in the lumbar epidural group (Group L) and 45 patients in the caudal epidural group (Group C). Pain scores were categorized into three grades: mild (0-3), moderate (4-6), and severe (7-10), and compared between the two groups. Additionally, operation time, operation site, blood loss, scoliosis, oral analgesic medications, and catheter or nerve-related complications were compared. Results: There were no significant differences in operation time, operation site, scoliosis, and blood loss between the two groups. The percentage of moderate to severe pain during movement was significantly higher in Group L than in Group C, with 37.5% versus 17.5% on the second-day post-operation (P=0.039). However, no statistically significant difference was observed on other days. Additionally, there was no significant difference in oral medication consumption and complications between the two groups. Conclusion: Both lumbar and caudal epidural analgesia can be effectively used postoperatively, and a caudal epidural should be considered where performing a lumbar epidural is challenging in OI pediatric patients.

Osteogenesis imperfecta (OI) is a rare genetic disorder that affects the body's connective tissues, particularly the bones and ligaments. It is caused by abnormalities in type I collagen, which leads to skeletal fragility known as "brittle bones". This fragility can cause various issues, including an increased risk of fractures from minor trauma, limb deformities, and unusual fractures such as vertebral compressions. OI patients may also experience spinal manifestations such as scoliosis and kyphosis. Lumbar epidural analgesia has been found to be effective in providing pain relief for surgeries that involve the lower extremities. Additionally, caudal epidural analgesia has also demonstrated its effectiveness in providing postoperative analgesia for surgeries that affect the lower limbs. However, there is still debate about the safety of epidural analgesia in patients with skeletal dysplasias, especially those with OI. Despite this uncertainty, our center, which was supported by the Rare Diseases Public Welfare Organization, has successfully used epidural analgesia since 2015 in the southern part of China for OI surgeries. We conducted a retrospective study to share our experiences of nine years of practice and compare lumbar epidural with caudal epidural using a propensity score matching to balance basic demographics. We also compared the presence of scoliosis. Our findings suggest that both lumbar and caudal epidural analgesia can be safely used in OI patients. In cases where lumbar punctures may pose challenges due to potential spine deformities, the caudal route can be an alternative.

Maternal exposure to polystyrene nanoplastics causes defective retinal development and function in progeny mice by disturbing metabolic profiles.

Microplastics (MPs) and nanoplastics (NPs) are widely spreading in our living environment, accumulating in the human body and potentially threating human health. The retina, which is a terminally differentiated extension of the central nervous system, is essential for the visual system. However, the effects and molecular mechanisms of MPs/NPs on retina development and function are still unclear. Here, we investigated the effects and modes of action of polystyrene NPs (PS-NPs) on the retina using mice as a mammalian model species. Maternal PS-NP exposure (100 nm) at an environmentally realistic concentration of 10 mg L-1 (or 2.07 *1010 particles mL-1) via drinking water from the first day of pregnancy till the end of lactation (21 days after birth) caused defective neural retinal development in the neonatal mice, by depositing in the retinal tissue and reducing the number of retinal ganglion cells and bipolar cells. Exposure to PS-NPs retarded retinal vascular development, while abnormal electroretinogram (ERG) responses and an increased level of oxidative stress were also observed in the retina of the progeny mice after maternal PS-NP exposure. Metabolomics showed significant dysregulation of amino acids that are pivotal to neuron retinal function, such as glutamate, aspartate, alanine, glycine, serine, threonine, taurine, and serotonin. Transcriptomics identified significantly dysregulated genes, which were enriched in processes of angiogenesis, visual system development and lens development. Regulatory analysis showed that Fos gene mediated pathways could be a potential key target for PS-NP exposure in retinal development and function. Our study revealed that maternal exposure to PS-NPs generated detrimental effects on retinal development and function in progeny mice, offering new insights into the visual toxicity of PS-NPs.

Hsa_circ_0084912 Drives the Progression of Cervical Cancer Via Regulating miR-429/SOX2 Pathway.

We focus on hsa_circ_0084912's role in Cervical cancer (CC) and its molecular pathways. In order to determine the expression of Hsa_circ_0084912, miR-429, and SOX2 in CC tissues and cells, Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) were utilized. Cell counting kit 8 (CCK-8), colony formation and Transwell assays were respectively to analyze CC cell proliferation viability, clone formation ability and migration. RNA immunoprecipitation (RIP) assay and dual-luciferase assay were used to assure the targeting correlation among hsa_circ_0084912/SOX2 and miR-429. By using a xenograft tumor model, the hsa_circ_0084912 impact on CC cell proliferation in vivo was confirmed. Hsa_circ_0084912 and SOX2 expressions were aggrandized, however, miR-429 expression was descended in CC tissues and cells. Silencing hsa_circ_0084912 inhibited cell proliferation, colony formation and migration in vitro of CC, meanwhile reducing growth of tumor in vivo. MiR-429 might be sponged by Hsa_circ_0084912 to control SOX2 expression. Hsa_circ_0084912 knockdown impact on the malignant phenotypes of CC cells was restored by miR-429 inhibitor. Moreover, SOX2 silencing eliminated the promotive effects of miR-429 inhibitors on CC cell malignancies. By raising SOX2 expression by targeting miR-429, hsa_circ_0084912 accelerated the development of CC, offering fresh proof that it is a viable target for CC treatment.

LncRNA CERS6-AS1 Is a Tumor Promoter in Cervical Cancer by Sponging miR-195-5p.

OBJECTIVE: CERS6 antisense RNA 1 (CERS6-AS1), a long non-coding RNA (lncRNA), plays a role in the malignant progression of a variety of cancers. However, it is unclear whether it affects the malignant behavior of cervical cancer (CC) cells. METHODS: CERS6-AS1 and miR-195-5p expression was estimated in CC via qRT-PCR. CCK-8, caspase-3 activity, scratch, and Transwell assays were performed to detect CC cell viability, caspase-3 activity, migration, and invasion in vitro. A tumor xenograft experiment was designed to study the growth of CC tumors in vivo. RIP and luciferase reporter experiments verified the relationship between CERS6-AS1 and miR-195-5p. RESULTS: CERS6-AS1 overexpression and poor miR-195-5p levels were observed in CC. Inhibition of CERS6-AS1 impaired the viability, invasion, and migration of CC cells, promoted apoptosis, and suppressed tumor growth. In terms of the underlying mechanism, CERS6-AS1, as a competitive endogenous RNA (ceRNA), participated in the regulation of miR-195-5p levels in CC cells. Functionally, miR-195-5p interference attenuated the inhibitory effect of CERS6-AS1 on the malignant behaviors of CC cells. CONCLUSION: CERS6-AS1 acts as an oncogene in CC, in vivo and in vitro, by negatively regulating miR-195-5p.

Maternal exposure to polystyrene nanoparticles retarded fetal growth and triggered metabolic disorders of placenta and fetus in mice.

Microplastics can enter the human body via direct body contact or the food chain, increasing the likelihood of adverse impacts on pregnancy and fetal development. We investigated the potential effects and modes of action of polystyrene nanoplastics (PS-NPs) in placenta and fetus using mice as a model species. Maternal PS-NP exposure (100 nm; 1 and 10 mg/L) via drinking water induced a significant decline in fetal weights at the higher exposure concentration. Abnormal morphologies of cells in the placenta and fetus were observed after exposure. For the placenta, transcriptomic analyses indicated that PS-NPs significantly disturbed cholesterol metabolism and complement and coagulation cascades pathways. Metabolomics showed appreciable metabolic disorders, particularly affecting sucrose and daidzein concentrations. For the fetal skeletal muscle, transcriptomics identified many significantly regulated genes, involving muscle tissue development, lipid metabolism, and skin formation. Transcriptomic analysis of the placenta and fetal skeletal muscle at the high PS-NP concentration showed that APOA4 and its transcriptional factors, facilitating cholesterol transportation, were significantly regulated in both tissues. Our study revealed that PS-NPs caused fetal growth restriction and significantly disturbed cholesterol metabolism in both placenta and fetus, offering new insights into the mechanisms underlying the placental and fetal effects in mice exposed to PS-NPs.

CERT1 mutations perturb human development by disrupting sphingolipid homeostasis.

Neural differentiation, synaptic transmission, and action potential propagation depend on membrane sphingolipids, whose metabolism is tightly regulated. Mutations in the ceramide transporter CERT (CERT1), which is involved in sphingolipid biosynthesis, are associated with intellectual disability, but the pathogenic mechanism remains obscure. Here, we characterize 31 individuals with de novo missense variants in CERT1. Several variants fall into a previously uncharacterized dimeric helical domain that enables CERT homeostatic inactivation, without which sphingolipid production goes unchecked. The clinical severity reflects the degree to which CERT autoregulation is disrupted, and inhibiting CERT pharmacologically corrects morphological and motor abnormalities in a Drosophila model of the disease, which we call ceramide transporter (CerTra) syndrome. These findings uncover a central role for CERT autoregulation in the control of sphingolipid biosynthetic flux, provide unexpected insight into the structural organization of CERT, and suggest a possible therapeutic approach for patients with CerTra syndrome.

Generation of a human induced pluripotent stem cell line FMUPDCi001-A from a patient with mental retardation, autosomal recessive 36 (MRT36) carrying the variants c.219dupA and c.587C > T in ADAT3.

We generated a human induced pluripotent stem cell (iPSC) line, FMUPDCi001-A, from peripheral blood mononuclear cells of a patient with mental retardation, autosomal recessive 36 (MRT36), and compound heterozygous c.219dupA and c.587C > T variants in ADAT3. This line will be a valuable resource for investigating disease mechanisms and testing gene therapies for MRT36.

A 6.3 Mb maternally derived microduplication of 20p13p12.2 in a fetus with Brachydactyly type D and related literature review.

BACKGROUND: With the introduction of genetic tests such as chromosomal microarray analysis (CMA) and exome sequencing (ES) into fetal medical practices, genotype-phenotype correlations in intrauterine-onset disorders have substantially improved. The BMP2 gene, located on the long arm of chromosome 20 plays a role in bone and cartilage development and is associated with Brachydactyly type A2, an autosomal dominant disease characterized by malformations of the middle phalanx of the index finger and abnormalities of the second toe. However, the BMP2 gene has so far never been reported as a candidate gene for Brachydactyly type D (BDD) affecting only the thumbs. METHODS AND RESULTS: Here, we report one family possessing a maternally inherited 6.3 Mb microduplication of 20p13p12.2 including the BMP2 gene with discordant phenotypes between the mother and the fetus. The mother was affected with BDD alongside mild facial dysmorphism and learning difficulties, while the female fetus showed BDD, severe symmetric intrauterine growth restriction combined with oligohydramnios. The CMA and Trio ES tests were implemented. Trio ES ruled out other possible monogenic causes for the family. After reviewing cases and literature with duplications within this genomic region, we found that they are extremely rare and most of the cited cases were too small for comparison. The disturbance of the BMP2 gene could explain BDD, but the other clinical presentations in the mother and fetus are not yet fully understood. CONCLUSION: This study provides important evidence for the current understanding of genotype-phenotype association of this 6.3 Mb size duplication in the 20p13p12.2 region. This duplication is a unique CNV occurring so far only in this family. Further cases and research are needed to understand the discordance in the phenotypes between the mother and fetus and establish the relationship between BMP2 gene and BDD.

Applying and assessing the PEERS model on genetic counseling training in China: A mixed-method approach.

Objective: Due to the changing medical demands in the healthcare system, there is a need for a standardized and professionalized curriculum for genetic counselors. This mixed-method study will observe and evaluate the first Peer Experiential and Reciprocal Supervision (PEERS) training program on genetic counseling among medical practitioners in China; to provide feedback and recommendation for future training and practices. Methods: A genetic counselor training program was held from December 10-11, 2016 in a fetal medicine unit and prenatal diagnosis center in Shanghai with 59 participants from clinical centers, hospitals, and organizations in China. An ethnographic reflexive assessment with a structured questionnaire were used to provide insights and feedback on the training experience. Results: Results indicate an inadequate mastery of genetic and fetal knowledge; lack of empathetic understanding and cultural sensitivity; difficulties in adopting a non-directive counseling approach; distance between reality and fictionality in the training; overall training's helpfulness. Conclusion: The professionalization of genetic counseling in China is in the making with the soaring demands for genetic counseling services; this first experiment of PEERS training turned out to be needed, worth to be adapted toward medical centers across China, to better understand and face the challenges rising from genetic counseling practice.

An Investigation of the Etiologies of Non-Immune Hydrops Fetalis in the Era of Next-Generation Sequence-A Single Center Experience.

(1) Background: Numerous etiologies may lead to non-immune hydrops fetalis (NIHF). However, the causes remain unclear in half of NIHF cases following current standard assessment. The application of prenatal chromosomal microarray analysis (CMA) and exome sequencing (ES) can improve the identification of the etiologies. This study aimed to investigate the etiologies of NIHF in the era of next-generation sequence (NGS) following a unified prenatal work-up flow for diagnosis. (2) Methods: A retrospective analysis was conducted on NIHF cases that were collected prospectively to explore the underlying etiologies according to a unified prenatal diagnosis work-up flow at Shanghai First Maternity and Infant Hospital between Jan 2016 and Dec 2019. The medical records for all NIHF cases were reviewed, and the causes of NIHF were classified as confirmed (diagnostic), suspected, or unknown. (3) Results: Prenatal and postnatal medical records for a total of 145 NIHF cases were reviewed, 48.3% (70/145) of the cases were identified to be with confirmed etiologies, and 10.3% (15/145) with suspected etiologies. Among 85 cases with confirmed or suspected etiologies, 44.7% were diagnosed with genetic disorders, 20% with chylothorax/chyloascites diagnosed postnatally, 12.9% with fetal structural anomalies, 12.9% with fetal anemia, 7% (6 cases) with fetal arrhythmia, and 2.3% (2 cases) with placenta chorioangioma. In cases with genetic disorders, 8 aneuploidies were detected by CMA, and 30 cases had single-gene disorders identified by ES (29/30) or targeted gene panel (1/30). There were still 41.4% cases (60/145) with unknown causes after this unified prenatal diagnostic work-up flow. (4) Conclusions: In the era of NGS, the causes of NIHF were identified in 58.6% of cases, with genetic disorders being the most common ones. NGS is helpful in determining the genetic etiology of NIHF when CMA results cannot explain NIHF, but 41.4% of cases were still with unknown causes under the unified prenatal diagnostic work-up flow in this single-center study.

Association of -27T>C and its haplotype at the putative promoter for IgA-specific receptor gene with IgA nephropathy among the Chinese Han population.

BACKGROUND: One-third to half of IgA nephropathy (IgAN) patients have raised serum IgA levels. Decreased clearance of IgA/IgA complex has been observed in IgAN patients. FCAR codes for IgA-specific receptor and plays an important role in IgA metabolism. Previous small sample-sized studies reported controversial findings in its association with IgAN. METHODS: We re-sequenced the FCAR in 107 IgAN patients and 112 controls. Association of -27T/C and their haplotypes were performed in 606 patients versus 606 controls, its two independent subsets: 293 single patients with family members and 313 cases versus 606 controls. Functional impact of -27T>C and their haplotypes were analyzed by bioinformatics, allelic differential expression and luciferase activity assays. Cell surface FCAR density between -27T/C heterozygous patients and -27T/T homozygous controls was assessed by flow cytometry. RESULTS: -27T>C, on the consensus TATA box of transcription factor-binding motif in the putative promoter of the gene was the only variation identified in all coding, splice-site and known protein-binding sequence in re-sequencing. -27C and its haplotype were associated with IgAN (P = 0.0034/0.0013, 0.0099/0.0054, 0.0129/0.0076 and 0.00039/0.00014 in 606 cases versus 606 controls, family-based study, 313 cases versus 606 controls and meta-analysis, respectively). Bioinformatics predicted 2 bp binding changes by -27C. Allelic differential expression and luciferase activity assays showed a reduced expression/activity by the associated haplotype/allele (P < 0.001). -27T/C heterozygous patients had a lower receptor density on cell surface compared to -27T/T homozygous controls (P < 0.001). CONCLUSIONS: Our results provide evidence for genetic variation at the putative promoter region of FCAR conferring susceptibility to IgAN, suggesting -27C and its haplotype may be causative for the susceptibility among the Chinese Han population.

Whole Genome Sequencing in the Evaluation of Fetal Structural Anomalies: A Parallel Test with Chromosomal Microarray Plus Whole Exome Sequencing.

Whole genome sequencing (WGS) is a powerful tool for postnatal genetic diagnosis, but relevant clinical studies in the field of prenatal diagnosis are limited. The present study aimed to prospectively evaluate the utility of WGS compared with chromosomal microarray (CMA) and whole exome sequencing (WES) in the prenatal diagnosis of fetal structural anomalies. We performed trio WGS (≈40-fold) in parallel with CMA in 111 fetuses with structural or growth anomalies, and sequentially performed WES when CMA was negative (CMA plus WES). In comparison, WGS not only detected all pathogenic genetic variants in 22 diagnosed cases identified by CMA plus WES, yielding a diagnostic rate of 19.8% (22/110), but also provided additional and clinically significant information, including a case of balanced translocations and a case of intrauterine infection, which might not be detectable by CMA or WES. WGS also required less DNA (100 ng) as input and could provide a rapid turnaround time (TAT, 18 ± 6 days) compared with that (31 ± 8 days) of the CMA plus WES. Our results showed that WGS provided more comprehensive and precise genetic information with a rapid TAT and less DNA required than CMA plus WES, which enables it as an alternative prenatal diagnosis test for fetal structural anomalies.