Case report: A novel compound heterozygous variant in the TNXB gene causes single kidney agenesis and vesicoureteral reflux.

Primary vesicoureteral reflux (VUR) is the prevailing congenital anomaly of the kidneys and urinary tract, posing a significant risk for pyelonephritis scarring and chronic renal insufficiency in pediatric patients. Nevertheless, the precise genetic etiology of VUR remains enigmatic. In this current investigation, we conducted whole-exome sequencing on a child exhibiting single kidney, devoid of any familial VUR background, along with both biological parents. Two missense variants (NM_019105.8: exon11: c.4111G>A and NM_019105.8: exon2: c.31A>T) in the TNXB gene were identified through whole-exome sequencing of the child. These variants were found to be inherited from the child's parents, with each parent carrying one of the variants. Molecular dynamics simulations were conducted to assess the impact of these variants on the tenascin XB proteins encoded by them, revealing varying degrees of impairment. Based on our findings, it is suggested that the TNXB compound heterozygous variant, consisting of c.4111G>A and c.31A>T, may be the underlying cause of right renal agenesis and left hydronephrosis in afflicted child. This discovery broadens the genetic range of the TNXB gene and establishes a genetic foundation for disease-specific preimplantation genetic diagnosis (PGD) in prospective pregnancies involving the parents of this afflicted child.

[Genetic analysis and in vitro validation of a case of Alport syndrome due to a splicing variant of COL4A5 gene].

OBJECTIVE: To explore the genetic basis for a patient with Alport syndrome (AS) and confirm the existence of a splicing variant. METHODS: An AS patient diagnosed at the Affiliated Hospital of Inner Mongolia Medical University on January 8, 2021 for significant proteinuria and occult hematuria was selected as the study subject. Clinical data was collected. Peripheral blood samples were collected for the extraction of genomic DNA. Whole exome sequencing and Sanger sequencing were carried out to identify potential genetic variants. An in vitro experiment was also conducted to verify the abnormal mRNA splicing. Bioinformatic software was used to analyze the conservation of amino acids of the variant sites and simulate the 3D structure of the variant collagen IV protein. Immunofluorescence and immunohistochemistry were carried out on renal tissues from the patient to confirm the presence of AS kidney injury. RESULTS: The patient, a 21-year-old male, had a 24-hour urine protein of 3.53 g/24 h, which fulfilled the diagnostic criteria for proteinuria. His blood uric acid has also increased to 491 µmol/L. DNA sequencing revealed that he has harbored a c.835-9T>A splice variant of the COL4A5 gene, which was not found in either of his parents. In vitro experiment confirmed that the variant has removed 57 bp from the exon 15 of the mRNA of the COL4A5 gene. The deletion may cause loss of amino acid residues from positions 279 to 297, which in turn may affect the stability of the secondary structure of the α5 chain encoded by the COL4A5 gene. The amino acids are conserved across various species. The result of homology modeling indicated that the trimerization of Col-IV with the mutated α5 chain could be achieved, however, the 3D structure was severely distorted. The AS kidney damage was confirmed through immunofluorescence assays. Based on the guidelines from the American College of Medical Genetics and Genomics, the c.835-9T>A variant was classified as likely pathogenic (PVS1_Moderate+PS3_Moderate+PM2_Supporting+PS2+PP3+PP4). CONCLUSION: The c.835-9T>A variant of the COL4A5 gene probably underlay the AS in this patient. In vitro experiment has confirmed the abnormal splicing caused by the variant. Histopathological examination of the kidney tissue has provided in vivo evidence for its pathogenicity. Above finding has expanded the mutational spectrum of the COL4A5 gene.

Genetic analysis of acute intermittent porphyria caused by novel classical splicing variant in the insertion region of 29-residue specific to human HMBS protein.

Background: Acute intermittent porphyria (AIP; OMIM#176000) is a genetic disorder that is caused by mutations in the hydroxymethylbilane synthetase (HMBS) gene. This gene encodes the third enzyme in the heme biosynthesis pathway. Human HMBS (hHMBS) contains a 29-residue insert (residues 296-324) at the interface between domains 1 and 3. The function of this insert is currently unknown. In this study, a previously unidentified classical Splicing variant was discovered in the HMBS gene of a female AIP patient from China. The variant was validated through comparison with the patient's husband and daughter. Methods: Peripheral blood samples were obtained from the patient, the patient's husband, and their daughter. Gene expression was analyzed using whole exon sequencing and Sanger sequencing. To validate alternative splicing, RNA was extracted from the patient's peripheral blood and reverse transcribed into cDNA. Aberrant splicing caused by variants was predicted using I-TASSER and PyMOL software to simulate protein structures. Finally, molecular dynamics of the proteins were simulated using the AMBER14sb software. Results: The patient and her daughter have a classical Splicing variant c.912 + 1G>C of the HMBS gene. This variant was not found in the patient's husband and has not been previously reported in scientific literature. Analysis of the patient's peripheral blood transcripts revealed that c.912 + 1G>C retained intron 13 and resulted in an exon 13 skipping. Further analysis through homology modelling and molecular dynamics showed that this variant alters the secondary structure of the HMBS protein, leading to functional differences. Conclusion: This research has discovered a new classical Splicing variant c.912 + 1G>C in the HMBS gene that has been identified as pathogenic. This finding not only expands the molecular heterogeneity of AIP but also provides crucial information for genetic diagnosis.

Risk Factors for Macrosomia in Multipara: A Multi-Center Retrospective Study.

The increased incidence of macrosomia has caused an enormous burden after the transition from the almost 40-year one-child policy to the universal two-child policy in 2015 and further to the three-child policy in 2021 in China. However, studies on risk factors of macrosomia in multipara under the new fertility policy in China are limited. We aim to explore the incidence and risk factors for macrosomia in multipara to provide the scientific basis for preventing macrosomia in multipara. A multi-center retrospective study was conducted among 6200 women who had two consecutive deliveries in the same hospital and their second newborn was delivered from January to October 2018 at one of 18 hospitals in 12 provinces in China. Macrosomia was defined as birth weight ≥ 4000 g. Logistic regression models were performed to analyze risk factors for macrosomia in multipara. The incidence of macrosomia in multipara was 7.6% (470/6200) and the recurrence rate of macrosomia in multipara was 27.2% (121/445). After adjusting for potential confounders, a higher prepregnancy BMI, higher gestational weight gain, history of macrosomia, a longer gestation in the subsequent pregnancy were independent risk factors of macrosomia in multipara (p < 0.05). Healthcare education and preconception consultation should be conducted for multipara patients with a history of macrosomia to promote maintaining optimal prepregnancy BMI and avoid excessive gestational weight gain to prevent macrosomia.

Risk of gestational diabetes recurrence and the development of type 2 diabetes among women with a history of gestational diabetes and risk factors: a study among 18 clinical centers in China.

BACKGROUND: Gestational diabetes mellitus (GDM) brings health issues for both mothers and offspring, and GDM prevention is as important as GDM management. It was shown that a history of GDM was significantly associated with a higher maternal risk for GDM recurrence. The incidence of GDM recurrence was unclear because of the incidence of second-child was low before 2016 in China. We aim to investigate the prevalence of GDM recurrence and its associated high-risk factors which may be useful for the prediction of GDM recurrence in China. METHODS: A retrospective study was conducted which enrolled participants who underwent regular prenatal examination and delivered twice in the same hospital of 18 research centers. All participants were enrolled from January 2018 to October 2018, where they delivered the second baby during this period. A total of 6204 women were enrolled in this study, and 1002 women with a history of GDM were analyzed further. All participants enrolled in the study had an oral glucose tolerance test (OGTT) result at 24 to 28 weeks and were diagnosed as GDM in the first pregnancy according to the OGTT value (when any one of the following values is met or exceeded to the 75-g OGTT: 0 h [fasting], ≥5.10 mmol/L; 1 h, ≥10.00 mmol/L; and 2 h, ≥8.50 mmol/L). The prevalence of GDM recurrence and development of type 2 diabetes mellitus were calculated, and its related risk factors were analyzed. RESULTS: In 6204 participants, there are 1002 women (1002/6204,16.15%) with a history of GDM and 5202 women (5202/6204, 83.85%) without a history of GDM. There are significant differences in age (32.43 ±â€Š4.03 years vs. 33.00 ±â€Š3.34 years vs. 32.19 ±â€Š3.37 years, P  < 0.001), pregnancy interval (4.06 ±â€Š1.44 years vs. 3.52 ±â€Š1.43 years vs. 3.38 ±â€Š1.35 years, P  = 0.004), prepregnancy body mass index (BMI) (27.40 ±â€Š4.62 kg/m2vs. 23.50 ±â€Š3.52 kg/m2vs. 22.55 ±â€Š3.47 kg/m2, P < 0.001), history of delivered macrosomia (22.7% vs. 11.0% vs. 6.2%, P < 0.001) among the development of diabetes mellitus (DM), recurrence of GDM, and normal women. Moreover, it seems so important in the degree of abnormal glucose metabolism in the first pregnancy to the recurrence of GDM and the development of DM. There are significant differences in OGTT levels of the first pregnancy such as area under the curve of OGTT value (18.31 ±â€Š1.90 mmol/L vs. 16.27 ±â€Š1.93 mmol/L vs. 15.55 ±â€Š1.92 mmol/L, P < 0.001), OGTT fasting value (5.43 ±â€Š0.48 mmol/L vs. 5.16 ±â€Š0.49 mmol/L vs. 5.02 ±â€Š0.47 mmol/L, P < 0.001), OGTT 1-hour value (10.93 ±â€Š1.34 mmol/L vs. 9.69 ±â€Š1.53 mmol/L vs. 9.15 ±â€Š1.58 mmol/L, P < 0.001), OGTT 2-hour value (9.30 ±â€Š1.66 mmol/L vs. 8.01 ±â€Š1.32 mmol/L vs. 7.79 ±â€Š1.38 mmol/L, P < 0.001), incidence of impaired fasting glucose (IFG) (fasting plasma glucose ≥5.6 mmol/L) (31.3% vs. 14.6% vs. 8.8%, P < 0.001), and incidence of two or more abnormal OGTT values (68.8% vs. 39.7% vs. 23.9%, P < 0.001) among the three groups. Using multivariate analysis, the factors, such as age (1.07 [1.02-1.12], P = 0.006), prepregnancy BMI (1.07 [1.02, 1.12], P  = 0.003), and area under the curve of OGTT in the first pregnancy (1.14 [1.02, 1.26], P  = 0.02), have an effect on maternal GDM recurrence; the factors, such as age (1.28 [1.01-1.61], P  = 0.04), pre-pregnancy BMI (1.26 [1.04, 1.53], P = 0.02), and area under the curve of OGTT in the first pregnancy (1.65 [1.04, 2.62], P = 0.03), have an effect on maternal DM developed further. CONCLUSIONS: The history of GDM was significantly associated with a higher maternal risk for GDM recurrence during follow-up after the first pregnancy. The associated risk factors for GDM recurrence or development of DM include age, high pre-pregnancy BMI, history of delivered macrosomia, the OGTT level in the first pregnancy, such as the high area under the curve of OGTT, IFG, and two or more abnormal OGTT values. To prevent GDM recurrence, women with a history of GDM should do the preconception counseling before preparing next pregnancy.

Heterogeneous Ni3S2@FeNi2S4@NF nanosheet arrays directly used as high efficiency bifunctional electrocatalyst for water decomposition.

Developing and designing bifunctional electrocatalysts are very important for the production of hydrogen from water electrolysis. The reasonable interface modulation can effectively lead to the optimization of electronic configuration through the interface electron transfer in the heterostructures and thus resulting in the enhanced efficiency. In this work, self-supported and heterogeneous interface-rich Ni3S2@FeNi2S4@NF electrocatalyst for overall water splitting was designed and prepared through a controllable step-wise hydrothermal process. Density functional theory calculations suggest that heterogeneous interface formed between Ni3S2 and FeNi2S4 can optimize the Gibbs free energy for H* adsorption (ΔGH*). Benefiting from the open structure of the nanosheet arrays, the abundant heterogeneous interfaces in Ni3S2@FeNi2S4@NF composite, the positive synergistic effect between Ni3S2 and FeNi2S4, and the good conductivity of foamed nickel (NF) substrate, the optimized Ni3S2@FeNi2S4@NF nanoarray catalyst displayed excellent electrocatalytic activities, the overpotential is only 83 mV and 235 mV for hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) at 10 mA cm-2, respectively. Importantly, an alkaline electrolyser directly using the Ni3S2@FeNi2S4@NF as both the anode and cathode achieved an ultralow cell voltage of 1.46 V, accompanied by outstanding stability. The performance is better than that of most other transition-metal sulfides electrocatalysts. This work may provide a useful strategy for reasonably regulating heterogeneous interfaces to effectively improve the performance of materials, thus accelerating the practical application of transition-metal sulfides electrocatalysts for overall water splitting.

The meconium microbiota shares more features with the amniotic fluid microbiota than the maternal fecal and vaginal microbiota.

The early-life gut microbiota is associated with potential development of diseases in adulthood. The sterile womb paradigm has been challenged by recent reports that revealed the presence of the meconium, amniotic fluid, and placenta microbiome. This study aimed to explore the maternal origin of the microbiota of neonate meconium by using the PacBio single-molecule real-time circular consensus sequencing technology. Such technology could produce high fidelity reads of full-length 16S rRNA genes, improving the sensitivity and specificity of taxonomic profiling. It also reduced the risk of false positives. This study analyzed the full-length 16S rRNA-based microbiota of maternal samples (amniotic fluid, feces, vaginal fluid, saliva) and first-pass meconium of 39 maternal-neonate pairs. Alpha- and beta-diversity analyses revealed sample type-specific microbiota features. Most sample types were dominated by sequences representing different genera (Lactobacillus and Curvibacter in the amniotic fluid and vaginal fluid microbiota; Bacillus and Escherichia/Shigella in the meconium microbiota; Bacteroides and Faecalibacterium in the maternal fecal microbiota; Streptococcus and Prevotella in the maternal saliva microbiota). Moreover, specific operational taxonomic units (OTUs) were identified in all sample types. Dyad analysis revealed common OTUs between the meconium microbiota and microbiota of multiple maternal samples. The meconium microbiota shared more features with the amniotic fluid microbiota than the maternal fecal and vaginal microbiota. Our results strongly suggested that the meconium microbiota was seeded from multiple maternal body sites, and the amniotic fluid microbiota contributed most to the seeding of the meconium microbiota among the investigated maternal body sites.

Seasonal response of the synergism of maternal comorbidities and long-term air pollution exposure on birth outcomes.

Air pollution has been considered as one of the most important factors associating with various birth outcomes. However, the seasonal response of maternal comorbidities effects associated with air pollution has not been investigated, especially in the city with distinguish seasonal pattern and long heating seasons. In this work, 69,945 live births were investigated from 2013 to 2016, and the seasonal relationship between air pollution and preterm birth and low birth weight were assessed, as well as the synergism of maternal comorbidities. Exposures of six pollutants were assigned to maternal residences during pregnancy. The potential effect modification by maternal comorbidities on the associations was evaluated between prenatal air pollution and preterm birth (PTB), as well as effects of seasons and trimesters. Adjusting for seasonality, all six pollutants presented seasonal relationship with preterm birth, which CO, PM10, NO2, and PM2.5 were with [odds ratio (OR) = 1.035 95% CI: 1.015, 1.055, OR = 1.039 95% CI: 1.034, 1.045, OR = 1.042, 95% CI: 1.029, 1.056 and OR = 1.085 95% CI 1.073, 1.097, respectively] for tenth quartile of 10 µg/m3 range increased in autumn (the beginning of heating season). For O3, it associated with PTB in winter and spring with OR = 1.113 95% CI: 1.104, 1.123, and OR = 1.155 95% CI: 1.145, 1.165, respectively. The OR increase of PTB for exposure to all six pollutants was higher among women with preeclampsia and gestational hypertension. The associations between ambient air pollution and preterm birth were modified by gestational hypertension and preeclampsia. The seasonal patterns of six studied air pollutants increases the risk of PTB in autumn and winter distinguishably, which may due to the sudden increased concentrations of pollutants emitted by traditional heating. The seasonal response of the synergism of maternal comorbidities and long-term air pollution exposure on birth outcomes is supported by the data sets of preterm birth.

Increasing risk of congenital anomalies associated with seasonal pattern of air pollution: Differences by maternal comorbidities.

To interpret the relationship of the seasonal pattern of air pollution exposure associated with increased risk of congenital anomalies (CA) and the trimester-specific effects. In this work, 55,428 hospital records with 847 doctor-diagnosed CA from July 2013 to December 2016 were collected in Hohhot, China. Maternal exposure to critical air pollutants (SO2, CO, PM10, O3, NO2 and PM2.5) were estimated using an inverse distance weighted (IDW) method on the basis of the ambient air quality monitoring stations. Logistic regression analysis was employed to determine the association of CA (in terms of odds ratio (OR) and 95% confidence interval (CI)) in three trimesters with heating/none heating season exposure. The results showed that CO exposure was found a significant association with ORs (95% CI) 1.58 (1.09, 2.27) changing from IQR2-3 and 1.40 (1.01, 1.93) changing from IQR3-IQR4 in 1st trimester and 1.51 (1.12, 2.04) changing from IQR2-3 in 2nd trimester, respectively. PM10 also presented significant association with ORs (95% CI) 1.42(1.08, 1.86) changing from IQR3-4 in 2nd trimester. Exposure effects were found more obvious in heating season, i.e. CO exposure levels were associated with the risks of CA with IQR changing ORs (95% CI) of 5.21(2.02, 7.44), 2.24 (1.21, 4.15) and 1.84 (1.10, 3.11) in 1st trimester, respectively; PM2.5 exposure levels were associated with the risks of CA with IQR changing ORs (95% CI) of 3.76 (1.48, 6.55), 2.45 (1.10, 5.44) and 3.30 (1.63, 6.67) in 2nd trimester, respectively. Our findings suggested some positive associations of pregnancy and CA with maternal exposure to ambient CO and PM2.5 during the 1st and 2nd trimester after controlling for maternal comorbidities general covariates and other pollutants. PM10 was also found significantly associated with increased risk of CA in 2nd trimester besides seasons. There was no association found in 3rd trimester.

The value of the 24-h proteinuria in evaluating the severity of preeclampsia and predicting its adverse maternal outcomes.

BACKGROUND: To identify the 24-h proteinuria value with quantitative analysis and how it correlates with the severity of preeclampsia and subsequent adverse maternal outcomes in the Chinese population. STUDY DESIGN: Eleven hospitals in 10 provinces across China were chosen, in which 1,738 pregnant women complicated by hypertensive disorders of pregnancy (HDP) with the records of 24 h proteinuria were enrolled. They were allocated into four groups: patients with maximal quantified proteinuria < 0.3 g/24 h (Group 1, n = 328); patients with maximal quantified proteinuria ≥ 0.3 g/24 h and < 2.0 g/24 h (Group 2, n = 638); patients with maximal quantified proteinuria ≥ 2.0 g/24 h and < 5.0 g/24 h (Group 3, n = 353); and patients with maximal quantified proteinuria ≥ 5.0 g/24 h (Group 4, n = 419). Logistic regression analysis were conducted to assess the differences in maternal outcomes between different subgroups of 24-h proteinuria and to identify independent risk factors of adverse maternal outcomes in preeclampsia. The multivariable risk prediction model of adverse maternal outcome for HDP was established with receiver operating characteristic curve (ROC) curve and its predicted value was assessed. RESULTS: Thrombocytopenia and cerebral or visual symptoms were more frequent in Groups 3 and 4 than Groups 1 and 2 but no differences were found between Groups 3 and 4 or Groups 1 and 2. Maternal complications were more frequent in Groups 3 and 4 than in Groups 1 and 2 [Group 3 vs. Group 1, odds ratios (ORs) = 3.359 (1.067-10.571); Group 4 vs. Group 1, OR = 3.628 (1.189-11.086); Group 3 vs. Group 2, OR = 2.845 (1.155-7.003); Group 4 vs. Group 2, OR = 3.082 (1.304-7.288)]. However, no significant difference was found between Groups 4 and 3 or between Groups 2 and 1. The proteinuria ≥ 2 g/24 h had an area under the receiver operating characteristic curve (AUC ROC) of 0.668 (95% confidence interval (CI) 0.632-0.705) for predicting adverse maternal outcome. After adjusting for the effects of other symptoms, signs, and laboratory tests, it was the independent risk factor and predictor factor of the adverse maternal outcome (OR = 3.683, 95% CI 2.439-5.562, P<0.001). The final risk prediction model had an AUC ROC of 0.800 (95% CI 0.769-0.830, P<0.001). CONCLUSION: The proteinuria ≥ 2 g/24 h is an independent predictive factor of adverse maternal outcomes in preeclampsia, but its individual predictive value is limited. The risk prediction model is effective in assessing the risk of adverse maternal outcomes in patients with HDP.

Association between apolipoprotein E gene polymorphism and the risk of recurrent pregnancy loss: a meta-analysis.

PURPOSE: The association between apolipoprotein E (ApoE) gene polymorphism and the risk of recurrent pregnancy loss (RPL) remains controversial. The present meta-analysis was performed to derive a precise estimate of the relationship. METHOD(S): We searched the PubMed, Embase, and Web of Science data- bases for studies related to the association between the ApoE genotype and the risk of RPL. We estimated the summary odds ratio (OR) with 95% confidence interval (CI) to assess the association. RESULT(S): Seven studies, including 2,090 RPL cases and 742 control samples, were identified. The results showed a significant association between ApoE E4 mutation and RPL risk (for E4 allele: OR =1.98, 95 %CI =1.14-3.43, P=0.499; for E2E3 vs. E3E3: OR =1.33, 95%CI =1.12-1.42, P=0.008; for E2E4 vs. E3E3: OR =1.26, 95 % CI =1.07-1.49, P=0.005). CONCLUSION(S): The meta-analysis suggests an association between ApoE E4 mutation and increased risk of RPL.