A multicenter study of fetal chromosomal abnormalities in Chinese women of advanced maternal age

AbstractObjectiveThis study aimed to determine the rates of different fetal chromosomal abnormalities among women of advanced maternal age in China and to discuss the possible misdiagnosis risks of newer molecular techniques, for selection of appropriate prenatal screening and diagnostic technologies.Materials and MethodsSecond trimester amniocentesis and fetal karyotype results of 46,258 women were retrospectively reviewed. All women were ≥ 35 years old with singleton pregnancies. The rates of clinically significant chromosomal abnormalities (CSCAs), incidence of chromosomal abnormalities, and correlations with age were determined.ResultsFrom 2001 to 2010, the proportion of women of advanced maternal age undergoing prenatal diagnosis increased from 20% to 46%. The mean age was 37.4 years (range, 35–46 years). A total of 708 cases of CSCAs, with a rate of 1.53% were found. Trisomy 21 was the most common single chromosome abnormality and accounted for 55.9% of all CSCAs with an incidence of 0.86%. Trisomy 13, trisomy 18, and trisomy 21, the most common chromosome autosomal aneuploidies, accounted for 73.6% of all CSCAs, with a rate of 1.13%. As a group, the most common chromosomal aneuploidies (13/18/21/X/Y) accounted for 93.9% of all abnormalities, with a rate of 1.44%. The incidence of trisomy 21, trisomy 13/18/21 as a group, and 13/18/21/X/Y as a group was significantly greater in women aged 39 years and older (p < 0.001), but was not different between women aged 35 years, 36 years, 37 years, and 38 years.ConclusionThese findings may assist in genetic counseling of advanced maternal age pregnant women, and provide a basis for the selection of prenatal screening and diagnostic technologies

The interactions between ineffective erythropoiesis and ferroptosis in β-thalassemia

In Guangxi, Hainan, and Fujian Province in southern China, β-thalassemia is a frequent monogenic hereditary disorder that is primarily defined by hemolytic anemia brought on by inefficient erythropoiesis. It has been found that ineffective erythropoiesis in β-thalassemia is closely associated with a high accumulation of Reactive oxygen species, a product of oxidative stress, in erythroid cells. During recent years, ferroptosis is an iron-dependent lipid peroxidation that involves abnormalities in lipid and iron metabolism as well as reactive oxygen species homeostasis. It is a recently identified kind of programmed cell death. β-thalassemia patients experience increased iron release from reticuloendothelial cells and intestinal absorption of iron, ultimately resulting in iron overload. Additionally, the secretion of Hepcidin is inhibited in these patients. What counts is both ineffective erythropoiesis and ferroptosis in β-thalassemia are intricately linked to the iron metabolism and Reactive oxygen species homeostasis. Consequently, to shed further light on the pathophysiology of β-thalassemia and propose fresh ideas for its therapy, this paper reviews ferroptosis, ineffective erythropoiesis, and the way they interact

Chromosome 1p36 candidate gene ZNF436 predicts the prognosis of neuroblastoma: a bioinformatic analysis

Abstract Background Genetic 1p deletion is reported in 30% of all neuroblastoma and is associated with the unfavorable prognosis of neuroblastoma. The expressions and prognosis of 1p candidate genes in neuroblastoma are unclear. Methods Public neuroblastoma cohorts were obtained for secondary analysis. The prognosis of 1p candidate genes in neuroblastoma was determined using Kaplan-Meier and cox regression analysis. The prediction of the nomogram model was determined using timeROC. Results First, we confirmed the bad prognosis of 1p deletion in neuroblastoma. Moreover, zinc finger protein 436 (ZNF436) located at 1p36 region was down-regulated in 1p deleted neuroblastoma and higher ZNF436 expression was associated with the longer event free survival and overall survival of neuroblastoma. The expression levels of ZNF436 were lower in neuroblastoma patients with MYCN amplification or age at diagnosis ≥ 18months, or with stage 4 neuroblastoma. ZNF436 had robust predictive values of MYCN amplification and overall survival of neuroblastoma. Furthermore, the prognostic significance of ZNF436 in neuroblastoma was independent of MYCN amplification and age of diagnosis. Combinations of ZNF436 with MYCN amplification or age of diagnosis achieved better prognosis. At last, we constructed a nomogram risk model based on age, MYCN amplification and ZNF436. The nomogram model could predict the overall survival of neuroblastoma with high specificity and sensitivity. Conclusions Chromosome 1p36 candidate gene ZNF436 was a prognostic maker of neuroblastoma

Additional file 1 of Transforming growth factor-induced gene TGFBI is correlated with the prognosis and immune infiltrations of breast cancer

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Prenatal diagnosis of BACs‐on‐Beads assay in 1520 cases from Fujian Province, China

Abstract Background The aim of this study was to evaluate the application of BACs‐on‐Beads (BoBs™) assay for rapid detection of chromosomal abnormalities for prenatal diagnosis (PND). Methods A total of 1520 samples, including seven chorionic villi biopsy samples, 1328 amniotic fluid samples, and 185 umbilical cord samples from pregnant women were collected to detect the chromosomal abnormalities using BoBs™ assay and karyotyping. Furthermore, abnormal specimens were verified by chromosome microarray analysis (CMA) and fluorescence in situ hybridization (FISH). Results The results demonstrated that the success rate of karyotyping and BoBs™ assay in PND was 98.09% and 100%, respectively. BoBs™ assay was concordant with karyotyping for Trisomy 21, Trisomy 18, and Trisomy 13, sex chromosomal aneuploidy, Wolf–Hirschhorn syndrome, and mosaicism. BoBs™ assay also detected Smith–Magenis syndrome, Williams–Beuren syndrome, DiGeorge syndrome, Miller–Dieker syndrome, Prader–Willi syndrome, Xp22.31 microdeletions, 22q11.2, and 17p11.2 microduplications. However, karyotyping failed to show these chromosomal abnormalities. A case of 8q21.2q23.3 duplication which was found by karyotyping was not detected by BoBs™ assay. Furthermore, all these chromosomal abnormalities were consistent with CMA and FISH verifications. According to the reports, we estimated that the detection rates of karyotyping, BoBs™, and CMA in the present study were 4.28%, 4.93%, and 5%, respectively, which is consistent with the results of a previous study. The respective costs for the three methods were about $135–145,$270–290, and $540–580. Conclusion BoBs™ assay is considered a reliable, rapid test for use in PND. A variety of comprehensive technological applications can complement each other in PND, in order to maximize the diagnosis rate and reduce the occurrence of birth defects

Age related gene DST represents an independent prognostic factor for MYCN non-amplified neuroblastoma

Abstract Background MYCN amplification and age are two critical prognostic factors of pediatric neuroblastoma. Previously, we had revealed the prognosis of MYCN target genes. However, the prognostic effects of age related genes in neuroblastoma are unclear. Methods The prognostic significance of age and MYCN amplification was determined through multivariate cox regression and Kaplan-Meier survival analysis. Genes differentially expressed in MYCN non-amplified younger neuroblastoma patients were identified using Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and Gene Expression Omnibus (GEO) datasets. The prognostic effects of age related genes ALCAM, CACNA2D3, DST, EPB41L4A and KIF1B in pediatric neuroblastoma patients were determined by Kaplan-Meier survival. Results In a pediatric pan-cancer analysis, age was associated with the overall survival of pediatric B-lineage acute lymphoblastic leukemia, neuroblastoma and wilms tumor in TARGET dataset. Moreover, the prognostic effects of age in neuroblastoma were validated using two independent neuroblastoma cohorts. Furthermore, age and MYCN amplification were independent prognostic factors in pediatric neuroblastoma. Compared with MYCN non-amplified older neuroblastoma patients, MYCN non-amplified younger neuroblastoma patients had better clinical outcomes. ALCAM, CACNA2D3, DST, EPB41L4A and KIF1B were highly expressed in MYCN non-amplified younger neuroblastoma patients. And the higher expression levels of ALCAM, CACNA2D3, DST, EPB41L4A or KIF1B were associated with better prognosis of MYCN non-amplified neuroblastoma patients. DST was an independent prognostic factor in MYCN non-amplified neuroblastoma patients and MYCN non-amplified neuroblastoma younger patients with higher DST expression levels had the best clinical overall survival. Conclusions Age related gene DST was an independent prognostic factor in MYCN non-amplified neuroblastoma. MYCN non-amplified younger neuroblastoma patients with higher DST expression levels had the best clinical overall survival

Genetic and ultrasonographic analyses of fetuses with 1q21.1q21.2 microdeletion/microduplication: a retrospective study

Abstract Background 1q21.1q21.2 microdeletions/microduplications are rare and incompletely penetrant genetic mutations, and only a few reports regarding their prenatal diagnosis are currently available. Here, we analyzed the ultrasonographic phenotypic characteristics of fetuses with these mutations to improve the understanding, diagnosis, and screening of these mutations during gestation. Methods We retrospectively analyzed 8700 cases of pregnant women who underwent invasive prenatal screening by karyotyping and chromosomal microarray analysis (CMA) between November 2016 and November 2021. Results CMA revealed copy number changes in the 1q21.1q21.2 region of eleven fetuses, of which five had microdeletions and six had microduplications. These eleven fetuses exhibited variable ultrasonographic phenotypes. Of the five fetuses with the microdeletion, one exhibited a right-dominant heart, permanent right umbilical vein, and mild tricuspid regurgitation, another showed thickened nuchal translucency, and the remaining three had normal ultrasound phenotypes. Two of the six cases with 1q21.1q21.2 microduplication had structural malformations; one of them had a bilateral subependymal cyst, neck mass, and enlarged cardiothoracic ratio, while the other had right ventricular hypoplasia. Of the remaining four cases, two exhibited nasal bone dysplasia, one showed measurement slower than that during menopause and mild tricuspid regurgitation, and another did not show any notable abnormality in ultrasound examination. Among the eleven cases of 1q21.1q21.2 microdeletion/microduplication, only the parents of two fetuses underwent pedigree verification. The parents of these two fetuses with 1q21.1q21.2 microdeletion syndrome chose to continue the pregnancy, and all aspects of postnatal follow-up were normal. The parents of the other nine fetuses refused pedigree verification; of these cases, four cases terminated, and five cases continued the pregnancies. The five continued pregnancies were followed up after birth; no abnormalities were found. Conclusions Fetuses with 1q21.1q21.2 microdeletion/microduplication show different ultrasound characteristics and may have congenital heart disease, thickened nuchal translucency, and nasal bone dysplasia or show no notable abnormalities in an ultrasound examination. Our study highlights that CMA as a powerful diagnostic tool for these diseases can provide an accurate genetic diagnosis, while improving prenatal diagnosis standards

Autophagic Network Analysis of the Dual Effect of Sevoflurane on Neurons Associated with GABARAPL1 and 2

Background. Sevoflurane is commonly used as a general anesthetic in neonates to aged patients. Preconditioning or postconditioning with sevoflurane protects neurons from excitotoxic injury. Conversely, sevoflurane exposure induces neurotoxicity during early or late life. However, little is known about the underlying mechanism of the dual effect of sevoflurane on neurons. Autophagy is believed to control neuronal homeostasis. We hypothesized that autophagy determined the dual effect of sevoflurane on neurons. Methods. DTome was used to identify the direct protein target (DPT) of sevoflurane. The STRING database was employed to investigate the proteins associated with the DPTs. Protein-protein interaction was assessed using Cytoscape. WebGestalt was used to analyze gene set enrichment. The linkage between candidate genes and autophagy was identified using GeneCards. Results. This study found that 23 essential DPTs of sevoflurane interacted with 77 proteins from the STRING database. GABARAPL1 and 2, both of which are DPT- and autophagy-associated proteins, were significantly expressed in the brain and enriched in GABAergic synapses. Conclusions. Taken together, our findings showed that the network of sevoflurane-DPT-GABARAPL1 and 2 is related to the dual effect of sevoflurane on neurons

Prenatal diagnosis and genetic etiology analysis of talipes equinovarus by chromosomal microarray analysis

Abstract Background With the advancement of molecular technology, fetal talipes equinovarus (TE) is believed to be not only associated with chromosome aneuploidy, but also related to chromosomal microdeletion and microduplication. The study aimed to explore the molecular etiology of fetal TE and provide more information for the clinical screening and genetic counseling of TE by Chromosomal Microarray Analysis (CMA). Methods This retrospectively study included 131 fetuses with TE identified by ultrasonography. Conventional karyotyping and SNP array analysis were performed for all the subjects. They were divided into isolated TE group (n = 55) and complex group (n = 76) according to structural anomalies. Results Among the total of 131 fetuses, karyotype analysis found 12(9.2%) abnormal results, while SNP array found 27 (20.6%) cases. Trisomy 18 was detected most frequently among abnormal karyotypes. The detection rate of SNP array was significantly higher than that of traditional chromosome karyotype analysis (P  0.05). Abnormal chromosomes were most frequently detected in fetuses with TE plus cardiovascular system abnormalities. Conclusion Fetal TE is related to chromosomal microdeletion or microduplication. Prenatal diagnosis is recommended for fetuses with TE, and CMA testing is preferred. CMA can improve the detection rate of chromosomal abnormalities associated with fetal TE, especially in pregnancies with complex TE

Molecular cytogenetic identification of small supernumerary marker chromosomes using chromosome microarray analysis

Abstract Background This study aimed to evaluate the feasibility of chromosomal microarray analysis (CMA) in detecting the origin and structure of small supernumerary marker chromosomes (sSMCs) in prenatal and postnatal cases and to clarify sSMC-related genotype-phenotype correlations. Results Thirty-three cases carrying sSMCs were identified by banding cytogenetics. Of these cases, twenty-nine were first characterized by CMA and only two by FISH. The remaining two cases were excluded for their refusal to accept further examination. The chromosomal origins of twenty-two cases were successfully identified, in which pathogenetic copy number variations (PCNVs) were found in sixteen cases, four cases showed variants of uncertain significance (VOUS), one case showed benign CNVs, and one case showed probable PCNVs. For the nine cases with negative CMA results, only one of them contained centromere heterochromatin likely due to its normal phenotype, whereas reasons for the remaining eight cases were uncertain. We also found that CMA results indicating pathogenic abnormalities further affect the rate of pregnancy termination. Conclusions This study showed that CMA combined with cytogenetic analysis is particularly effective in identifying sSMCs. However, in order to establish sSMC-related genotype-phenotype correlations, the inclusion of more sSMC cases will be necessary in future studies