-
Diagnostics (Basel, Switzerland) Dec 2022Fetal Nuchal fluid collections can manifest with two distinct presentations attributable to the same phenotypic spectrum: increased nuchal translucency (iNT) and cystic... (Review)
Review
A Pain in the Neck: Lessons Learnt from Genetic Testing in Fetuses Detected with Nuchal Fluid Collections, Increased Nuchal Translucency versus Cystic Hygroma-Systematic Review of the Literature, Meta-Analysis and Case Series.
Fetal Nuchal fluid collections can manifest with two distinct presentations attributable to the same phenotypic spectrum: increased nuchal translucency (iNT) and cystic hygroma. The prenatal detection of these findings should prompt an accurate assessment through genetic counseling and testing, including karyotype, chromosomal microarray analysis (CMA) and multigene RASopathy panel. We performed a systematic review of the literature and meta-analysis, to calculate diagnostic yields of genetic testing in fetuses with iNT and cystic hygroma. We compared the results with a cohort of 96 fetuses with these isolated findings. Fetuses with isolated NT ≥ 2.5 mm showed karyotype anomalies in 22.76% of cases and CMA presented an incremental detection rate of 2.35%. Fetuses with isolated NT ≥ 3 mm presented aneuploidies in 14.36% of cases and CMA had an incremental detection rate of 3.89%. When the isolated NT measured at least 3.5 mm the diagnostic yield of karyotyping was 34.35%, the incremental CMA detection rate was 4.1%, the incremental diagnostic rate of the RASopathy panel was 1.44% and it was 2.44% for exome sequencing. Interestingly, CMA presents a considerable diagnostic yield in the group of fetuses with NT ≥ 3.5 mm. Similarly, exome sequencing appears to show promising results and could be considered after a negative CMA result.
PubMed: 36611340
DOI: 10.3390/diagnostics13010048 -
Ultrasound in Obstetrics & Gynecology :... Jan 2022To determine the diagnostic yield of exome or genome sequencing (ES/GS) over chromosomal microarray analysis (CMA) in fetuses with increased nuchal translucency (NT) and... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To determine the diagnostic yield of exome or genome sequencing (ES/GS) over chromosomal microarray analysis (CMA) in fetuses with increased nuchal translucency (NT) and no concomitant anomalies.
METHODS
This systematic review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria. PubMed, Scopus and Web of Science were searched for studies describing ES/GS in fetuses with isolated increased NT. Inclusion criteria were: (1) study written in English; (2) more than two fetuses with increased NT > 99 percentile and no concomitant anomalies; and (3) a negative CMA result considered as the reference standard. Only positive variants identified on ES/GS that were classified as likely pathogenic or pathogenic and determined to be causative of the fetal phenotype were considered. Risk was assessed as the pooled effect size by single-proportion analysis using random-effects modeling (weighted by inverse of variance).
RESULTS
Eleven studies reporting on the diagnostic yield of ES/GS in fetuses with isolated increased NT > 99 percentile were identified and included 309 cases. All studies were high quality according to Standards for Reporting of Diagnostic Accuracy. Overall, a pathogenic or likely pathogenic variant was identified on ES/GS in 15 fetuses, resulting in a pooled incremental yield of 4% (95% CI, 2-6%). Six (40%) of these fetuses had NT of 5 mm or more. The observed inheritance pattern was autosomal dominant in 12 cases, including four fetuses with Noonan syndrome, autosomal recessive in two cases and X-linked in one case.
CONCLUSIONS
There is a 4% incremental diagnostic yield of ES/GS over CMA in fetuses with increased NT > 99 percentile without a concomitant anomaly. It is unclear whether a NT cut-off higher than 3.5 mm may be more useful in case selection for ES/GS. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.
Topics: Female; Fetus; High-Throughput Nucleotide Sequencing; Humans; Microarray Analysis; Nuchal Translucency Measurement; Predictive Value of Tests; Pregnancy; Prenatal Diagnosis; Reference Values
PubMed: 34309942
DOI: 10.1002/uog.23746 -
Journal of Translational Medicine Aug 2023Accurately predicting the outcome of isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM) remains hitherto challenging. This study aims to Construct and Validate...
BACKGROUND
Accurately predicting the outcome of isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM) remains hitherto challenging. This study aims to Construct and Validate a Robust Prognostic Model for IDH wild-type GBM (COVPRIG) for the prediction of overall survival using a novel metric, gene-gene (G × G) interaction, and explore molecular and cellular underpinnings.
METHODS
Univariate and multivariate Cox regression of four independent trans-ethnic cohorts containing a total of 800 samples. Prediction efficacy was comprehensively evaluated and compared with previous models by a systematic literature review. The molecular underpinnings of COVPRIG were elucidated by integrated analysis of bulk-tumor and single-cell based datasets.
RESULTS
Using a Cox-ph model-based method, six of the 93,961 G × G interactions were screened to form an optimal combination which, together with age, comprised the COVPRIG model. COVPRIG was designed for RNA-seq and microarray, respectively, and effectively identified patients at high risk of mortality. The predictive performance of COVPRIG was satisfactory, with area under the curve (AUC) ranging from 0.56 (CGGA693, RNA-seq, 6-month survival) to 0.79 (TCGA RNAseq, 18-month survival), which can be further validated by decision curves. Nomograms were constructed for individual risk prediction for RNA-seq and microarray-based cohorts, respectively. Besides, the prognostic significance of COVPRIG was also validated in GBM including the IDH mutant samples. Notably, COVPRIG was comprehensively evaluated and externally validated, and a systemic review disclosed that COVPRIG outperformed current validated models with an integrated discrimination improvement (IDI) of 6-16%. Moreover, integrative bioinformatics analysis predicted an essential role of METTL1 neural-progenitor-like (NPC-like) malignant cell in driving unfavorable outcome.
CONCLUSION
This study provided a powerful tool for the outcome prediction for IDH wild-type GBM, and preliminary molecular underpinnings for future research.
Topics: Humans; Glioblastoma; Isocitrate Dehydrogenase; Brain Neoplasms; Prognosis; Nomograms; Methyltransferases
PubMed: 37553713
DOI: 10.1186/s12967-023-04382-2 -
Journal of Dairy Science Jan 2021Development of ketosis in high-producing dairy cows contributes to several animal health issues and highlights the need for a better understanding of the genetic basis... (Meta-Analysis)
Meta-Analysis
Development of ketosis in high-producing dairy cows contributes to several animal health issues and highlights the need for a better understanding of the genetic basis of metabolic diseases. To evaluate the pattern of differential gene expression in the liver of cows under negative energy balance (NEB), and under subclinical and clinical ketosis, a meta-analysis of gene expression and genome-wide association studies results was performed. An initial systematic review identified 118 articles based on the key words "cow," "liver," "negative energy balance," "ketosis," "expression," "qPCR," "microarray," "proteomic," "RNA-Seq," and "GWAS." After further screening for only peer-reviewed and pertinent articles for gene expression during NEB and clinical and subclinical ketosis (considering plasma levels of β-hydroxybutyrate), 20 articles were included in the analysis. From the systematic review, 430 significant SNPs identified by genome-wide association studies (GWAS) were assigned to genes reported in gene expression studies by considering chromosome and base pair positions in the ARS-UCD 1.2 bovine assembly. Venn diagrams were created to integrate the data obtained in the systematic review, and Gene Ontology enrichment analysis was carried out using official gene names. A QTL enrichment analysis was also performed to identify potential positional candidate loci. Twenty-four significant SNPs were located within the coordinates of differentially expressed genes located on chromosomes 2, 3, 6, 9, 11, 14, 27, and 29. Three significant metabolic pathways were associated with NEB and subclinical and clinical ketosis. In addition, 2 important genes, PPARA (peroxisome proliferator activated receptor alpha) and ACACA (acetyl-coenzyme A carboxylase α), were identified, which were differentially expressed in the 3 metabolic conditions. The PPARA gene is involved in the regulation of lipid metabolism and fatty liver disease and the ACACA gene encodes an enzyme that catalyzes the carboxylation of acetyl-coenzyme A to malonyl-coenzyme A, which is a rate-limiting step in fatty acid synthesis. Gene network analysis revealed co-expression interactions among 34 genes associated with functions involving fatty acid transport and fatty acid metabolism. For the annotated QTL, 9 QTL were identified for ketosis. The genes FN1 (fibronectin 1) and PTK2 (protein tyrosine kinase 2), which are mainly involved in cell adhesion and formation of extracellular matrix constituents, were enriched for QTL previously associated with the trait "ketosis" on chromosome 2 and for the trait "milk iron content" on chromosome 14, respectively. This integration of gene expression and GWAS data provides an additional understanding of the genetic background of NEB and subclinical and clinical ketosis in dairy cattle. Thus, it is a useful approach to identify biological mechanisms underlying these metabolic conditions in dairy cattle.
Topics: Animals; Cattle; Cattle Diseases; Energy Metabolism; Female; Gene Expression
PubMed: 33189279
DOI: 10.3168/jds.2020-18883 -
Prenatal Diagnosis Jan 2022To identify what online patient information (presented in English) is available to parents about prenatal microarray (CMA) and exome sequencing (ES), and evaluate its...
OBJECTIVE
To identify what online patient information (presented in English) is available to parents about prenatal microarray (CMA) and exome sequencing (ES), and evaluate its content, quality, and readability.
METHOD
Systematic searches (Google and Bing) were conducted, and websites were categorised according to their purpose. Websites categorised as patient information were included if they were: in English, directed at patients, or were a text, video, or online version of an information leaflet. Author-developed content checklists, the DISCERN Genetics tool, and readability tests (the Flesch Reading Ease Score, the Gunning Fog Index, and the Simple Measure of Gobbledygook Index) were then used to assess those sources of patient information.
RESULTS
Of the 665 websites screened, 18 met the criteria. A further 8 sources were found through a targeted search of professional organisations, resulting in 26 sources available for further evaluation. In general, this was found to be low in quality, omitted details recommended by national or international guidance, and was written at a level too advanced for average readers.
CONCLUSION
Improvements should be made to the content, quality, and readability of online information so that it both reinforces and complements the discussions between parents and clinicians about testing options during pregnancy.
Topics: Adult; Comprehension; Education, Distance; Female; Health Literacy; Humans; Internet; Microarray Analysis; Noninvasive Prenatal Testing; Pregnancy; Exome Sequencing
PubMed: 34747021
DOI: 10.1002/pd.6066 -
Ultrasound in Obstetrics & Gynecology :... Jan 2021To determine the incremental yield of antenatal exome sequencing (ES) over chromosomal microarray analysis (CMA) or conventional karyotyping in prenatally diagnosed...
OBJECTIVE
To determine the incremental yield of antenatal exome sequencing (ES) over chromosomal microarray analysis (CMA) or conventional karyotyping in prenatally diagnosed congenital heart disease (CHD).
METHODS
A prospective cohort study of 197 trios undergoing ES following CMA or karyotyping owing to CHD identified prenatally and a systematic review of the literature were performed. MEDLINE, EMBASE, CINAHL and ClinicalTrials.gov (January 2000 to October 2019) databases were searched electronically for studies reporting on the diagnostic yield of ES in prenatally diagnosed CHD. Selected studies included those with more than three cases, with initiation of testing based upon prenatal phenotype only and that included cases in which CMA or karyotyping was negative. The incremental diagnostic yield of ES was assessed in: (1) all cases of CHD; (2) isolated CHD; (3) CHD associated with extracardiac anomaly (ECA); and (4) CHD according to phenotypic subgroup.
RESULTS
In our cohort, ES had an additional diagnostic yield in all CHD, isolated CHD and CHD associated with ECA of 12.7% (25/197), 11.5% (14/122) and 14.7% (11/75), respectively (P = 0.81). The corresponding pooled incremental yields from 18 studies (encompassing 636 CHD cases) included in the systematic review were 21% (95% CI, 15-27%), 11% (95% CI, 7-15%) and 37% (95% CI, 18-56%), respectively. The results did not differ significantly when subanalysis was limited to studies including more than 20 cases, except for CHD associated with ECA, in which the incremental yield was greater (49% (95% CI, 17-80%)). In cases of CHD associated with ECA in the primary analysis, the most common extracardiac anomalies associated with a pathogenic variant were those affecting the genitourinary system (23/52 (44.2%)). The greatest incremental yield was in cardiac shunt lesions (41% (95% CI, 19-63%)), followed by right-sided lesions (26% (95% CI, 9-43%)). In the majority (68/96 (70.8%)) of instances, pathogenic variants occurred de novo and in autosomal dominant (monoallelic) disease genes. The most common (19/96 (19.8%)) monogenic syndrome identified was Kabuki syndrome.
CONCLUSIONS
There is an apparent incremental yield of prenatal ES in CHD. While the greatest yield is in CHD associated with ECA, consideration could also be given to performing ES in the presence of an isolated cardiac abnormality. A policy of routine application of ES would require the adoption of robust bioinformatic, clinical and ethical pathways. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.
Topics: Female; Heart Defects, Congenital; Humans; Karyotyping; Microarray Analysis; Pregnancy; Prenatal Diagnosis; Prospective Studies; Exome Sequencing
PubMed: 32388881
DOI: 10.1002/uog.22072 -
Journal of Pediatric Genetics Sep 2020Oculoauriculovertebral spectrum (OAVS) is a rare class of heterogenous congenital craniofacial malformation conditions of unknown etiology. Although classic OAVS has... (Review)
Review
Microarray-Based Comparative Genomic Hybridization, Multiplex Ligation-Dependent Probe Amplification, and High-Resolution Karyotype for Differential Diagnosis Oculoauriculovertebral Spectrum: A Systematic Review.
Oculoauriculovertebral spectrum (OAVS) is a rare class of heterogenous congenital craniofacial malformation conditions of unknown etiology. Although classic OAVS has been described as hemifacial microsomia with facial asymmetry and microtia, there is no consensus regarding clinical criteria for diagnosis or genetic cause. This systematic review aims to assess the applicability of high-resolution (HR) karyotype, fluorescence in situ hybridization, multiplex ligation-dependent probe amplification (MLPA), and microarray-based comparative genomic hybridization (array-CGH) for differential diagnosis of OAVS. A search was performed in PubMed and Web of Science using all entry terms to the following descriptors: Goldenhar's syndrome, cytogenetic analysis, hybridization in situ, fluorescent, comparative genomic hybridization, multiplex polymerase chain reaction, whole genome sequencing, and karyotype analysis methods. After screening, 25 articles met eligibility. Of the included studies, 59 individuals had a genetic alteration identified. Array-CGH, MLPA, and HR karyotype appear to be viable approaches for molecular diagnosis in OAVS. Heterogeneity is a hallmark of OAVS. Establishing an enhanced framework for diagnosis would inform clinical decision making, and better resource utilization could improve health care facility efficiency and economy.
PubMed: 32714614
DOI: 10.1055/s-0040-1712118 -
Journal of Korean Medical Science Mar 2024Ultrasonographic soft markers are normal variants, rather than fetal abnormalities, and guidelines recommend a detailed survey of fetal anatomy to determine the... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Ultrasonographic soft markers are normal variants, rather than fetal abnormalities, and guidelines recommend a detailed survey of fetal anatomy to determine the necessity of antenatal karyotyping. Anecdotal reports have described cases with ultrasonographic soft markers in which chromosomal microarray analysis (CMA) revealed pathogenic copy number variants (CNVs) despite normal results on conventional karyotyping, but CMA for ultrasonographic soft markers remains a matter of debate. In this systematic review, we evaluated the clinical significance of CMA for pregnancies with isolated ultrasonographic soft markers and a normal fetal karyotype.
METHODS
An electronic search was conducted by an experienced librarian through the MEDLINE, Embase, and Cochrane CENTRAL databases. We reviewed 3,338 articles (3,325 identified by database searching and 13 by a hand search) about isolated ultrasonographic soft markers, and seven ultrasonographic markers (choroid plexus cysts, echogenic bowel, echogenic intracardiac focus, hypoplastic nasal bone, short femur [SF], single umbilical artery, and urinary tract dilatation) were included for this study.
RESULTS
Seven eligible articles were included in the final review. Pathogenic or likely pathogenic CNVs were found in fetuses with isolated ultrasonographic soft markers and a normal karyotype. The overall prevalence of pathogenic or likely pathogenic CNVs was 2.0% (41 of 2,048). The diagnostic yield of CMA was highest in fetuses with isolated SF (9 of 225, 3.9%).
CONCLUSION
CMA could aid in risk assessment and pregnancy counseling in pregnancies where the fetus has isolated ultrasonographic soft markers along with a normal karyotype.
Topics: Female; Humans; Pregnancy; Fetus; Karyotyping; Microarray Analysis; Ultrasonography, Prenatal
PubMed: 38442716
DOI: 10.3346/jkms.2024.39.e70 -
Prenatal Diagnosis Apr 2024Determine the incremental diagnostic yield of prenatal exome sequencing (pES) over chromosome microarray (CMA) or G-banding karyotype in fetuses with central nervous... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
Determine the incremental diagnostic yield of prenatal exome sequencing (pES) over chromosome microarray (CMA) or G-banding karyotype in fetuses with central nervous system (CNS) abnormalities.
METHODS
Data were collected via electronic searches from January 2010 to April 2022 in MEDLINE, Cochrane, Web of Science and EMBASE. The NHS England prenatal exome cohort was also included. Incremental yield was calculated as a pooled value using a random-effects model.
RESULTS
Thirty studies were included (n = 1583 cases). The incremental yield with pES for any CNS anomaly was 32% [95%CI 27%-36%; I = 72%]. Subgroup analysis revealed apparent incremental yields in; (a) isolated CNS anomalies; 27% [95%CI 19%-34%; I = 74%]; (b) single CNS anomaly; 16% [95% CI 10%-23%; I = 41%]; (c) more than one CNS anomaly; 31% [95% Cl 21%-40%; I = 56%]; and (d) the anatomical subtype with the most optimal yield was Type 1 malformation of cortical development, related to abnormal cell proliferation or apoptosis, incorporating microcephalies, megalencephalies and dysplasia; 40% (22%-57%; I = 68%). The commonest syndromes in isolated cases were Lissencephaly 3 and X-linked hydrocephalus.
CONCLUSIONS
Prenatal exome sequencing provides a high incremental diagnostic yield in fetuses with CNS abnormalities with optimal yields in cases with multiple CNS anomalies, particularly those affecting the midline, posterior fossa and cortex.
Topics: Pregnancy; Female; Humans; Prospective Studies; Hydrocephalus; Nervous System Malformations; Karyotyping; Karyotype; Fetus; Prenatal Diagnosis; Ultrasonography, Prenatal
PubMed: 38054560
DOI: 10.1002/pd.6466 -
Medicine Feb 2022Diabetic nephropathy (DN) is a common microvascular complication of diabetic patients, along with hypertension, hyperlipemia, proteinuria, edema, and other clinical...
Diabetic nephropathy (DN) is a common microvascular complication of diabetic patients, along with hypertension, hyperlipemia, proteinuria, edema, and other clinical manifestations. Astragalus membranaceus (AM) is a traditional Chinese medicine and has shown significant clinical efficacy against DN. However, the overall molecular mechanism of this therapeutic effect has not been entirely elucidated. Using network pharmacology, we aimed to identify the key active ingredients and potential pharmacological mechanisms of AM in treating DN and provide scientific evidence of its clinical efficacy.The active ingredients of AM were obtained from the traditional Chinese medicine systems pharmacology database, and the potential targets of AM were identified using the therapeutic target database. DN-related target genes were acquired from the Gene Expression Omnibus microarray dataset GSE1009 and 3 widely used databases-DisGeNET, GeneCards, and Comparative Toxicogenomics Database. The DN-AM common target protein interaction network was established by using the STRING database. Active ingredients candidate targets proteins networks were constructed using Cytoscape software for visualization. Additionally, gene ontology (GO) and Kyoto encyclopedia of genes and genomes pathway analyses were performed using the Database for Annotation, Visualization, and Integrated Discovery database. Target-regulating microRNAs (miRNAs) of these hub genes were obtained from the therapeutic target database, which could then be used for further identification of AM-regulated key miRNAs.A total of 17 active ingredients and 214 target proteins were screened from AM. 61 candidate co-expressed genes with therapeutic effects against DN were obtained and considered as potential therapeutic targets. GO and Kyoto encyclopedia of genes and genomes enrichment analysis showed that these genes were mainly involved in inflammatory response, angiogenesis, oxidative stress reaction, HIF signaling pathway, tumor necrosis factor signaling pathway, and VEGF signaling pathway. In all, 636 differentially expressed genes were identified between the DN patients and control group by using microarray data, GSE1009. Lastly, VEGFA, epidermal growth factor receptor, STAT1, and GJA1 were screened as hub genes. The relationships between miRNAs and hub genes were constructed, which showed that miR-302-3p, miR-372-3p, miR-373-3p, and miR-520-3p were regulated by VEGFA and epidermal growth factor receptor. Meanwhile, VEGFA also influenced miR-15-5p, miR-16-5p, miR-17-5p, miR-20-5p, miR-93-5p, miR-106-5p, miR-195-5p, miR-424-5p, miR-497-5p, and miR-519-3p. In addition, miR-1-3p and miR-206 were regulated by VEGFA and GJA1, and miR-23-3p was regulated by STAT1 and GJA1.To our knowledge, this study revealed for the first time the characteristic multiple components, multiple targets, and multiple pathways of AM that seem to be the underlying mechanisms of action of AM in the treatment of DN with respect to miRNAs.Private information from individuals will not be published. This systematic review also does not involve endangering participant rights. Ethical approval will not be required. The results may be published in a peer-reviewed journal or disseminated at relevant conferences.
Topics: Astragalus propinquus; Diabetes Mellitus; Diabetic Nephropathies; Drugs, Chinese Herbal; ErbB Receptors; Humans; Medicine, Chinese Traditional; MicroRNAs; Network Pharmacology
PubMed: 35119030
DOI: 10.1097/MD.0000000000028747