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American Journal of Obstetrics and... Apr 2023This study aimed to determine the incremental yield of prenatal exome sequencing over chromosomal microarray or G-banding karyotype in fetuses with: (1) intrauterine... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
This study aimed to determine the incremental yield of prenatal exome sequencing over chromosomal microarray or G-banding karyotype in fetuses with: (1) intrauterine growth restriction related to placental insufficiency or (2) short long bones, in isolated and nonisolated instances for both scenarios.
DATA SOURCES
Data were collected via electronic searches for relevant citations from January 2010 to April 10, 2022 in MEDLINE, Embase, Web of Science, and Cochrane, and using relevant bibliographies and data generated in-house.
STUDY ELIGIBILITY CRITERIA
Included were prospective or retrospective cohort studies and/or case series with: (1) n>5 cases of short long bones and/or intrauterine growth restriction undergoing prenatal sequencing with a clearly defined phenotype including assessment of placental function; (2) testing based on prenatal phenotype only; (3) a nondiagnostic chromosomal microarray/karyotype; and (4) known results of genetic testing.
METHODS
Incremental yield was calculated for each study and as a pooled value for the aforementioned groups using a random-effects model. Results were displayed in forest plots with 95% confidence intervals. Heterogeneity was assessed statistically using Higgins' I. Publication bias was assessed graphically using funnel plots. Quality assessment was performed using modified Standards for Reporting of Diagnostic Accuracy criteria (International Prospective Register of Systematic Reviews registration number CRD42022324680).
RESULTS
Nineteen studies were included (n=452 cases). The apparent incremental yields with prenatal sequencing were: (1) 4% (95% confidence interval, -5.0 to 12; I=0%) in isolated intrauterine growth restriction with evidence of placental insufficiency, (2) 30% (95% confidence interval, 13-47; I=1%) in intrauterine growth restriction with additional structural anomalies, (3) 48% (95% confidence interval, 26-70; I=73%) in isolated short long bones, and (4) 68% (95% confidence interval, 58-77; I=51%) in short long bones with additional skeletal anomalies. Of the 37 short long bone cases with a diagnosis, 32 had a skeletal dysplasia, with thanatophoric dysplasia and osteogenesis imperfecta being the most common (both 21.6% [n=8/37]). In fetuses with short long bones and additional skeletal features, osteogenesis imperfecta was the most common diagnosis (28% [n=57/204]). Where documented, the inheritance patterns were de novo in 75.4% (n=150) of cases.
CONCLUSION
Prenatal sequencing adds substantially to incremental yield over chromosomal microarray in fetuses with short long bones or multisystem intrauterine growth restriction. Robust studies are required to assess the utility of fetal sequencing in isolated intrauterine growth restriction with evidence of placental insufficiency, which cannot be recommended on the basis of current evidence.
Topics: Humans; Pregnancy; Female; Fetal Growth Retardation; Placental Insufficiency; Exome Sequencing; Retrospective Studies; Osteogenesis Imperfecta; Placenta; Prenatal Diagnosis; Ultrasonography, Prenatal
PubMed: 36209938
DOI: 10.1016/j.ajog.2022.09.045 -
Genetics in Medicine : Official Journal... Nov 2019For neurodevelopmental disorders (NDDs), etiological evaluation can be a diagnostic odyssey involving numerous genetic tests, underscoring the need to develop a... (Meta-Analysis)
Meta-Analysis
PURPOSE
For neurodevelopmental disorders (NDDs), etiological evaluation can be a diagnostic odyssey involving numerous genetic tests, underscoring the need to develop a streamlined algorithm maximizing molecular diagnostic yield for this clinical indication. Our objective was to compare the yield of exome sequencing (ES) with that of chromosomal microarray (CMA), the current first-tier test for NDDs.
METHODS
We performed a PubMed scoping review and meta-analysis investigating the diagnostic yield of ES for NDDs as the basis of a consensus development conference. We defined NDD as global developmental delay, intellectual disability, and/or autism spectrum disorder. The consensus development conference included input from genetics professionals, pediatric neurologists, and developmental behavioral pediatricians.
RESULTS
After applying strict inclusion/exclusion criteria, we identified 30 articles with data on molecular diagnostic yield in individuals with isolated NDD, or NDD plus associated conditions (such as Rett-like features). Yield of ES was 36% overall, 31% for isolated NDD, and 53% for the NDD plus associated conditions. ES yield for NDDs is markedly greater than previous studies of CMA (15-20%).
CONCLUSION
Our review demonstrates that ES consistently outperforms CMA for evaluation of unexplained NDDs. We propose a diagnostic algorithm placing ES at the beginning of the evaluation of unexplained NDDs.
Topics: Autism Spectrum Disorder; Developmental Disabilities; Diagnostic Tests, Routine; Exome; Genetic Testing; Humans; Intellectual Disability; Neurodevelopmental Disorders; Exome Sequencing
PubMed: 31182824
DOI: 10.1038/s41436-019-0554-6 -
Prenatal Diagnosis May 2022We conducted a systematic review and meta-analysis to determine the diagnostic yield of exome sequencing (ES) for prenatal diagnosis of fetal structural anomalies, where... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
We conducted a systematic review and meta-analysis to determine the diagnostic yield of exome sequencing (ES) for prenatal diagnosis of fetal structural anomalies, where karyotype/chromosomal microarray (CMA) is normal.
METHODS
Following electronic searches of four databases, we included studies with ≥10 structurally abnormal fetuses undergoing ES or whole genome sequencing. The incremental diagnostic yield of ES over CMA/karyotype was calculated and pooled in a meta-analysis. Sub-group analyses investigated effects of case selection and fetal phenotype on diagnostic yield.
RESULTS
We identified 72 reports from 66 studies, representing 4350 fetuses. The pooled incremental yield of ES was 31% (95% confidence interval (CI) 26%-36%, p < 0.0001). Diagnostic yield was significantly higher for cases pre-selected for likelihood of monogenic aetiology compared to unselected cases (42% vs. 15%, p < 0.0001). Diagnostic yield differed significantly between phenotypic sub-groups, ranging from 53% (95% CI 42%-63%, p < 0.0001) for isolated skeletal abnormalities, to 2% (95% CI 0%-5%, p = 0.04) for isolated increased nuchal translucency.
CONCLUSION
Prenatal ES provides a diagnosis in an additional 31% of structurally abnormal fetuses when CMA/karyotype is non-diagnostic. The expected diagnostic yield depends on the body system(s) affected and can be optimised by pre-selection of cases following multi-disciplinary review to determine that a monogenic cause is likely.
Topics: Exome; Female; Humans; Pregnancy; Pregnancy Trimester, First; Prenatal Diagnosis; Ultrasonography, Prenatal; Exome Sequencing
PubMed: 35170059
DOI: 10.1002/pd.6115 -
JAMA Network Open Nov 2023Exome sequencing (ES) has been established as the preferred first line of diagnostic testing for certain neurodevelopmental disorders, such as global developmental delay... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Exome sequencing (ES) has been established as the preferred first line of diagnostic testing for certain neurodevelopmental disorders, such as global developmental delay and autism spectrum disorder; however, current recommendations are not specific to or inclusive of congenital hydrocephalus (CH).
OBJECTIVE
To determine the diagnostic yield of ES in CH and whether ES should be considered as a first line diagnostic test for CH.
DATA SOURCES
PubMed, Cochrane Library, and Google Scholar were used to identify studies published in English between January 1, 2010, and April 10, 2023. The following search terms were used to identify studies: congenital hydrocephalus, ventriculomegaly, cerebral ventriculomegaly, primary ventriculomegaly, fetal ventriculomegaly, prenatal ventriculomegaly, molecular analysis, genetic cause, genetic etiology, genetic testing, exome sequencing, whole exome sequencing, genome sequencing, microarray, microarray analysis, and copy number variants.
STUDY SELECTION
Eligible studies included those with at least 10 probands with the defining feature of CH and/or severe cerebral ventriculomegaly that had undergone ES. Studies with fewer than 10 probands, studies of mild or moderate ventriculomegaly, and studies using genetic tests other than ES were excluded. A full-text review of 68 studies was conducted by 2 reviewers. Discrepancies were resolved by consensus.
DATA EXTRACTION AND SYNTHESIS
Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and Meta-Analysis of Observational Studies in Epidemiology guidelines were used by 2 reviewers to extract data. Data were synthesized using a random-effects model of single proportions. Data analysis occurred in April 2023.
MAIN OUTCOMES AND MEASURES
The primary outcome was pooled diagnostic yield. Additional diagnostic yields were estimated for specific subgroups on the basis of clinical features, syndromic presentation, and parental consanguinity. For each outcome, a 95% CI and estimate of interstudy heterogeneity (I2 statistic) was reported.
RESULTS
From 498 deduplicated and screened records, 9 studies with a total of 538 CH probands were selected for final inclusion. The overall diagnostic yield was 37.9% (95% CI, 20.0%-57.4%; I2 = 90.1). The yield was lower for isolated and/or nonsyndromic cases (21.3%; 95% CI, 12.8%-31.0%; I2 = 55.7). The yield was higher for probands with reported consanguinity (76.3%; 95% CI, 65.1%-86.1%; I2 = 0) than those without (16.2%; 95% CI, 12.2%-20.5%; I2 = 0).
CONCLUSIONS AND RELEVANCE
In this systematic review and meta-analysis of the diagnostic yield of ES in CH, the diagnostic yield was concordant with that of previous recommendations for other neurodevelopmental disorders, suggesting that ES should also be recommended as a routine diagnostic adjunct for patients with CH.
Topics: Female; Pregnancy; Humans; Autism Spectrum Disorder; Exome Sequencing; Pathology, Molecular; Patients; Hydrocephalus
PubMed: 37991765
DOI: 10.1001/jamanetworkopen.2023.43384 -
The Journal of Maternal-fetal &... Dec 2023To estimate the incremental yield of detecting pathogenic or likely pathogenic diagnostic genetic variants (DGV) by whole exome sequencing (WES) over standard karyotype... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To estimate the incremental yield of detecting pathogenic or likely pathogenic diagnostic genetic variants (DGV) by whole exome sequencing (WES) over standard karyotype and chromosomal microarray (CMA) analyses in fetuses with isolated increased nuchal translucency (NT) and normal fetal anatomy at the time of 11-14 weeks scan.
MATERIALS AND METHODS
Medline and Embase databases were searched. Inclusion criteria were fetuses with NT >95 percentile, normal karyotype and CMA and no associated structural anomalies at the time of the 11-14 weeks scan. The primary outcome was to estimate the incremental yield of detecting pathogenic or likely pathogenic genetic variants by WES over standard karyotype and CMA analyses in fetuses with isolated increased nuchal translucency. The secondary outcomes were the detection of a genetic variant of unknown significance. Sub-analysis according to different NT cutoffs (between 3.0 and 5.5 mm and > 5.5 mm) and considering fetuses with isolated NT in which fetal anatomy was confirmed to be normal at the anomaly scan were also performed. Random effects model meta-analyses of proportion were used to analyze the data.
RESULTS
Eight articles (324 fetuses) were included in the systematic review. Of the fetuses with negative standard karyotype and CMA analysis, the 8.07% (95% CI 5.4-11.3) had pathogenic or likely pathogenic genetic variants detected exclusively by WES. When stratifying the analysis according to NT cutoffs, genetic anomalies detected exclusively at WES analysis were found in 44.70% (95% CI 26.8-63.4) of fetuses with NT between 3.0 mm and 5.5 mm and 55.3% (95% CI 36.6-73.2) in those fetuses with NT >5.5 mm and positive WES results. The 7.84% (95% CI 1.6-18.2) had variants of unknown significance identified by WES. When considering fetuses with isolated increased NT and normal fetal anatomy at the anomaly scan, the rate of pathogenic or likely pathogenic genetic variants detected by WES was 3.87% (95% CI 1.6-7.1), while variants of unknown significance were detected in 4.27% (95% CI 2.2-7.0) of cases.
CONCLUSIONS
Pathogenic and likely pathogenic genetic variants detected by WES are present in a significant proportion of fetuses with increased NT but normal standard karyotype and CMA analysis, also when no anomalies are detected at the anomaly scan. Further large studies sharing objective protocols of imaging assessment are needed to confirm these findings and to elucidate which gene panels should be assessed in fetuses with isolated increased NT to rule out associated genetic anomalies, which may potentially impact post-natal outcomes.
Topics: Pregnancy; Female; Humans; Nuchal Translucency Measurement; Exome Sequencing; Fetus; Karyotyping; Karyotype; Prenatal Diagnosis
PubMed: 37019452
DOI: 10.1080/14767058.2023.2193285 -
Prenatal Diagnosis May 2023The aim of this study was to determine the diagnostic yield of exome sequencing (ES) above that of chromosomal microarray analysis (CMA) or karyotyping in fetuses with... (Meta-Analysis)
Meta-Analysis Review
The aim of this study was to determine the diagnostic yield of exome sequencing (ES) above that of chromosomal microarray analysis (CMA) or karyotyping in fetuses with isolated fetal growth restriction (FGR). This was a systematic review conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Selected studies included those with (a) only fetuses with FGR in the absence of fetal structural anomalies and (b) negative CMA or karyotyping results. Only positive variants classified as likely pathogenic or pathogenic determined as causative of the fetal phenotype were considered. A negative CMA or karyotype result was treated as the reference standard. Eight studies with data on ES diagnostic yield, including 146 fetuses with isolated FGR, were identified. Overall, a pathogenic variant determined as potentially causative of the fetal phenotype was found in 17 cases, resulting in a 12% (95% CI: 7%-18%) incremental performance pool of ES. The vast majority were studied before 32 weeks'gestation. In conclusion, a monogenic disorder was prenatally found in association with apparently isolated FGR in 12% of these fetuses.
Topics: Pregnancy; Humans; Female; Fetal Growth Retardation; Exome Sequencing; Ultrasonography, Prenatal; Karyotyping; Microarray Analysis
PubMed: 36869857
DOI: 10.1002/pd.6339 -
Movement Disorders Clinical Practice Apr 2023Chromosome microarray analysis (CMA) can detect copy number variants (CNV) beyond the resolution of standard G-banded karyotyping. De novo or inherited microdeletions... (Review)
Review
BACKGROUND
Chromosome microarray analysis (CMA) can detect copy number variants (CNV) beyond the resolution of standard G-banded karyotyping. De novo or inherited microdeletions may cause autosomal dominant movement disorders.
OBJECTIVES
The purpose of this study was to analyze the clinical characteristics, associated features, and genetic information of children with deletions in known genes that cause movement disorders and to make recommendations regarding the diagnostic application of CMA.
METHODS
Clinical cases published in English were identified in scientific databases (PubMed, ClinVar, and DECIPHER) from January 1998 to July 2019 following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Cases with deletions or microdeletions greater than 300 kb were selected. Information collected included age, sex, movement disorders, associated features, and the size and location of the deletion. Duplications or microduplications were not included.
RESULTS
A total of 18.097 records were reviewed, and 171 individuals were identified. Ataxia (30.4%), stereotypies (23.9%), and dystonia (21%) were the most common movement disorders. A total of 16% of the patients demonstrated more than one movement disorder. The most common associated features were intellectual disability or developmental delay (78.9%) and facial dysmorphism (57.8%). The majority (77.7%) of microdeletions were smaller than 5 Mb. We find no correlation between movement disorders, their associated features, and the size of microdeletions.
CONCLUSIONS
Our results support the use of CMA as an investigational test in children with movement disorders. As the majority of identified articles were case reports and small case series (low quality), future efforts should focus on larger prospective studies to examine the causation of microdeletions in pediatric movement disorders.
PubMed: 37070051
DOI: 10.1002/mdc3.13711 -
JAMA Neurology Dec 2022There are many known acquired risk factors for cerebral palsy (CP), but in some cases, CP is evident without risk factors (cryptogenic CP). Early CP cohort studies... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
There are many known acquired risk factors for cerebral palsy (CP), but in some cases, CP is evident without risk factors (cryptogenic CP). Early CP cohort studies report a wide range of diagnostic yields for sequence variants assessed by exome sequencing (ES) and copy number variants (CNVs) assessed by chromosomal microarray (CMA).
OBJECTIVE
To synthesize the emerging CP genetics literature and address the question of what percentage of individuals with CP have a genetic disorder via ES and CMA.
DATA SOURCES
Searched articles were indexed by PubMed with relevant queries pertaining to CP and ES/CMA (query date, March 15, 2022).
STUDY SELECTION
Inclusion criteria were as follows: primary research study, case series with 10 or more nonrelated individuals, CP diagnosis, and ES and/or CMA data used for genetic evaluation. Nonblinded review was performed.
DATA EXTRACTION AND SYNTHESIS
Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were used for assessing data quality and validity. Data were extracted by a single observer.
MAIN OUTCOMES AND MEASURES
A separate meta-analysis was performed for each modality (ES, CMA). The primary outcome was proportion/molecular diagnostic yield (number of patients with a discovered genetic disorder divided by the total number of patients in the cohort), evaluated via meta-analysis of single proportions using random-effects logistic regression. A subgroup meta-analysis was conducted, using risk factor classification as a subgroup. A forest plot was used to display diagnostic yields of individual studies.
RESULTS
In the meta-analysis of ES yield in CP, the overall diagnostic yield of ES among the cohorts (15 study cohorts comprising 2419 individuals from 11 articles) was 23% (95% CI, 15%-34%). The diagnostic yield across cryptogenic CP cohorts was 35% (95% CI, 27%-45%), compared with 7% (95% CI, 4%-12%) across cohorts with known risk factors (noncryptogenic CP). In the meta-analysis of CMA yield in CP, the diagnostic yield of CMA among the cohorts (5 study cohorts comprising 294 individuals from 5 articles) was 5% (95% CI, 2%-12%).
CONCLUSIONS AND RELEVANCE
Results of this systematic review and meta-analysis suggest that for individuals with cryptogenic CP, ES followed by CMA to identify molecular disorders may be warranted.
Topics: Humans; Pathology, Molecular; Cerebral Palsy; Microarray Analysis; Exome Sequencing; DNA Copy Number Variations
PubMed: 36279113
DOI: 10.1001/jamaneurol.2022.3549 -
International Journal of Molecular... Jun 2020The purpose of this review was to evaluate the expression patterns of miRNAs in periodontal and peri-implant diseases, while identifying potential miRNAs with the... (Meta-Analysis)
Meta-Analysis Review
AIM
The purpose of this review was to evaluate the expression patterns of miRNAs in periodontal and peri-implant diseases, while identifying potential miRNAs with the greatest diagnostic ability as an oral fluid biomarker.
MATERIALS AND METHODS
Human and animal studies were included when evaluating expression of miRNAs between health and different forms/stages of diseases, in which microarray and/or real-time polymerase chain reaction (RT-PCR) was carried out to detect fold changes in gene expression. After full-text analysis, 43 articles were considered for a qualitative assessment, and 16 miRNAs were selected to perform meta-analysis.
RESULTS
Based on human studies, results showed an overall upregulation of most of the evaluated miRNAs in periodontitis, with miRNA-142-3p and miRNA-146a being the most conclusive on both microarray and RT-PCR values and potentially serving as diagnostic biomarkers for disease activity. Conversely, miR-155 was the only miRNA revealing a statistically significant difference (SSD) ( < 0.05*) in experimental periodontitis models from RT-PCR values. Scarce scientific evidence is available from peri-implant diseases, however, most explored miRNAs in peri-implantitis were downregulated except for miR-145.
CONCLUSIONS
Although our results revealed that a distinct differential expression of specific miRNAs can be noted between the state of health and disease, future research remains necessary to explore the functional role of specific miRNAs and their potential as therapeutic targets in periodontal and peri-implant diseases. MeSH Terms: periodontitis, peri-implantitis, epigenomics, microarray analysis, real-time polymerase chain reaction, microRNAs.
CLINICAL RELEVANCE
Scientific background: Although most research identified different expression levels of miRNAs in periodontal and peri-implant diseases compared to their counterparts, their actual role in the pathogenesis of these conditions remains unclear. Therefore, we aimed to present a systematic review and meta-analysis on the expression patterns of miRNAs in periodontitis and peri-implantitis, while identifying potential miRNAs with the greatest diagnostic ability as an oral fluid biomarker.
PRINCIPAL FINDINGS
In periodontitis-related studies, miRNA-142-3p and miRNA-146a were the most conclusive on both microarray and RT-PCR values. Scarce scientific evidence is available from peri-implant diseases.
PRACTICAL IMPLICATIONS
Both miRNA-142-3p and miRNA-146a might serve as future diagnostic biomarkers for disease activity in periodontitis. Yet, future research remains necessary to explore the functional role of specific miRNAs and their potential as therapeutic targets in periodontal and peri-implant diseases.
Topics: Animals; Biomarkers; Humans; MicroRNAs; Oligonucleotide Array Sequence Analysis; Peri-Implantitis; Periodontitis
PubMed: 32532036
DOI: 10.3390/ijms21114147 -
Urologic Oncology May 2022Determining meta-analysis of transcriptional profiling of muscle-invasive bladder cancer (MIBC) through Gene Expression Omnibus (GEO) datasets has not been investigated.... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Determining meta-analysis of transcriptional profiling of muscle-invasive bladder cancer (MIBC) through Gene Expression Omnibus (GEO) datasets has not been investigated. This study aims to define gene expression profiles in MIBC and to identify potential candidate genes and pathways.
OBJECTIVES
To review and evaluate gene expression studies in MIBC through publicly available RNA sequencing (RNA-Seq) and microarray data in order to identify potential prognostic and therapeutic targets for MIBC.
METHODS
A systematic literature search of the Ovid MEDLINE, PubMed, and Wiley Cochrane Central Register of Controlled Trials databases was performed using the terms "gene," "gene expression," and "bladder cancer" January 1, 1990 through March 2021 focused on populations with MIBC.
RESULTS
In the final analysis, GEO datasets were included. Fixed effect model was employed in the meta-analysis. Gene networking connections and gene-set functional analyses of the identified genes as differentially expressed in MIBC were performed using ImaGEO and GeneMANIA software. A heatmap for the upregulated and downregulated genes was generated along with the correlated pathways.
CONCLUSION
A total of 9 genes were reported in this analysis. Six genes were reported as upregulated (ProTα, SPINT1, UBE2E1, RAB25, KPNB1, HDAC1) and 3 genes as downregulated (NUP188, IPO13, NUP124). Genes were found to be involved in "ubiquitin mediated proteolysis," "protein processing in endoplasmic reticulum," "transcriptional misregulation in cancer," and "RNA transport" pathways.
Topics: Female; Gene Expression Profiling; Gene Regulatory Networks; Humans; Male; Muscles; Neoplasm Invasiveness; Prognosis; Urinary Bladder Neoplasms; rab GTP-Binding Proteins
PubMed: 35039218
DOI: 10.1016/j.urolonc.2021.11.003