Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study.
Ontology highlight
ABSTRACT:
SUBMITTER: Lord J
PROVIDER: S-EPMC6386638 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:To determine the diagnostic yield of exome sequencing (ES), a microarray analysis was carried out of fetuses with recurrent fetal structural anomalies (with similar anomalies in consecutive pregnancies). This is a systematic review conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. The selected studies describing ES in fetuses with recurrent fetal malformation were assessed using the Standards for Reporting of Diagnostic Accuracy Studies (STARD) criteria for risk of bias. Incidence was used as the pooled effect size by single-proportion analysis using random-effects modeling (weighted by inverse of variance). We identified nine studies on ES diagnostic yield that included 140 fetuses with recurrent structural anomalies. A pathogenic or likely pathogenic variant was found in 57 fetuses, resulting in a 40% (95%CI: 26% to 54%) incremental performance pool of ES. As expected, the vast majority (86%: 36/42) of the newly identified diseases had a recessive inheritance pattern, and among these, 42% (15/36) of variants were found in homozygosity. Meckel syndrome was the monogenic disease most frequently found, although the genes involved were diverse. The ES diagnostic yield in pregnancies with recurrent fetal structural anomalies was 40% (57/140). Homozygous disease-causing variants were found in 36% (15/57) of the newly identified monogenic disorders.
| S-EPMC8538791 | biostudies-literature
Project description:As prenatal exome sequencing becomes integrated into clinical care, it is critical that providers caring for women with fetal anomalies recognize not only the benefits, but also the challenges and considerations related to this technology. This overview of prenatal sequencing includes information about indications for sequencing, methods, diagnostic yield, clinical utility, variant interpretation, ethical considerations and dilemmas, practical considerations (ie, turnaround time and cost), pre- and posttest counseling points, and psychological impact of testing on families.
| S-EPMC9877148 | biostudies-literature
Project description:IntroductionIn light of the prospective Prenatal Assessment of Genomes and Exomes (PAGE) study, this paper aimed to determine the additional costs of using exome sequencing (ES) alongside or in place of chromosomal microarray (CMA) in a fetus with an identified congenital anomaly.MethodsA decision tree was populated using data from a prospective cohort of women undergoing invasive diagnostic testing. Four testing strategies were evaluated: CMA, ES, CMA followed by ES ("stepwise"); CMA and ES combined.ResultsWhen ES is priced at GBP 2,100 (EUR 2,407/USD 2,694), performing ES alone prenatally would cost a further GBP 31,410 (EUR 36,001/USD 40,289) per additional genetic diagnosis, whereas the stepwise would cost a further GBP 24,657 (EUR 28,261/USD 31,627) per additional genetic diagnosis. When ES is priced at GBP 966 (EUR 1,107/USD 1,239), performing ES alone prenatally would cost a further GBP 11,532 (EUR 13,217/USD 14,792) per additional genetic diagnosis, whereas the stepwise would cost a further additional GBP 11,639 (EUR 13,340/USD 14,929) per additional genetic diagnosis. The sub-group analysis suggests that performing stepwise on cases indicative of multiple anomalies at ultrasound scan (USS) compared to cases indicative of a single anomaly, is more cost-effective compared to using ES alone.Discussion/conclusionPerforming ES alongside CMA is more cost-effective than ES alone, which can potentially lead to improvements in pregnancy management. The direct effects of test results on pregnancy outcomes were not examined; therefore, further research is recommended to examine changes on the projected incremental cost-effectiveness ratios.
| S-EPMC7446299 | biostudies-literature
Project description:Background: Skeletal dysplasias (SDs) are a heterogeneous group of genetic disorders that primarily affect bone and cartilage. This study aims to identify the genetic causes for fetal SDs, and evaluates the diagnostic yield of prenatal whole-exome sequencing (WES) for this disorder. Methods: WES was performed on 38 fetuses with sonographically identified SDs and normal results of karyotype and single nucleotide polymorphism (SNP) analysis. Candidate variants were selected by bioinformatics analysis, and verified by Sanger sequencing. Results: WES revealed pathogenic or likely pathogenic variants associated with SDs in 65.79% (25/38) of fetuses, variants of uncertain significance (VUS) in SDs-related genes in 10.53% (4/38) cases, and incidental findings in 31.58% (12/38) fetuses. The SDs-associated variants identified in the present study affected 10 genes, and 35.71% (10/28) of the variants were novel. Conclusion: WES has a high diagnostic rate for prenatal SDs, which improves pregnancy management, prenatal counseling and recurrence risk assessment for future pregnancies. The newly identified variants expanded mutation spectrum of this disorder.
| S-EPMC8461062 | biostudies-literature
Project description:PurposeWe investigated the diagnostic and clinical performance of trio exome sequencing (ES) in parent-fetus trios where the fetus had sonographic abnormalities but normal karyotype, microarray and, in some cases, normal gene-specific sequencing.MethodsES was performed from DNA of 102 anomalous fetuses and from peripheral blood from their parents. Parents provided consent for the return of diagnostic results in the fetus, medically actionable findings in the parents, and identification as carrier couple for significant autosomal recessive conditions.ResultsIn 21/102 (20.6%) fetuses, ES provided a positive-definitive or positive-probable diagnosis. In 10/102 (9.8%), ES provided an inconclusive-possible result. At least 2/102 (2.0%) had a repeat pregnancy during the study period and used the information from the study for prenatal diagnosis in the next pregnancy. Six of 204 (2.9%) parents received medically actionable results that affected their own health and 3/102 (2.9%) of couples received results that they were carriers for the same autosomal recessive condition.ConclusionES has diagnostic utility in a select population of fetuses where a genetic diagnosis was highly suspected. Challenges related to genetics literacy, variant interpretation, and various types of diagnostic results affecting both fetal and parental health must be addressed by highly tailored pre- and post-test genetic counseling.
| S-EPMC7205580 | biostudies-literature
Project description:Fetal structural congenital abnormalities (SCAs) complicate 2-3% of all pregnancies. Whole-exome sequencing (WES) has been increasingly adopted prenatally when karyotyping and chromosomal microarray do not yield a diagnosis. This is a retrospective cohort study of 104 fetuses with SCAs identified on antenatal ultrasound in Hong Kong, where whole exome sequencing is performed. Molecular diagnosis was obtained in 25 of the 104 fetuses (24%). The highest diagnostic rate was found in fetuses with multiple SCAs (29.2%), particularly those with involvement of the cardiac and musculoskeletal systems. Variants of uncertain significance were detected in 8 out of the 104 fetuses (7.7%). Our study shows the utility of WES in the prenatal setting, and the extended use of the technology would be recommended in addition to conventional genetic workup.
| S-EPMC9778831 | biostudies-literature
Project description:Background: Prenatal diagnosis of fetal short long bones (SLBs) was reported to be associated with skeletal dysplasias, chromosomal abnormalities, and genetic syndromes. This study aims to identify the genetic causes for fetal short long bones, and retrospectively evaluate the additional diagnostic yield of exome sequencing (ES) for short long bones following the use of conventional genetic testing. Methods: A cohort of ninety-four fetuses with sonographically identified short long bones was analyzed by trio-exome sequencing between January 2016 and June 2021. Fetuses with abnormal results of karyotype or chromosomal microarray analysis were excluded. Variants were interpreted based on ACMG/AMP guidelines. All diagnostic de novo variants were validated by Sanger sequencing. Results: Of the 94 fetuses, 38 (40.4%) were found to carry causal genetic variants (pathogenic or likely pathogenic) in sixteen genes with 38 variants. Five fetuses (5.3%) had variant(s) of uncertain significance. Thirty-five cases (37.2%) were diagnosed as genetic skeletal dysplasias including 14 different diseases that were classified into 10 groups according to the Nosology and Classification of Genetic Skeletal Disorders. The most common disease in the cohort was achondroplasia (28.9%), followed by osteogenesis imperfecta (18.4%), thanatophoric dysplasia (10.5%), chondrogenesis (7.9%), and 3-M syndrome (5.3%). The diagnostic yield in fetuses with isolated short long bones was lower than the fetuses with non-isolated short long bones, but not reached statistical significance (27.3% vs. 44.4%; p = 0.151). Whereas, the rate in the fetuses with other skeletal abnormalities was significantly higher than those with non-skeletal abnormalities (59.4% vs. 32.5%, p = 0.023), and the diagnostic rate was significantly higher in femur length (FL) below -4SDs group compared with FL 2-4SDs below GA group (72.5% vs. 16.7%; p < 0.001). A long-term follow-up showed that outcomes for fetuses with FL 2-4SDs below GA were significantly better than those with FL below -4SDs. Additionally, fourteen (36.8%) novel short long bones-related variants were identified in the present study. Conclusion: The findings suggest that in fetuses with short long bones routine genetic tests failed to determine the underlying causes, exome sequencing could add clinically relevant information that could assist the clinical management of pregnancies. Novel pathogenic variants identified may broaden the mutation spectrum for the disorders and contributes to clinical consultation and subsequent pregnancy examination.
| S-EPMC10010437 | biostudies-literature
Project description:BackgroundBirth defects are responsible for approximately 7% of neonatal deaths worldwide by World Health Organization in 2004. Many methods have been utilized for examining the congenital anomalies in fetuses. This study aims to investigate the efficiency of simultaneous CNV-seq and whole-exome sequencing (WES) in the diagnosis of fetal anomaly based on a large Chinese cohort.MethodsIn this cohort study, 1800 pregnant women with singleton fetus in Hubei Province were recruited from 2018 to 2020 for prenatal ultrasonic screening. Those with fetal structural anomalies were transferred to the Maternal and Child Health Hospital of Hubei Province through a referral network in Hubei, China. After multidisciplinary consultation and decision on fetal outcome, products of conception (POC) samples were obtained. Simultaneous CNV-seq and WES was conducted to identify the fetal anomalies that can compress initial DNA and turnaround time of reports.ResultsIn total, 959 couples were finally eligible for the enrollment. A total of 227 trios were identified with a causative alteration (CNV or variant), among which 191 (84.14%) were de novo. Double diagnosis of pathogenic CNVs and variants have been identified in 10 fetuses. The diagnostic yield of multisystem anomalies was significantly higher than single system anomalies (32.28% vs. 22.36%, P = 0.0183). The diagnostic rate of fetuses with consistent intra- and extra-uterine phenotypes (172/684) was significantly higher than the rate of these with inconsistent phenotypes (17/116, P = 0.0130).ConclusionsSimultaneous CNV-seq and WES analysis contributed to fetal anomaly diagnosis and played a vital role in elucidating complex anomalies with compound causes.
| S-EPMC8722033 | biostudies-literature
Project description: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.
| S-EPMC7999180 | biostudies-literature
Project description:Prenatal exome sequencing (pES) is a promising tool for diagnosing genetic disorders when structural anomalies are detected on prenatal ultrasound. The aim of this study was to investigate the diagnostic yield and clinical impact of pES as an additional modality for fetal neurologists who counsel parents in case of congenital anomalies of the central nervous system (CNS). We assessed 20 pregnancies of 19 couples who were consecutively referred to the fetal neurologist for CNS anomalies. pES had a diagnostic yield of 53% (10/19) with most diagnosed pregnancies having agenesis or hypoplasia of the corpus callosum (7/10). Overall clinical impact was 63% (12/19), of which the pES result aided parental decision making in 55% of cases (6/11), guided perinatal management in 75% of cases (3/4), and was helpful in approving a late termination of pregnancy request in 75% of cases (3/4). Our data suggest that pES had a high diagnostic yield when CNS anomalies are present, although this study is limited by its small sample size. Moreover, pES had substantial clinical impact, which warrants implementation of pES in the routine care of the fetal neurologist in close collaboration with gynecologists and clinical geneticists.
| S-EPMC9297851 | biostudies-literature