Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study.
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ABSTRACT:
SUBMITTER: Lord J
PROVIDER: S-EPMC6386638 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:INTRODUCTION:In 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. METHODS:A 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. RESULTS:When 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/CONCLUSION:Performing 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:PURPOSE:We 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. METHODS:ES 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. RESULTS:In 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. CONCLUSION:ES 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: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
Project description:Fetal therapy can be defined as any prenatal treatment administered to the mother with the primary indication to improve perinatal or long-term outcomes for the fetus or newborn. This review provides an update of the pharmacological therapies that are solely directed at the fetus with anomalies and outlines a future transcriptomic approach. Fetal anomalies targeted with prenatal pharmacotherapy are a heterogeneous group of structural, endocrine, and metabolic conditions, including congenital cystic adenomatoid malformation (CCAM), congenital adrenal hyperplasia, congenital heart block, fetal tachyarrhythmias, inborn errors of metabolism, fetal thyroid disorders, and polyhydramnios. To date, the majority of pharmacotherapies for fetal anomalies have been evaluated only in retrospective, uncontrolled studies. The way forward will be with an evidence-based approach to prenatal pharmacological interventions.
| S-EPMC4378899 | biostudies-literature
Project description:IntroductionThe aim of this retrospective cohort study was to determine the potential diagnostic yield of prenatal whole exome sequencing in fetuses with structural anomalies on expert ultrasound scans and normal chromosomal microarray results.Material and methodsIn the period 2013-2016, 391 pregnant women with fetal ultrasound anomalies who received normal chromosomal microarray results, were referred for additional genetic counseling and opted for additional molecular testing pre- and/or postnatally. Most of the couples received only a targeted molecular test and in 159 cases (40.7%) whole exome sequencing (broad gene panels or open exome) was performed. The results of these molecular tests were evaluated retrospectively, regardless of the time of the genetic diagnosis (prenatal or postnatal).ResultsIn 76 of 391 fetuses (19.4%, 95% CI 15.8%-23.6%) molecular testing provided a genetic diagnosis with identification of (likely) pathogenic variants. In the majority of cases (91.1%, 73/76) the (likely) pathogenic variant would be detected by prenatal whole exome sequencing analysis.ConclusionsOur retrospective cohort study shows that prenatal whole exome sequencing, if offered by a clinical geneticist, in addition to chromosomal microarray, would notably increase the diagnostic yield in fetuses with ultrasound anomalies and would allow early diagnosis of a genetic disorder irrespective of the (incomplete) fetal phenotype.
| S-EPMC8247008 | biostudies-literature
Project description:PurposeTo evaluate associations between prenatal trio exome sequencing (trio-ES) and psychological outcomes among women with an anomalous pregnancy.MethodsTrio-ES study enrolling patients with major fetal anomaly and normal microarray. Women completed self-reported measures and free response interviews at two timepoints: pre- (1) and post- (2) sequencing. Pre-sequencing responses were compared with post-sequencing responses; post-sequencing responses were stratified by women who received trio-ES results that may explain fetal findings, secondary findings (medically actionable or couples with heterozygous variants for the same recessive disorder), or negative results.ResultsOne hundred fifteen trios were enrolled. Of those, 41/115 (35.7%) received results from trio-ES, including 36 (31.3%) who received results that may explain the fetal phenotype. These women had greater post-sequencing distress compared with women who received negative results, including generalized distress (p = 0.03) and test-related distress (p = 0.2); they also had worse psychological adaptation to results (p = 0.001). Genomic knowledge did not change from pre- to post-sequencing (p = 0.51).ConclusionWomen show more distress after receiving trio-ES results compared with those who do not, suggesting that women receiving results may need additional support or counseling to inform current and future reproductive decisions.
| S-EPMC8503913 | biostudies-literature
Project description:ImportanceFirst branchial cleft anomalies (FBCAs) are rare congenital malformations, accounting for < 8% of all branchial cleft anomalies. However, little is currently known about the cause of FBCAs at the molecular level.ObjectiveTo identify genomic alterations related to the genetic etiology of FBCAs in Chinese children.MethodsWe performed whole-exome sequencing of samples from 10 pediatric patients with FBCAs. Data analysis was carried out using the Burrow-Wheeler Alignment software package, and the dbSNP database for comparisons. Rare variants were further validated by Sanger sequencing. Insertion/deletions (indels) were examined using the Genome Analysis Toolkit.ResultsWe identified 14 non-synonymous mutations in seven potential FBCA-susceptibility genes (TRAPPC12, NRP2, NPNT, SH3RF2, RHPN1, TENM4, and ARMCX4). We also detected 133 shared small indels in 125 genes. Gene Ontology analysis indicated that most of the identified genes played critical roles in development and differentiation pathways involved in regulating organ development.InterpretationWe characterized the mutational landscape in pathways involved in development and differentiation in Chinese children with FBCA. The results identified potential pathogenic genes and mutations related to FBCA, and provide molecular-level support for the branchial theory of FBCA pathogenesis.
| S-EPMC8458719 | biostudies-literature