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Prenatal exome and genome sequencing for fetal structural abnormalities.

ABSTRACT: 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.

SUBMITTER: Vora NL

PROVIDER: S-EPMC9877148 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Prenatal exome and genome sequencing for fetal structural abnormalities.

Vora Neeta L NL Norton Mary E ME

American journal of obstetrics and gynecology 20220824 2

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- ...[more]

PMID: 36027950

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Exome sequencing improves genetic diagnosis of structural fetal abnormalities revealed by ultrasound.

Project description:The genetic etiology of non-aneuploid fetal structural abnormalities is typically investigated by karyotyping and array-based detection of microscopically detectable rearrangements, and submicroscopic copy-number variants (CNVs), which collectively yield a pathogenic finding in up to 10% of cases. We propose that exome sequencing may substantially increase the identification of underlying etiologies. We performed exome sequencing on a cohort of 30 non-aneuploid fetuses and neonates (along with their parents) with diverse structural abnormalities first identified by prenatal ultrasound. We identified candidate pathogenic variants with a range of inheritance models, and evaluated these in the context of detailed phenotypic information. We identified 35 de novo single-nucleotide variants (SNVs), small indels, deletions or duplications, of which three (accounting for 10% of the cohort) are highly likely to be causative. These are de novo missense variants in FGFR3 and COL2A1, and a de novo 16.8 kb deletion that includes most of OFD1. In five further cases (17%) we identified de novo or inherited recessive or X-linked variants in plausible candidate genes, which require additional validation to determine pathogenicity. Our diagnostic yield of 10% is comparable to, and supplementary to, the diagnostic yield of existing microarray testing for large chromosomal rearrangements and targeted CNV detection. The de novo nature of these events could enable couples to be counseled as to their low recurrence risk. This study outlines the way for a substantial improvement in the diagnostic yield of prenatal genetic abnormalities through the application of next-generation sequencing.

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Exome Sequencing for Prenatal Detection of Genetic Abnormalities in Fetal Ultrasound Anomalies: An Economic Evaluation.

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.

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Prenatal Exome Sequencing in Recurrent Fetal Structural Anomalies: Systematic Review and Meta-Analysis.

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Prenatal whole-exome sequencing for fetal structural anomalies: a retrospective analysis of 145 Chinese cases.

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| S-EPMC10601195 | biostudies-literature

Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study.

Project description: Not available

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Prenatal exome sequencing: A useful tool for the fetal neurologist.

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

Same performance of exome sequencing before and after fetal autopsy for congenital abnormalities: toward a paradigm shift in prenatal diagnosis?

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Application of whole exome sequencing in fetal cases with skeletal abnormalities.

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Noninvasive prenatal exome sequencing diagnostic utility limited by sequencing depth and fetal fraction.

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Whole-exome sequencing applications in prenatal diagnosis of fetal bowel dilatation.

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| S-EPMC10199320 | biostudies-literature

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