Prenatal Exome Sequencing: Background, Current Practice and Future Perspectives—A Systematic Review

Abstract

The introduction of Next Generation Sequencing (NGS) technologies has exerted a significant impact on prenatal diagnosis. Prenatal Exome Sequencing (pES) is performed with increasing frequency in fetuses with structural anomalies and negative chromosomal analysis. The actual diagnostic value varies extensively, and the role of incidental/secondary or inconclusive findings and negative results has not been fully ascertained. We performed a systematic literature review to evaluate the diagnostic yield, as well as inconclusive and negative-result rates of pES. Papers were divided in two groups. The former includes fetuses presenting structural anomalies, regardless the involved organ; the latter focuses on specific class anomalies. Available findings on non-informative or negative results were gathered as well. In the first group, the weighted average diagnostic yield resulted 19%, and inconclusive finding rate 12%. In the second group, the percentages were extremely variable due to differences in sample sizes and inclusion criteria, which constitute major determinants of pES efficiency. Diagnostic pES availability and its application have a pivotal role in prenatal diagnosis, though more homogeneity in access criteria and a consensus on clinical management of controversial information management is envisageable to reach widespread use in the near future.

Molecular Approaches in Fetal Malformations, Dynamic Anomalies and Soft Markers: Diagnostic Rates and Challenges—Systematic Review of the Literature and Meta-Analysis

“…These are among the most impacting findings in decision making, and prospective parents often do not have the time to evaluate what information they want to receive [329]. Indeed, there are no univocal protocols between the various countries, so there is great heterogeneity about what should be reported, who decides what to report [330], who must pay [331] and more.…”

“…To complicate things, genetic findings are always reported under the mother's name. Consequently, it can be impracticable to retrieve data during postnatal examinations [319,329]. As a final remark, negative results from genetic tests could be mistakenly interpreted by the consultants as necessarily reassuring findings [329], but it should be discussed that a negative analysis reduces the risk of a genetically determined condition without ever being able to exclude it.…”

Diagnostic yield of exome sequencing for prenatal diagnosis of fetal structural anomalies: A systematic review and meta‐analysis

“…[9][10][11] Two large prospective studies demonstrated the diagnostic utility of ES for prenatal diagnosis of unselected fetal structural abnormalities, reporting diagnostic rates of 8.5%-10%, 12,13 while numerous smaller studies report diagnostic rates above 80% in highly-selected case series. 7,14,15 This body of literature has been previously reviewed 4,16,17 but has rapidly expanded over the last 2 years.…”

High rate of abnormal findings in Prenatal Exome Trio in low risk pregnancies and apparently normal fetuses

“…A small number of highly selective case studies reported a 8%-47% diagnostic rate of genetic diseases. [15][16][17] The prenatal ES analysis in fetal structural anomalies detected by ultrasonography study (PAGE study) found that in large-scale fetus studies, with a broad spectrum of fetal structural abnormalities demonstrated by US, diagnostic or potentially relevant variants were identified in 8.5%-12.5% of the cases. 18 Another prospective study of 234 cases reached a yield of 10%.…”