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

Abstract

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. Key pointsWhat's already known about this topic? � Prenatal exome sequencing (ES) increases genetic diagnoses in fetuses with structural abnormalities and a normal karyotype and chromosomal microarray.� Published diagnostic yields from ES are varied and may be influenced by study size, case selection and fetal phenotype.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

International Society for Prenatal Diagnosis Updated Position Statement on the use of genome‐wide sequencing for prenatal diagnosis

“…[6][7][8] Presently, prenatal exome sequencing (pES) is the predominant approach used for genome-wide sequencing in prenatal clinical practice and research. 3 Multiple studies, small series and case reports, have illustrated the value of pES, 2,3 but it is important to recognize the differences between these studies and the studyspecific sequencing and interpretive approaches (Table 1). Some include sequencing and interpretation of variants in the exons of nearly all genes, while others focus on the "clinical exome", a collection of 4000-5000 genes causatively associated with known single gene disorders catalogued in OMIM, or alternatively, on the ∼1600 genes clearly associated with genetic conditions known to present with malformations detectable in the fetus or neonate.…”

“…Some include sequencing and interpretation of variants in the exons of nearly all genes, while others focus on the "clinical exome", a collection of 4000-5000 genes causatively associated with known single gene disorders catalogued in OMIM, or alternatively, on the ∼1600 genes clearly associated with genetic conditions known to present with malformations detectable in the fetus or neonate. 3 Furthermore, small series of prenatal genome sequencing (pGS) are now emerging 9 and there are ongoing trials evaluating pGS. The use of pES and pGS is likely to increase as interpretive tools and appropriate data sources continue to be improved, and costs continue to fall.…”

“…1At that time, this was an emerging genomic diagnostic method being evaluated in a limited number of centers 2. Since then, both its research and clinical use have rapidly increased 3. This has led to the development of local guidance or "points to consider" statements by national professional societies in some countries, but for many parts This is an ISPD Position Statement that has not undergone peer review by this journal.…”

Prenatal exomes and genomes – so much new and so much more to learn

“…These were systematically reviewed by Mellis and colleagues, who show that the accumulated data is now large enough that we can begin to provide estimates of which prenatal phenotypes are more likely to be molecularly solved with pES, such as skeletal abnormalities, central nervous system (CNS) defects, and multiple anomalies. 7 This data is paving the way for a more personalized approach to decisions regarding which tests to order first in the time-sensitive setting of prenatal diagnosis. These data, along with those of several of the primary papers in these two issues, also show that the overall incremental yield of pES for fetuses with structural birth defects (after non-diagnostic standard testing), exceeds that of chromosomal microarray (CMA).…”

“…Since then, many more papers have been published on pES. These were systematically reviewed by Mellis and colleagues, who show that the accumulated data is now large enough that we can begin to provide estimates of which prenatal phenotypes are more likely to be molecularly solved with pES, such as skeletal abnormalities, central nervous system (CNS) defects, and multiple anomalies 7 . This data is paving the way for a more personalized approach to decisions regarding which tests to order first in the time‐sensitive setting of prenatal diagnosis.…”