Incremental yield of exome sequencing over standard prenatal testing in structurally normal fetuses: systematic review and meta‐analysis
Bibliographic record
Abstract
OBJECTIVE: To critically review the literature and synthesize evidence on the incremental yield of prenatal exome sequencing (PES) in fetuses with an apparently normal phenotype with a normal G-banded karyotype or chromosomal microarray (CMA). METHODS: This systematic review and meta-analysis was conducted using a predetermined protocol and registered with PROSPERO (ID: CRD42024593349). We included observational cohort studies reporting on the incremental yield of PES in fetuses with an apparently normal phenotype and a previously normal G-banded karyotype/CMA. The risk of bias of the included studies was assessed using the Newcastle-Ottawa Scale. The pooled proportion of events was calculated using generalized linear mixed models, using the metaprop function in R version 2.15.1. RESULTS: Four studies (1916 fetuses) were included in this systematic review and meta-analysis, of which 32 cases had a pathogenic or likely pathogenic variant. The pooled incremental yield of PES in fetuses with an apparently normal phenotype was 1.6% (95% CI, 1.0-2.6%); the majority of variants were de novo within genes associated with autosomal dominant inherited conditions (pooled incremental yield, 0.9% (95% CI, 0.5-1.7%)). Based on the expected severity of the associated disease, the pooled incremental yield was 0.5% (95% CI, 0.1-1.5%) for severe disease and 0.5% (95% CI, 0.2-1.5%) for moderate disease. There were insufficient data to conduct the predefined secondary analyses according to normality of phenotype at birth, variants of uncertain significance and expected age of disease onset. CONCLUSION: Pooling data from four studies, we found that 1.6% of phenotypically normal fetuses with a normal G-banded karyotype or CMA may have a pathogenic or likely pathogenic variant identified on PES, most of which occur de novo. The likelihood of a variant being associated with severe disease in such fetuses is 0.5%. However, more research is needed regarding the development of a universal classification of disease severity and the utilization of this evidence in clinical practice. © 2025 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.148 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.007 | 0.000 |
| Bibliometrics | 0.001 | 0.003 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".