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Volume 17
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10.3390/genes17010037
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Prenatal Exome Sequencing: When Does Diagnostic Yield Meet Clinical Utility?

by
Alessia Carrer
1,2,
Francesco Maria Crupano
3,
Berardo Rinaldi
2,*,
Giulietta Scuvera
2,
Claudia Cesaretti
2,
Valeria Nicotra
2,
Silvana Gangi
4,
Lorenzo Colombo
4,
Gabriella Araimo
4,
Matilde Tagliabue
5,
Daniela Marchetti
6,
Laura Pezzoli
6,
Maria Garzo
7,
Veronica Accurti
3,
Grazia Volpe
3,
Simona Boito
3,
Palma Finelli
7,8,
Monica Fumagalli
4,5,
Maria Francesca Bedeschi
2,
Maria Iascone
6,
Nicola Persico
3,5 and
Federica Natacci
2add Show full author list remove Hide full author list
1
Department of Health Sciences, University of Milan, 20122 Milan, Italy
2
Medical Genetics Unit, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
3
Fetal Medicine and Surgery Service, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
4
Neonatal Intensive Care Unit, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
5
Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy
6
Medical Genetics Laboratory, ASST Papa Giovanni XXIII, 24127 Bergamo, Italy
7
Medical Genetics Laboratory, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
8
Department of Medical Biotechnology and Translational Medicine, University of Milan, 20122 Milan, Italy
*
Author to whom correspondence should be addressed.
Genes 2026, 17(1), 37; https://doi.org/10.3390/genes17010037 (registering DOI)
Submission received: 14 November 2025 / Revised: 19 December 2025 / Accepted: 22 December 2025 / Published: 30 December 2025
(This article belongs to the Special Issue Next-Generation Sequencing in Rare Genetic Diseases)
Versions Notes

Abstract

Background/Objectives: Prenatal Exome Sequencing (pES) has revolutionized prenatal diagnosis in fetuses with congenital anomalies. Although its performance is very promising, previous pES studies have mainly focused on diagnostic yield, often without considering the actual impact on ongoing pregnancies. In this study, we aim to (1) assess whether a prenatal molecular diagnosis can reliably predict the clinical features of the unborn child and (2) determine the gestational age (gw) at which ultrasound (US) findings are sufficient to support the pathogenicity of genetic variants detected by pES. Methods: We retrospectively selected 47 cases complicated by US anomalies that underwent Exome Sequencing (ES) and for which complete clinical assessment was available. A blinded reanalysis of ES data was performed, considering only prenatal features. Results: In our cohort, standard ES led to a molecular diagnosis in 43% of cases. The blinded reanalysis revealed that a complete or partial retrospective prenatal diagnosis was achievable in 95% of diagnosed cases. The mean gestational week at which US data would have supported molecular diagnosis was 22 + 5 weeks. The clinical follow-up confirmed a syndromic presentation in 21 out of 23 newborns and in all terminated pregnancies. Conclusions: Our study further confirms that pES is a valuable diagnostic tool for detecting genetic etiology in fetuses with congenital malformations. In most cases, pES results accurately predict the postnatal phenotype. However, the prenatal setting requires specific adjustments and precautions, and a negative pES result cannot be considered reassuring.
Keywords: prenatal exome sequencing; fetal anomalies; diagnostic yield; clinical utility; genotype-phenotype correlation prenatal exome sequencing; fetal anomalies; diagnostic yield; clinical utility; genotype-phenotype correlation

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MDPI and ACS Style

Carrer, A.; Crupano, F.M.; Rinaldi, B.; Scuvera, G.; Cesaretti, C.; Nicotra, V.; Gangi, S.; Colombo, L.; Araimo, G.; Tagliabue, M.; et al. Prenatal Exome Sequencing: When Does Diagnostic Yield Meet Clinical Utility? Genes 2026, 17, 37. https://doi.org/10.3390/genes17010037

AMA Style

Carrer A, Crupano FM, Rinaldi B, Scuvera G, Cesaretti C, Nicotra V, Gangi S, Colombo L, Araimo G, Tagliabue M, et al. Prenatal Exome Sequencing: When Does Diagnostic Yield Meet Clinical Utility? Genes. 2026; 17(1):37. https://doi.org/10.3390/genes17010037

Chicago/Turabian Style

Carrer, Alessia, Francesco Maria Crupano, Berardo Rinaldi, Giulietta Scuvera, Claudia Cesaretti, Valeria Nicotra, Silvana Gangi, Lorenzo Colombo, Gabriella Araimo, Matilde Tagliabue, and et al. 2026. "Prenatal Exome Sequencing: When Does Diagnostic Yield Meet Clinical Utility?" Genes 17, no. 1: 37. https://doi.org/10.3390/genes17010037

APA Style

Carrer, A., Crupano, F. M., Rinaldi, B., Scuvera, G., Cesaretti, C., Nicotra, V., Gangi, S., Colombo, L., Araimo, G., Tagliabue, M., Marchetti, D., Pezzoli, L., Garzo, M., Accurti, V., Volpe, G., Boito, S., Finelli, P., Fumagalli, M., Bedeschi, M. F., ... Natacci, F. (2026). Prenatal Exome Sequencing: When Does Diagnostic Yield Meet Clinical Utility? Genes, 17(1), 37. https://doi.org/10.3390/genes17010037

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