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Prenatal diagnosis by trio exome sequencing in fetuses with ultrasound anomalies: A powerful diagnostic tool.

ABSTRACT: Introduction: Prenatal ultrasound (US) anomalies are detected in around 5%-10% of pregnancies. In prenatal diagnosis, exome sequencing (ES) diagnostic yield ranges from 6% to 80% depending on the inclusion criteria. We describe the first French national multicenter pilot study aiming to implement ES in prenatal diagnosis following the detection of anomalies on US. Patients and methods: We prospectively performed prenatal trio-ES in 150 fetuses with at least two US anomalies or one US anomaly known to be frequently linked to a genetic disorder. Trio-ES was only performed if the results could influence pregnancy management. Chromosomal microarray (CMA) was performed before or in parallel. Results: A causal diagnosis was identified in 52/150 fetuses (34%) with a median time to diagnosis of 28 days, which rose to 56/150 fetuses (37%) after additional investigation. Sporadic occurrences were identified in 34/56 (60%) fetuses and unfavorable vital and/or neurodevelopmental prognosis was made in 13/56 (24%) fetuses. The overall diagnostic yield was 41% (37/89) with first-line trio-ES versus 31% (19/61) after normal CMA. Trio-ES and CMA were systematically concordant for identification of pathogenic CNV. Conclusion: Trio-ES provided a substantial prenatal diagnostic yield, similar to postnatal diagnosis with a median turnaround of approximately 1 month, supporting its routine implementation during the detection of prenatal US anomalies.

SUBMITTER: Tran Mau-Them F

PROVIDER: S-EPMC10076577 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Prenatal diagnosis by trio exome sequencing in fetuses with ultrasound anomalies: A powerful diagnostic tool.

Tran Mau-Them Frédéric F Delanne Julian J Denommé-Pichon Anne-Sophie AS Safraou Hana H Bruel Ange-Line AL Vitobello Antonio A Garde Aurore A Nambot Sophie S Bourgon Nicolas N Racine Caroline C Sorlin Arthur A Moutton Sébastien S Marle Nathalie N Rousseau Thierry T Sagot Paul P Simon Emmanuel E Vincent-Delorme Catherine C Boute Odile O Colson Cindy C Petit Florence F Legendre Marine M Naudion Sophie S Rooryck Caroline C Prouteau Clément C Colin Estelle E Guichet Agnès A Ziegler Alban A Bonneau Dominique D Morel Godelieve G Fradin Mélanie M Lavillaureix Alinoé A Quelin Chloé C Pasquier Laurent L Odent Sylvie S Vera Gabriella G Goldenberg Alice A Guerrot Anne-Marie AM Brehin Anne-Claire AC Putoux Audrey A Attia Jocelyne J Abel Carine C Blanchet Patricia P Wells Constance F CF Deiller Caroline C Nizon Mathilde M Mercier Sandra S Vincent Marie M Isidor Bertrand B Amiel Jeanne J Dard Rodolphe R Godin Manon M Gruchy Nicolas N Jeanne Médéric M Schaeffer Elise E Maillard Pierre-Yves PY Payet Frédérique F Jacquemont Marie-Line ML Francannet Christine C Sigaudy Sabine S Bergot Marine M Tisserant Emilie E Ascencio Marie-Laure ML Binquet Christine C Duffourd Yannis Y Philippe Christophe C Faivre Laurence L Thauvin-Robinet Christel C

Frontiers in genetics 20230323

<b>Introduction:</b> Prenatal ultrasound (US) anomalies are detected in around 5%-10% of pregnancies. In prenatal diagnosis, exome sequencing (ES) diagnostic yield ranges from 6% to 80% depending on the inclusion criteria. We describe the first French national multicenter pilot study aiming to implement ES in prenatal diagnosis following the detection of anomalies on US. <b>Patients and methods:</b> We prospectively performed prenatal trio-ES in 150 fetuses with at least two US anomalies or one ...[more]

PMID: 37035737

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Project description:BackgroundExome sequencing (ES) is becoming more widely available in prenatal diagnosis. However, data on its clinical utility and integration into clinical management remain limited in practice. Herein, we report our experience implementing prenatal ES (pES) in a large cohort of fetuses with anomalies detected by ultrasonography using a hospital-based in-house multidisciplinary team (MDT) facilitated by a three-step genotype-driven followed by phenotype-driven analysis framework.MethodsWe performed pES in 1618 fetal cases with positive ultrasound findings but negative for karyotyping and chromosome microarray analysis between January 2014 and October 2021, including both retrospective (n=565) and prospective (n=1053) cohorts. The diagnostic efficiency and its correlation to organ systems involved, phenotypic spectrum, and the clinical impacts of pES results on pregnancy outcomes were analyzed.ResultsA genotype-driven followed by phenotype-driven three-step approach was carried out in all trio pES. Step 1, a genotype-driven analysis resulted in a diagnostic rate of 11.6% (187/1618). Step 2, a phenotype-driven comprehensive analysis yielded additional diagnostic findings for another 28 cases (1.7%; 28/1618). In the final step 3, data reanalyses based on new phenotypes and/or clinical requests found molecular diagnosis in 14 additional cases (0.9%; 14/1618). Altogether, 229 fetal cases (14.2%) received a molecular diagnosis, with a higher positive rate in the retrospective than the prospective cohort (17.3% vs. 12.4%, p<0.01). The diagnostic rates were highest in fetuses with skeletal anomalies (30.4%) and multiple organ involvements (25.9%), and lowest in fetuses with chest anomalies (0%). In addition, incidental and secondary findings with childhood-onset disorders were detected in 11 (0.7%) cases. Furthermore, we described the prenatal phenotypes for the first time for 27 gene-associated conditions (20.0%, 27/135) upon a systematic analysis of the diagnosed cases and expanded the phenotype spectrum for 26 (19.3%) genes where limited fetal phenotypic information was available. In the prospective cohort, the combined prenatal ultrasound and pES results had significantly impacted the clinical decisions (61.5%, 648/1053).ConclusionsThe genotype-driven approach could identify about 81.7% positive cases (11.6% of the total cohort) with the initial limited fetal phenotype information considered. The following two steps of phenotype-driven analysis and data reanalyses helped us find the causative variants in an additional 2.6% of the entire cohort (18.3% of all positive findings). Our extensive phenotype analysis on a large number of molecularly confirmed prenatal cases had greatly enriched our current knowledge on fetal phenotype-genotype correlation, which may guide more focused prenatal ultrasound in the future. This is by far the largest pES cohort study that combines a robust trio sequence data analysis, systematic phenotype-genotype correlation, and well-established MDT in a single prenatal clinical setting. This work underlines the value of pES as an essential component in prenatal diagnosis in guiding medical management and parental decision making.

Dataset Information

Prenatal diagnosis by trio exome sequencing in fetuses with ultrasound anomalies: A powerful diagnostic tool.

Publications

Prenatal diagnosis by trio exome sequencing in fetuses with ultrasound anomalies: A powerful diagnostic tool.

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