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Parallel Sequencing of Fetal Genome and RNA in the Presence of Ultrasound Warning Signs: a Complementary Approach for the Prenatal Diagnosis of Rare Diseases. (PrenOmics)

25 sierpnia 2026 zaktualizowane przez: Assistance Publique - Hôpitaux de Paris

Parallel Sequencing of the Fetal Genome and RNA in the Presence of Ultrasound Warning Signs: a Complementary Approach for the Prenatal Diagnosis of Rare Diseases.

Prenatal exome sequencing (ES) is increasingly used for fetuses with ultrasound-detected anomalies but yields 10-15% variants of uncertain significance (VUS), limiting diagnostic performance, particularly in prenatal settings with incomplete phenotypes.

This study aims to evaluate the added value of combined prenatal genome sequencing (GS) and RNA sequencing (RNA-Seq), which are not currently part of routine care. Conducted at AP-HP, it will compare the diagnostic yield of GS + RNA-Seq with the current standard approach (chromosomal microarray analysis + ES), according to variant type (coding, non-coding, and structural). The contribution of systematic RNA-Seq to rapid VUS resolution will be specifically assessed.

Overall, this project will assess the feasibility, diagnostic performance, and clinical utility of implementing GS + RNA-Seq in prenatal diagnosis, supporting future integration into routine care in France.

Przegląd badań

Status

Jeszcze nie rekrutacja

Warunki

Interwencja / Leczenie

Szczegółowy opis

Couples will be enrolled during a "pre-test" genetic consultation by a physician or a research-trained collaborator (genetic counselor or another investigator).

As part of routine clinical care: chromosomal microarray analysis (CMA) and exome sequencing (ES) will be performed locally, with interpretation by a biologist from the site providing follow-up to the couple.

For research purposes, after obtaining written consent from both the pregnant woman and her partner: samples will be prepared for pre-analytical processing at Pitié-Salpêtrière and sequenced at SeqOIA. Interpretation will be conducted by a biologist at a site different from the one performing the exome analysis, using the Gleaves-P interface dedicated to the project (MOABI).

Transcriptomic analysis (RNA-Seq) will be performed on RNA extracted from amniotic fluid cultures, with and without emetine (a NMD inhibitor). Sequencing will be carried out after Agilent capture at the Genetics Laboratory of Necker-Enfants Malades Hospital (AP-HP). Bioinformatics analysis will be performed by the Imagine platform. Study biologists will interpret results using the PolyRNASEQ interface (qualitative splice junction analysis) and IGV (semi-quantitative analysis and expression).

All results from CMA + ES and GS + RNA-Seq will be reviewed during weekly meetings. In cases of discordant or unexpected results (anticipated for ~10 couples), a reference method will be applied to provide clinically validated results through an accredited prenatal diagnostic center, ensuring no loss of care opportunity.

Results will be discussed in a multidisciplinary prenatal diagnosis meeting (RCP) and integrated into the prognostic discussion. Couples will be seen during a "post-test" genetic consultation for communication of results.

For couples included at Necker-Enfants Malades Hospital only: two additional maternal blood tubes will be collected during routine pregnancy follow-up before amniocentesis. Circulating DNA will be extracted from maternal plasma and subjected to genome sequencing under the same conditions as the amniotic DNA. The generated data will be analysed using bioinformatic approaches integrating artificial intelligence methods to improve the distinction between fetal- and maternal-derived DNA fragments. Interpretation will be performed via the Gleaves-P interface. Non-invasive prenatal genome sequencing results are strictly for research purposes: they will not be communicated to couples and will not be used for clinical decision-making. Their objective is to evaluate the feasibility, accuracy, and performance of non-invasive genome sequencing.

Typ studiów

Obserwacyjny

Zapisy (Szacowany)

100

Kontakty i lokalizacje

Ta sekcja zawiera dane kontaktowe osób prowadzących badanie oraz informacje o tym, gdzie badanie jest przeprowadzane.

Kontakt w sprawie studiów

Kopia zapasowa kontaktu do badania

Lokalizacje studiów

  • Francja
    • Île-de-France Region
      • Paris, Île-de-France Region, Francja, 75015
        • Hôpital Necker Enfants malades
        • Kontakt:
        • Kontakt:

Kryteria uczestnictwa

Badacze szukają osób, które pasują do określonego opisu, zwanego kryteriami kwalifikacyjnymi. Niektóre przykłady tych kryteriów to ogólny stan zdrowia danej osoby lub wcześniejsze leczenie.

Kryteria kwalifikacji

Wiek uprawniający do nauki

  • Dorosły
  • Starszy dorosły

Akceptuje zdrowych ochotników

Nie

Metoda próbkowania

Próbka bez prawdopodobieństwa

Badana populacja

Couples whose indication for prenatal exome sequencing has been reviewed and approved by a multidisciplinary prenatal diagnostic center.

Opis

Inclusion Criteria:

  • Participating couple aged ≥ 18 years
  • Ongoing pregnancy for which the indication for exome sequencing has been discussed and validated by a Multidisciplinary Prenatal Diagnosis Center (CPDPN).

While a strict list of indications is not appropriate in the prenatal setting, examples include multiple anomalies not related to a malformation sequence, persistent increased nuchal translucency, hydrops fetalis (anasarca), cleft palate, multiple contractures/arthrogryposis, skeletal dysplasia, bowed femurs, or brain anomalies.

  • Sequencing performed on an amniotic fluid sample (chorionic villus sampling is excluded)
  • Attendance at a genetic counseling consultation
  • Written informed consent obtained for study participation

Exclusion Criteria:

  • Couple not covered by the social security system
  • Couple deprived of liberty or under legal guardianship or curatorship
  • Monoparental pregnancies

Plan studiów

Ta sekcja zawiera szczegółowe informacje na temat planu badania, w tym sposób zaprojektowania badania i jego pomiary.

Jak projektuje się badanie?

Szczegóły projektu

Kohorty i interwencje

Grupa / Kohorta
Interwencja / Leczenie
Genome Sequencing (GS) + RNA-Sequencing (RNA-Seq)
Couples (pregnant woman and partner) with a fetal indication requiring prenatal exome sequencing, reviewed and approved by a multidisciplinary prenatal diagnosis center, will be included. Fetal samples (amniotic fluid, including cell cultures) and parental blood samples collected during routine care will be used for standard genetic analyses (chromosomal microarray and exome sequencing) and for research analyses, including genome sequencing (GS), RNA sequencing (RNA-Seq), and bioinformatic evaluations. Non-invasive genome sequencing performed from maternal blood samples (for couples included at Necker-Enfants Malades Hospital only) will be conducted for research purposes only; results will not be returned to couples and will not influence clinical management.
Test diagnostyczny: Genome Sequencing (GS) + RNA-Sequencing (RNA-Seq)

Couples whose indication for trio exome sequencing is approved by a multidisciplinary prenatal diagnostic center are enrolled during a pre-test genetic consultation, during which written informed consent is obtained from both partners.

As part of routine care, fetal samples are collected by amniocentesis and parental blood samples are obtained for chromosomal microarray analysis (CMA) and trio exome sequencing (ES), analyzed locally. Amniotic fluid cell cultures are systematically prepared and stored.

For research purposes, portions of fetal and parental samples are processed at Pitié-Salpêtrière and sequenced at SeqOIA for trio genome sequencing (GS). Bioinformatics analysis is performed using the MOABI platform, with interpretation via the Gleaves-P interface.

RNA sequencing (RNA-Seq) is performed on RNA extracted from amniotic fluid cell cultures at Necker Hospital.

For couples included at Necker only, maternal plasma DNA is also sequenced. Non-invasive GS results are for rese

Co mierzy badanie?

Podstawowe miary wyniku

Miara wyniku
Opis środka
Ramy czasowe
Evaluation of the diagnostic contribution of RNA sequencing (RNA-Seq) performed in parallel with genome sequencing (GS) in prenatal diagnosis, compared with chromosomal microarray analysis (CMA) and exome sequencing (ES).
Ramy czasowe: 18 months
Comparison of variants identified by each strategy and the number of additional diagnoses achieved using genome sequencing (GS) combined with RNA sequencing (RNA-Seq) compared with chromosomal microarray analysis (CMA) and exome sequencing (ES) in the prenatal setting. Diagnostic yield will be analyzed according to variant type (single-nucleotide and structural variants) and genomic location (coding vs non-coding regions).
18 months

Miary wyników drugorzędnych

Miara wyniku
Opis środka
Ramy czasowe
Comparison of turnaround times for result delivery between genome sequencing combined with RNA sequencing (GS + RNA-Seq) and the current standard approach of chromosomal microarray analysis and exome sequencing (CMA + ES) in prenatal diagnosis.
Ramy czasowe: 18 months
Time interval between test prescription and receipt of results for GS + RNA-Seq compared to CMA + ES in prenatal diagnosis
18 months
Comparison of the costs associated with GS + RNA-Seq versus CMA + ES in prenatal diagnostic settings.
Ramy czasowe: 18 months
Evaluation and comparison of the costs associated with GS + RNA-Seq and CMA + ES approaches.
18 months
Evaluation of the feasibility and analytical performance of non-invasive prenatal genome sequencing performed on circulating cell-free fetal DNA extracted from maternal blood.
Ramy czasowe: 18 months
Correlation of diagnostic results between invasive foetal genome sequencing performed on DNA extracted from amniotic fluid and non-invasive genome sequencing performed on circulating cell-free foetal DNA extracted from maternal plasma.
18 months
Identification and characterization of potential challenges and obstacles to the implementation of these diagnostic methods in clinical practice.
Ramy czasowe: 18 months
List of difficulties encountered at each stage, from pre- to post-analytical.
18 months

Współpracownicy i badacze

Tutaj znajdziesz osoby i organizacje zaangażowane w to badanie.

Sponsor

Assistance Publique - Hôpitaux de Paris

Współpracownicy

URC-CIC Paris Descartes Necker Cochin
Laboratoire SeqOIA
Imagine
MOABI

Śledczy

  • Główny śledczy: Lucile BOUTAUD, Pharm.D PhD, Hôpital Necker Enfants Malades AP-HP

Daty zapisu na studia

Daty te śledzą postęp w przesyłaniu rekordów badań i podsumowań wyników do ClinicalTrials.gov. Zapisy badań i zgłoszone wyniki są przeglądane przez National Library of Medicine (NLM), aby upewnić się, że spełniają określone standardy kontroli jakości, zanim zostaną opublikowane na publicznej stronie internetowej.

Główne daty studiów

Rozpoczęcie studiów (Szacowany)

1 września 2026

Zakończenie podstawowe (Szacowany)

1 marca 2028

Ukończenie studiów (Szacowany)

1 marca 2028

Daty rejestracji na studia

Pierwszy przesłany

6 sierpnia 2026

Pierwszy przesłany, który spełnia kryteria kontroli jakości

25 sierpnia 2026

Pierwszy wysłany (Rzeczywisty)

27 sierpnia 2026

Aktualizacje rekordów badań

Ostatnia wysłana aktualizacja (Rzeczywisty)

27 sierpnia 2026

Ostatnia przesłana aktualizacja, która spełniała kryteria kontroli jakości

25 sierpnia 2026

Ostatnia weryfikacja

1 sierpnia 2026

Więcej informacji

Terminy związane z tym badaniem

Słowa kluczowe

Dodatkowe istotne warunki MeSH

Inne numery identyfikacyjne badania

  • APHP251082
  • N° IDRCB (Inny identyfikator: 2025-A01594-45)

Plan dla danych uczestnika indywidualnego (IPD)

Planujesz udostępniać dane poszczególnych uczestników (IPD)?

NIE

Informacje o lekach i urządzeniach, dokumenty badawcze

Bada produkt leczniczy regulowany przez amerykańską FDA

Nie

Bada produkt urządzenia regulowany przez amerykańską FDA

Nie

Te informacje zostały pobrane bezpośrednio ze strony internetowej clinicaltrials.gov bez żadnych zmian. Jeśli chcesz zmienić, usunąć lub zaktualizować dane swojego badania, skontaktuj się z register@clinicaltrials.gov. Gdy tylko zmiana zostanie wprowadzona na stronie clinicaltrials.gov, zostanie ona automatycznie zaktualizowana również na naszej stronie internetowej .

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