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

Condition(s) studied

Investigational drug(s) / intervention(s)

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

Study summary

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.

Eligibility

Primary outcome measure(s)

• 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). — 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).

Trial sites (1)

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