Comparison of the Non-invasive Approach and Fetal Exome Sequencing in Prenatal Diagnosis When Fetal Ultrasound Signs Are Discovered

The discovery of congenital malformations and/or non-specific signs by ultrasound (5% of pregnancies) represents a real medical challenge. Their prognosis is variable depending on the underlying etiology, ranging from acquired fetopathies to rare genetic diseases. In France, the diagnostic approach is currently based on imaging examinations (ultrasound, brain MRI, 3D bone scans, etc.) and/or biological examinations, generally on invasive sampling (trophoblast biopsy, amniocentesis or fetal blood puncture) with infectious (CMV, toxoplasmosis, parvovirus B19, etc.), metabolic (enzymes in the bloodstream, etc.), and genetic (standard karyotype, FISH, array CGH and targeted gene sequencing) investigations. The yield of this strategy is about 30%, leaving 70% of couples without a possible prognosis.

Over the last decade, medical genetics has undergone a technological revolution with the development of high-throughput DNA sequencing (HTS) allowing the analysis of targeted genes (panel) or the exome (ES). International studies published on the use of ES in prenatal diagnosis (PND) have become more common, with variable inclusion criteria, resulting in diagnostic rates between 15 and 36%, higher than those of array CGH (8-15%). In France, FHU TRANSLAD coordinates the national pilot study AnDDI-PRENATOME, which has made it possible to remove the technological barriers for PND ES and to obtain a diagnostic yield of 39% in 33 days on average.

In parallel, the recent development of NIPD (Non-invasive prenatal screening) on free fetal DNA circulating in maternal blood has made it possible to propose a non-invasive strategy. However, this technique is currently used in prenatal care only in a few indications: determination of the fetal sex, search for aneuploidies, analysis of the fetal rhesus status or, more rarely, the targeted diagnosis of monogenic diseases. The team in Strasbourg has recently conducted a pilot study using an NIPD-panel in couples with a history of neomutation in a gene responsible for intellectual disability, which has demonstrated the feasibility of capturing and then sequencing a panel of 500 genes on free fetal DNA circulating in maternal blood.

As high-depth exome sequencing from small amounts of DNA is now affordable and feasible, the investigators wish to compare invasive and non-invasive approaches for the discovery of fetal malformations on ultrasound: a trio exome analysis will be performed in parallel to circulating fetal DNA and fetal DNA extracted after an invasive puncture in order to compare the diagnostic performance of these two approaches.

The investigators propose a pilot study in order to prepare an organizational evaluation including an evaluation of the stakes for coordination and interactions between professionals, the relevance of the system (acceptability, expectations, satisfaction of couples and professionals...), its effectiveness and efficiency. The aim of this pilot project will be to observe the organizational impact on the Plurldisciplinary Centers for Prenatal Disagnostics and the genetic laboratories, and to refine the indicators necessary for monitoring the system; it will also involve conducting exploratory interviews with professionals and couples in order to prepare the qualitative study that will subsequently make it possible to evaluate the relevance of the organization.