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

Summary

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.

Conditions

• Antenatal Congenital Malformations

Interventions

OTHER

Collection of clinical data

family history, clinical data, ultrasound and all other data necessary for the study on a e-CRF (CleanWEB), allowing the collection of the family tree, and if necessary photographic elements.

BIOLOGICAL

Collection of samples

Collected during fetal and blood sampling performed as part of care for ACPA: * 4 Streck tubes maximum for the pregnant woman for NIPD-Exome, collected prior to invasive fetal sampling * 1 additional vial of fetal sample (amniotic fluid or fetal blood) and 1 EDTA tube for each of the two parents

OTHER

Questionnaires

within the framework of the pilot study (optional): questionnaires (about 20 minutes) for the evaluation of the experience, perceptions, impact of the analyses on the decision, satisfaction and concerns regarding exome sequencing (ES) and its results, opinion on certain types of results currently not reported, anxiety, possible psychological difficulties

OTHER

Parent interviews

as part of the pilot study (optional): interview (about 1 hour) with a sociologist to explore perceptions of ES and the impact of the results, expectations about certain types of results that are not currently available, emotional situation, position regarding the continuation of the pregnancy

OTHER

Professional interview and focus groups

Interview (approximately 45 minutes) to understand how the decision is formed Focus groups to help clarify whether the Variants of Unknown Significance (VUSs) should potentially be returned to the clinicians, or even the patient via the clinician

Sponsors & Collaborators

• Centre Hospitalier Universitaire Dijon

  lead OTHER

Study Design

Allocation

NON_RANDOMIZED

Purpose

DIAGNOSTIC

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2022-03-08

Primary Completion

2024-03-14

Completion

2024-03-14

Countries

• France

Study Locations