Genome-wide High Throughput Sequencing, Prenatal
Conditions
Brief summary
Prenatal diagnosis of genetic diseases is a real medical challenge. The discovery of antenatal abnormalities on ultrasound is frequent (5 to 10% of pregnancies), and when an abnormalities is seen on ultrasound, it raises the possibility of an underlying developmental anomaly. Currently, in France, when abnormalities are discovered with an ultrasound scan, the etiological diagnosis is based on additional imaging tests (cerebral MRI, 3D bone tomography, fetal CT, fetal CT) or diagnostic tests such as invasive chorionic villus sampling, amniocentesis or fetal blood for infectious, metabolic, immunological and genetic investigations (standard karyotype, FISH (fluorescence in situ hybridization) for the rapid detection of aneuploidy, Chromosome Analysis on DNA Chip (ACPA or CGH-array) and possible sequencing of targeted genes when they are available within a time frame compatible with pregnancy). NIPT (Non-invasive prenatal testing) on cell free fetal DNA circulating in maternal blood has more limited indications, allowing, from an early stage of pregnancy, the determination of fetal sex and fetal rhesus factor and the search for aneuploidy. However, establishing an etiological diagnosis during pregnancy has many benefits for the parents: clarifying the cause, obtaining a more precise prognosis to determine future management and outcome of the pregnancy, and establishing the risks of recurrence. Over the past decade, medical genetics has undergone a real technological revolution, leading to the development of high throughput genome-wide, exome (ES) and genome (GS) sequencing. However, few countries have currently embarked on ES/GS in prenatal care, due to the constraints of time and the difficulty of interpreting genomic data when the clinical data is limited to antenatal imaging data. In 2016, France launched the France Medicine Genomics 2025 Plan (PFMG2025) to deploy GS, particularly in the diagnosis of rare diseases. It is thus becoming essential to define the modalities of prescription of this testing, in particular during prenatal diagnosis. In parallel, from the first publications, the applications of genomic analysis on circulating fetal DNA seem to be able to extend to genome sequencing for research of SNVs responsible for developmental diseases. The AnDDI-rares health network therefore proposes this ANDDI-PRENATOME pilot project to study the feasibility of a "rapid" analysis of ES in prenatal diagnosis from 61 fetuses with ultrasound abnormalities, as a first step before considering future cost-effectiveness (PRME) or care system performance (PREPS) studies in conjunction with the PFMG2025.
Interventions
BIOLOGICALInvasive fetal sampling, blood sampling of mother and father
to perform an exome sequencing analysis in trio
BIOLOGICALblood sampling from the mother to recover the circulating cell free fetal DNA
to perform a sequencing analysis of the genome of circulating free fetal DNA
OTHERParent interviews (optional organizational study)
Interview with a sociologist or psychologist to explore perceptions of ES and the impact of the results, expectations regarding certain types of results not currently available, the emotional situation, and position regarding the continuation of the pregnancy At 4 different times: at inclusion, at the time of the CGA-array results, at the time of the ES results and at a distance from the ES results
OTHERparent questionnaire (optional organizational study)
To evaluate the experience, perceptions, the impact of the analyses on the decision, satisfaction and concerns regarding the ES and its results, opinions on certain types of results not currently available, as well as anxiety and possible psychological distress At 4 different points in time: at inclusion, at the delivery of the CGA-array results, at the delivery of the ES results and at a distance from the delivery of the ES results
OTHERprofessional interviews (optional organizational study)
interview to understand how the decision is formed
OTHERFocus group for professionals (optional organizational study)
interview to specify whether variants of unknown significance) VUS will potentially be returned to the clinicians, or even to the patient via the clinician.
Sponsors
Centre Hospitalier Universitaire Dijon
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Pregnant women with antenatal discovery of at least two obstetric ultrasound abnormalities (2 major malformations, or 1 major malformation and 1 minor malformation, or 1 isolated malformation with a high probability of a genetic condition) : who undergo invasive antenatal sampling for CGH-array diagnosis ; who has already had an invasive antenatal sampling for the diagnosis of CGH-array and for which the fetal CGH-array has been found to be normal (sufficient fetal DNA or amniotic fluid should be available to allow exome sequencing to be performed without further amniotic fluid puncture). * Pregnant woman and father aged 18 years or more * Written consent provided by the pregnant woman and the father of the fetus * Possibility of sufficient fetal specimen (amniotic fluid or fetal blood) to collect an additional sample for the pilot project * Possibility of sampling the pregnant woman and the father of the foetus (peripheral blood) * Pregnant woman and father of the fetus able to understand the study Pilot Organizational Study: In addition to the inclusion \&
Exclusion criteria
of the main study: * Pregnant woman and biological father of fetus who provided oral consent to be interviewed * Professionals (obstetrician, midwife, geneticist, biologist) agreeing to be interviewed
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Time required to return ES results to patients and their families in a context prenatal diagnosis | Through study completion, an average of 12 months |
| number of discrepancies between ES and WGS | Through study completion, an average of 12 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Questionnaire to understand the expectations of couples and their a priori perception of ES | Through study completion, an average of 12 months | To define feelings and to know better how couples perceive ES and its implications and in particular the risk of discovery of VUS (variants of unknown significance) and ID (incidental data). |
| Questionnaire to evaluate the organization of health professionals involved in the decision-making process | Through study completion, an average of 12 months | — |
Countries
France
Outcome results
None listed