ANDDI-PRENATOME - Feasibility Study for a " Fast " Pangenomic High Throughput Sequencing Analysis in Prenatal Diagnosis

ANDDI-PRENATOME - Feasibility Study for a " Fast " Pangenomic High Throughput Sequencing Analysis in Prenatal Diagnosis

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.

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

Exclusion Criteria:

• Diagnostic hypothesis considered highly probable that can be confirmed by an available molecular or cytogenetic test with a lower cost than ES (e. g. 22q11 microdeletion) or high suspicion of fetal infection (e. g. toxoplamosis seroconversion)
• Refusal of pregnant woman or father of fetus to participate in the study
• Pregnancy earlier than 15 weeks of amenorrhea or later than 34 weeks of amenorrhea
• Pregnant woman and father of the foetus not covered by the national health insurance system
• Pregnant woman and/or father of the fetus under partial judicial protection