Realization of Sequencing of All Known Human Genes in Case of Detection of Cerebral, Renal or Ophthalmological Fetal Malformations During Pregnancy in Order to Make an Etiological Diagnosis and to Precise the Fetal Prognosis

Pregnancy Related Clinical Trial

— PRENATEX  

Official title:

Contribution of the Exome Sequencing in Antenatal Period Behind Ultrasound Features Suggestive of a Rare Genetic Disease

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04406480
• Other study ID #: 7344
• Status: Recruiting
• Phase: N/A
• Start date: August 5, 2020
• Est. completion date: September 2023

Study information

• Verified date: November 2020
• Source: University Hospital, Strasbourg, France
• Contact: Elise SCHAEFER
• Phone: +33 3 88 12 81 20
• Email: elise.schaefer[@]chru-strasbourg.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Congenital malformations concern 3% of pregnancies; most of them can be seen during pregnancy. For some malformations, an invasive sample (trophoblast biopsy or amniocentesis) is proposed to search a chromosomal abnormality by the technique of DNA chip. However, some strongly suggestive signs of a genetic (and not chromosomal) pathology have a very low diagnostic rate with this technique. In the absence of an etiological diagnosis, the prognosis for the unborn child is very difficult to assess, as we can't know if the fetal malformation is really isolated or associted to other unseen features as part of a syndromic condition.

For some malformations strongly suggestive of a genetic condition, we propose to realize an exome (i.e. all coding parts of the genome) sequencing of the trio (child and the 2 parents) with a delivery time compatible with the emergency situation of a pregnancy (6 weeks maximum). We will apply bioinformatics filters to analyse only genes known to be involved in the malformation present in the unborn child and thus avoid the identification of variants in unrelated genes. These lists of genes have been previously validated by the Rare Disease Health Sectors and the affiliated diagnostic laboratories. The selected malformations are: 1) anomalies of the central nervous system (microcephaly (<- 2DS) with anomalies of gyration, anomalies of the posterior fossa, anomalies of the midline except agenesis of the corpus callosum), 2) ophthalmological anomalies (microphthalmia, hyperplasia vitreous) and 3) renal abnormalities (large hyperechoic kidneys).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 90
• Est. completion date: September 2023
• Est. primary completion date: September 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Father and mother of an unborn child past the age of majority

• Consent dated and signed by the mother and by the father

• Father and mother able to understand the objectives and risks of the study

• For the mother, pregnancy in progress (between 12 and 34 weeks)

• For the mother, pregnancy with the presence of a malformation on ultrasound, confirmed by a doctor from the multidisciplinary diagnostic prenatal center, entering into the indications retained for this study

• Clinical validation of the couple's eligibility by an expert for some of selected indications

• Father and mother affiliated to a social protection health

Exclusion Criteria:

• Identified genetic or chromosomal abnormality explaining the observed malformation

• Inability to give informations to the father and / or mother (father or mother in emergency or life-threatening situation)

• Father and / or mother under the protection of justice

• Father and / or mother under guardianship or curatorship

• Nursing woman

Related Conditions & MeSH terms

• Congenital Abnormalities
• Fetal Malformation
• Genetic Diseases, Inborn
• Pregnancy Related
• Rare Genetic Disease

Intervention

Genetic:
• CGH-array and exome sequencing
A blood sample will be used for CGH-array and exome sequencing

Locations

Country	Name	City	State
France	CHu de Besançon	Besançon
France	CHU de Dijon	Dijon
France	Hospices Civils de Lyon	Lyon
France	Groupe Hospitalier Region Mulhouse Et Sud Alsace	Mulhouse
France	CHU de Nancy	Nancy
France	Hôpital d'Enfants Armand-Trousseau	Paris
France	Hôpital de la Pitié Salpêtrière	Paris
France	Hôpital Necker Enfants Malades	Paris
France	CHU de Reims	Reims
France	CHU de Rennes	Rennes
France	Les Hôpitaux Universitaires de Strasbourg	Strasbourg
France	CHU de Toulouse	Toulouse

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Strasbourg, France

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Difficulties of interpretation of the exome sequencing in antenatal period	Numbers of variants of unknown signification identified by exome sequencing with and without bioinformatic filters (targeted exome)	13 months
Other	Identification of new genes responsible of fetal malformations	If the results of CGH-array and targeted exome sequencing are negative, analysis of the entire exome sequencing to find new genes implicated in fetal development	13 months
Primary	Diagnostic contribution of the exome sequencing in antenatal period in comparison with the chromosomal analysis (CGH-array) realized in current health care	Comparison of the number of genetic diagnoses made by exome sequencing and by CGH-array.	13 months
Secondary	Effects on pregnancy management and/or postnatal child care due to an etiological diagnosis	Percentage of antenatal and/or postnatal fetus/child care modified by the molecular result	13 months
Secondary	Feasibility study of carrying out exome sequencing in the antenatal period in terms of time to deliver results	Time to results from the inclusion of the trio (in days) specifying the time for each step (reception, sequencing, bioinformatics analysis, interpretation) (in days)	13 months