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 (PRENATEX)

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

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).

Study Overview

• Status: Recruiting
• Conditions: Pregnancy Related; Rare Genetic Disease; Fetal Malformation
• Intervention / Treatment: Genetic: CGH-array and exome sequencing

• Study Type: Interventional
• Enrollment (Anticipated): 90
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Elise SCHAEFER; Phone Number: +33 3 88 12 81 20; Email: elise.schaefer@chru-strasbourg.fr

Study Locations

• France
  • Besançon, France, 25030
    • Not yet recruiting
    • CHU de Besancon
    • Contact: Lionel VAN MALDERGEM; Phone Number: +33 3 81 21 81 87; Email: lionel.van-maldergem@inserm.fr
    • Principal Investigator: Lionel VAN MALDERGEM
    • Sub-Investigator: Juliette PIARD
    • Sub-Investigator: Elise BOUCHER
  • Dijon, France, 21079
    • Not yet recruiting
    • CHU de Dijon
    • Contact: Christel THAUVIN; Phone Number: +33 3 80 29 53 13; Email: Christel.thauvin@chu-dijon.fr
    • Principal Investigator: Christel THAUVIN
    • Sub-Investigator: Laurence FAIVRE
    • Sub-Investigator: Arthur SORLIN
    • Sub-Investigator: Sébastien MOUTTON
  • Lyon, France
    • Not yet recruiting
    • Hospices Civils de Lyon
    • Contact: Audrey PUTOUX; Phone Number: +33 4 27 85 50 83; Email: Audrey.putoux@chu-lyon.fr
    • Principal Investigator: Audrey PUTOUX
  • Mulhouse, France, 68070
    • Not yet recruiting
    • Groupe Hospitalier Region Mulhouse Et Sud Alsace
    • Contact: Emmanuelle GINGLINGER; Phone Number: +33 3 89 64 87 03; Email: GINGLINGERE@ghrmsa.fr
    • Principal Investigator: Emmanuelle GINGLINGER
    • Sub-Investigator: Edgar MONTOYA RAMIREZ
  • Nancy, France, 54042
    • Not yet recruiting
    • Chu de Nancy
    • Contact: Laetitia LAMBERT; Phone Number: +33 3 83 34 43 76; Email: l.lambert@chru-nancy.fr
    • Principal Investigator: Laetitia LAMBERT
    • Sub-Investigator: Bruno LEHEUP
  • Paris, France, 75013
    • Not yet recruiting
    • Hopital de la Pitie Salpetriere
    • Contact: Delphine HERON; Phone Number: +33 1 42 16 13 47; Email: Delphine.heron@aphp.fr
    • Principal Investigator: Delphine HERON
  • Paris, France, 75012
    • Not yet recruiting
    • Hôpital d'Enfants Armand-Trousseau
    • Contact: Alexandra AFENJAR; Phone Number: +33 1 44 73 61 86; Email: Alexandra.afenjar@aphp.fr
    • Principal Investigator: Alexandra AFENJAR
  • Paris, France, 75743
    • Not yet recruiting
    • Hôpital Necker Enfants Malades
    • Contact: Tania ATTIE-BITACH; Phone Number: +33 1 44 49 51 44; Email: tania.attie@inserm.fr
    • Principal Investigator: Tania ATTIE-BITACH
  • Reims, France, 51092
    • Not yet recruiting
    • CHU de Reims
    • Contact: Martine DOCO-FENZY; Phone Number: +33 3 26 78 90 03; Email: mdocofenzy@chu-reims.fr
    • Principal Investigator: Martine DOCO-FENZY
    • Sub-Investigator: Céline POIRSIER
  • Rennes, France, 35203
    • Not yet recruiting
    • CHU de Rennes
    • Contact: Sylvie ODENT; Phone Number: +33 2 99 26 67 44; Email: Sylvie.odent@chu-rennes.fr
    • Principal Investigator: Sylvie ODENT
  • Strasbourg, France, 67098
    • Recruiting
    • Les Hôpitaux Universitaires de Strasbourg
    • Sub-Investigator: Vincent LAUGEL
    • Contact: Elise SCHAEFER; Phone Number: +33 3 88 12 81 20; Email: elise.schaefer@chru-strasbourg.fr
    • Principal Investigator: Elise SCHAEFER
    • Sub-Investigator: Hélène DOLLFUS
    • Sub-Investigator: Salima EL CHEHADEH
    • Sub-Investigator: Romain FAVRE
  • Toulouse, France, 31059
    • Not yet recruiting
    • CHU de Toulouse
    • Contact: Patrick CALVAS; Phone Number: +33 5 61 77 90 51; Email: calvas.p@chu-toulouse.fr
    • Principal Investigator: Patrick CALVAS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: 90 trios (270 subjects: 90 fetus, 90 mothers, 90 fathers)	Genetic: CGH-array and exome sequencing; A blood sample will be used for CGH-array and exome sequencing

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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

Collaborators and Investigators

• Sponsor: University Hospital, Strasbourg, France

Study record dates

Study Major Dates

• Study Start (Actual): August 5, 2020
• Primary Completion (Anticipated): September 1, 2021
• Study Completion (Anticipated): September 1, 2023

Study Registration Dates

• First Submitted: May 26, 2020
• First Submitted That Met QC Criteria: May 26, 2020
• First Posted (Actual): May 28, 2020

Study Record Updates

• Last Update Posted (Actual): November 13, 2020
• Last Update Submitted That Met QC Criteria: November 10, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: Exome sequencing; Fetal malformations; antenatal cerebral malformations; antenatal ocular malformations; antenatal large hyperechoic kidneys
• Additional Relevant MeSH Terms: Congenital Abnormalities; Genetic Diseases, Inborn
• Other Study ID Numbers: 7344

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No