Whole Exome Sequencing in Prenatal Diagnosis of Agenesis of the Corpus Callosum

Study Overview
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Brief Summary
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Agenesis of the corpus callosum (ACC) is one of the most frequent cerebral malformations and is now diagnosed prenatally in most cases. Prenatal counseling is then challenging because of uncertain neurodevelopmental outcome, depending on the genetic cause of ACC. Our purpose is to evaluate the feasibility of sequencing known genes responsible for ACC by whole exome sequencing (WES) in trio (fetus and both parents) when ACC is diagnosed during the pregnancy, in order to provide complete and loyal information on the intellectual prognosis for the fetus.

Detailed Description
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Agenesis of the corpus callosum (ACC) is one of the most frequent cerebral malformations. The neurodevelopmental outcome of patients with ACC is extremely variable, ranging from normal intelligence to severe intellectual disability (ID). When ACC is discovered during the prenatal period, prenatal counseling is challenging because of this uncertain neurodevelopmental outcome. Currently, only chromosomal analyses are performed in cases of prenatal diagnoses, which are expected to bring the diagnosis in only few cases. No molecular studies of genes implied in ACC with or without ID are performed. Then, the couples are in the difficult situation of continuing or interrupting the pregnancy without complete information about the aetiology of ACC. All patients will have a consultation with an obstetrician and consultations with a paediatric neurologist and a geneticist. The geneticist will explain WES and its issues. Both parents will have to provide informed consent for the study.

Official Title
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Whole Exome Sequencing in Prenatal Diagnosis of Agenesis of the Corpus Callosum

Conditions
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Fetal Agenesis of the Corpus Callosum (ACC)

Intervention / Treatment
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* Genetic: whole exome sequencing (WES)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years old ACC diagnosed prenatally during the 2nd trimester of pregnancy, confirmed by ultrasound by a referee Fetal sample (amniotic fluid, 10 ml) et blood samples of both parents (2 tubes of 5 ml EDTA) Covered by social security Written consent obtain for routine and research genetic analysis Exclusion Criteria: Refusal to participate from one or both parents Pregnancies obtained with gamete donation (trio sequencing not feasible) If one parent is not available (trio sequencing not feasible) Inability to understand the given information One or both parents under juridical protection

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Intervention/Treatment |
| --- |
|Genetic: whole exome sequencing (WES)|WES analysis will be performed in the UF de Génomique du Développement (APHP, Pitié-Salpêtrière hospital), using DNA extracted from amniotic fluid for the foetus (also used for chromosomal studies) and DNA extracted from peripheral blood for both parents. There will be no supplemental invasive sampling for this study. The result of WES will be returned during a consultation with the geneticist and the associated prognosis will be explained in case of molecular diagnosis|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Technical success | Rate of technical success | 5th week post diagnosis | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Genetic diagnosis | Rate of genetic diagnoses | 5th week post diagnosis | 
| Technical failure | Rate of technical failures | up to 4 months | 
| Delay to genetic diagnosis Result | Delay between the ACC diagnosis and genetic sequencing known genes responsible for ACC | up to 4 months | 
| Parents decision to continue pregnancy | Number of continued pregnancies | up to 4 months | 
| Parents decision to interrupt pregnancy | Number of interrupted pregnancies | up to 4 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Agenesis of the corpus callosum, whole exome sequencing, prenatal diagnosis