Genetics of Ventriculo-arterial Discordance

Study Overview
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Brief Summary
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Number of centres planned : 16 centres in France Type of study / Study design : Research Involving the Human Person category 2. Multicentric. Prospective Planning of the study : Total duration: 22 years. Recruitment period: 24 months. Follow-up time per patients : 20 years Expected number of cases : 300 index cases: 150 single index cases and 150 trio families Treatment, procedure, combination of procedures under consideration : Blood samples for genetic analyses collected at the inclusion visit for patients and parents in case of trio families Schedule of different visits and examinations : Inclusion visit: Collection of demographic, clinical data from the index case and parents DNA sampling for genetic research (biocollection) of the index case or family trio Completion of the quality of life questionnaire Annual visit with a 20 year follow-up: Retrieval of data from the index case Completion of the quality of life questionnaire

Official Title
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Genetics of Ventriculo-arterial Discordance: Towards a PRECIsion Medicine in PEDiatric Cardiology

Conditions
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Heart Defects, Congenital

Intervention / Treatment
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* Biological: Genetic analyses: whole genome sequencing


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with transposition of the great arteries or transposition congenitally corrected of the great arteries with healthy parents and no family history of congenital heart disease (familial trio) Or patients with transposition of the great arteries or transposition congenitally corrected of the great arteries with or without a history of congenital heart disease (familial form or sporadic case) Affiliated or beneficiaries of a social security scheme or similar After obtaining oral consent from patients and/or parents if applicable Parents (for family trios) : - Biological parents of the child included in the PRECIPED study Exclusion Criteria: Patients with transposition of the great arteries or transposition congenitally corrected of the great arteries with hypoplastic ventricle or atrioventricular and/or ventriculoarterial valve atresia Patient with an identified malformation syndrome Patients under guardianship/curatorship Patients with State Medical Aid Refusal of consent by the patient and/or one of the two parents

Ages Eligible for Study
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Minimum Age: 1 Minute
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Interventional Model Description: 600 participants (150 single cases and 150 trio families)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Congenital heart disease<br> | Biological: Genetic analyses: whole genome sequencing<br>* Identification of de novo genetic variants using a whole genome sequencing (WGS) approach in the context of familial trios analysis<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Identification new genes/variants involved in congenital heart disease with transposition congenitally corrected of the great arteries, based on whole genome sequencing of familial trios. | Identification of de novo genetic variants using a whole genome sequencing (WGS) approach in the context of familial trios analysis | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation the diagnostic contribution of parental cardiovascular screening in case of ventriculo-arterial discordance (transposition of the great arteries, transposition congenitally corrected of the great arteries) in the index case. | Evolution of diagnostic performance for congenital heart disease in relatives of the index case with ventriculo-arterial discordance following the introduction of parental screening. | 24 months | 
| Identification new familial forms of ventriculo-arterial discordance. | Identification of genotype/phenotype relationships by studying associations between clinical features and identified genetic variants. | 24 months | 
| Identification epigenetic modifications by analysis of the epigenome of sporadic forms when genome sequencing is not contributory. | Detection of epigenetic modifications. | 24 months | 
| Identification allelic variants associated with prognosis and/or response to treatment, with the aim of eventually developing a precision medicine programme in paediatric cardiology | Identification of genotype/phenotype relationships in relation to prognosis and/or response to treatment | 20 years | 
| Assessing the quality of life of patients with ventriculo-arterial discordance as well as their parents | To document quality of life longitudinally in this patient population using Pediatric Quality of Life InventoryTM (scale from 0 to 4 ; 4 being the worst outcome) | 20 years | 
| Assessing the quality of life of patients with ventriculo-arterial discordance as well as their parents | To document quality of life longitudinally in this patient population using The Short Form (36) Health Survey (scale from 1 to 6 ; 6 being the worst outcome) | 20 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Congenital heart disease, Ventriculo-arterial discordance, Transposition of the great arteries, Transposition congenitally corrected of the great arteries, Genetic, Whole genome sequencing