RecruitingNCT06475651FOETEPISIGNUpdated Mar 27, 2026

Characterization and Contribution of Genome-wide DNA Methylation (DNA Methylation Episignatures) in Rare Diseases With Prenatal Onset

An observational study in Rare Fetal Genetic Diseases and Congenital Malformation, sponsored by Assistance Publique - Hôpitaux de Paris. Recruiting at 1 site in France. Open to participants aged 0 Years to 18 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2026-03-27.

Sponsored by Assistance Publique - Hôpitaux de Paris · Observational

From the registry’s dates

Started Feb 2026; still recruiting 8 months later.

Study type: Observational
Model: Other
Time perspective: Cross-sectional
Enrollment: 63
Ages: 0 Years to 18 Years
Sex: All

Study summary

It is necessary to define reference DNA Methylation Episignatures from fetal DNA. The hypotheses are:

It is possible to define reference DNA Methylation Episignatures from fetal DNA extracted from amniotic fluid or frozen tissues collected during the postmortem examination
Fetal DNA Methylation Episignatures may be different to postanal DNA Methylation Episignatures defined on DNA extracted from blood

Read the detailed description

Congenital anomalies (CA) complicate 3 to 5% of pregnancies and may be associated with genetic disorders. Diagnosis of genetic diseases is a major medical challenge, especially during pregnancy.

Over the past two decades, next-generation sequencing (NGS) has revolutionized our ability to identify the genetic condition associated with CA. During pregnancy, prenatal exome sequencing identified an additional diagnosis in around 30% of fetuses with CA when standard chromosomal investigations (karyotype and chromosomal microarray analysis, CMA) fail to provide a diagnosis.

Despite these major advances, around 40% of rare diseases remain unsolved, including 10-15% of patients harboring variants of uncertain significance (VUS).

After birth, additional functional analyses ("multi-OMICS"), including genome-wide DNA methylation studies, may be offered to reclassify VUS.

DNA methylation anomalies play an important role in pathologies (developmental disorders and oncology).

DNA methylation Episignatures, defined as the cumulative DNA methylation patterns occurring at multiple CpG dinucleotides across the genome, have been recognized to be intricately associated with many human traits, including age, sex, and disease status. Recently, DNA Methylation Episignatures have been identified in the blood of children or adults for several well-characterized genetic diseases. However, these postnatal DNA Methylation Episignatures cannot be used during pregnancy, because DNA methylation changes from one tissue to another and during time, especially during fetal developpement. In addition, the tissues available during pregnancy are different from those analyzed postnatally (blood).

Conditions studied

Rare Fetal Genetic Diseases
Congenital Malformation

Browse trials for

Congenital Abnormalities 781

Keywords

Congenital malformation
DNA methylation abnormalities
Episignature
CHD7 gene
KMT2D gene
HYLS1 gene
TCTN3 gene
FLVCR2 gene
CHARGE syndrome
KABUKI syndrome

In context

Congenital Abnormalities

781 studies on the registry are indexed under Congenital Abnormalities; 77 are open to participants now.

This study's planned enrollment of 63 is below the median of 250 across 257 observational studies indexed under Congenital Abnormalities.

Browse Congenital Abnormalities studies →

Lead sponsor

Assistance Publique - Hôpitaux de Paris is the lead sponsor of 3,592 studies on the registry; 1,033 are open to participants now.

Browse Assistance Publique - Hôpitaux de Paris studies →

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 0 Years to 18 Years
Sexes eligible: All
Accepts healthy volunteers: Yes
Sampling method: Non-probability sample

Study population

The study population is derived from the Department of Genomic Medicine for Rare Diseases and the Multidisciplinary Center for Prenatal Diagnosis of the Necker-Enfants malades Hospital - APHP - GHU Paris Cité.

The parents signed a consent to the storage and use of biological samples, stating that these samples taken as part of the treatment could be reused for medical research.

Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.

Inclusion criteria

Patient Inclusion Criteria:
- Fetuses with a postmortem examination as part of the etiological diagnosis of developmental abnormality within the Genomic Medicine of Rare Diseases department of the Necker Children's Hospital, and whose DNA extracted from lung and amniotic fluid is available
- OR a child cared for in the Genomic Medicine for Rare Diseases department of the Necker Children's Hospital, and whose DNA extracted from whole blood is available
- with pathogenic or probably pathogenic variation in a gene following CHD7, KMT2D, HYLS1, TCTN3 or FLVCR2
- whose parents have consented to molecular genetic testing as part of diagnosis and research
Negative Controls :
- Fetuses with a postmortem examination as part of the etiological diagnosis of developmental abnormality within the Genomic Medicine of Rare Diseases department of the Necker Children's Hospital, and whose DNA extracted from lung and amniotic fluid are available
- OR a child cared for in the Genomic Medicine for Rare Diseases department of the Necker Children's Hospital, and whose DNA extracted from whole blood is available
- does not have pathogenic or probably pathogenic variation in a gene following CHD7, KMT2D, HYLS1, TCTN3 or FLVCR2
- whose parents have consented to molecular genetic testing as part of diagnosis and research
For everyone:
- For living participants: Non-objection by holders of parental authority to the reuse of clinical data and biological samples collected and stored in the context of care (consent of care).
- For deceased participants:
Consent of the holders of parental authority to the use of the samples kept for research purposes, signed as part of the treatment
No mention of opposition to the reuse of clinical data from the treatment in the patient's medical record

Exclusion criteria

Exclusion Criteria:

Refusal of postmortem examination in case of fetal loss
Parents' refusal of molecular investigations

Study design

Observational model: Other
Time perspective: Cross-sectional
Enrollment: 63 participants (estimated)
Patient registry: No
Biospecimen retention: Samples with dna

Groups and cohorts

Workpackage 1, group 1
Patients (children) with CHARGE syndrome
Genetic: Methylation analysis
Workpackage 1, group 2
Healthy negative controls (children) matched for age and sex
Genetic: Methylation analysis
Workpackage 1, group 3
Fetuses with CHARGE syndrome
Genetic: Methylation analysis
Workpackage 1, group 4
Fetuses with no genetic pathology
Genetic: Methylation analysis
Workpackage 2, group 5
Patients (children) with KABUKI syndrome
Genetic: Methylation analysis
Workpackage 2, group 6
Fetuses with KABUKI syndrome
Genetic: Methylation analysis
Workpackage 3, group 7
Fetuses with hydrolethalus syndrome
Genetic: Methylation analysis
Workpackage 3, group 8
Fetuses with Meckel/OFD IV syndrome
Genetic: Methylation analysis
Workpackage 3, group 9
Fetuses with Fowler syndrome
Genetic: Methylation analysis

Interventions

GeneticMethylation analysis
Genomic DNA will be treated with bisulfite. 500 ng of processed DNA is then hybrized on an EPICv2 array Infinium methylation (Illumina, San Diego, CA, USA). This microarray enables the analysis of approximately 865 000 methylation sites at promoters, enhancers, CpG islands, intergenic and intragenic regions. It is the most widely used chip in the literature, including almost all of the EPIGENETIC SIGNATURES reported in human pathology.

What researchers measure

Primary outcomes

Epigenetic signature associated with pathogenic variations in the CHD7 gene (CHARGE Syndrome)
Evidence of epigenetic signature from fetal tissue DNA in fetuses with pathogenic or probably pathogenic variation
Time frame: 12 months
Epigenetic signature associated with pathogenic variations in the KMT2D gene (KABUKI syndrome)
Evidence of epigenetic signature from fetal tissue DNA in fetuses with pathogenic or probably pathogenic variation
Time frame: 12 months

Secondary outcomes

Differential methylation between fetal and postnatal epigenetic signature
Evidence of differential methylation between fetal an postnatal epigenetic signature
Time frame: 12 months
Differential methylation between tissue and amniotic fluid epigenetic signatures
Evidence of differential methylation between tissue and amniotic fluid epigenetic signatures
Time frame: 12 months
Statistical prediction parameter for each epigenetic signature
Measurement of the statistical prediction parameter for each epigenetic signature
Time frame: 12 months
Identification of a new epigenetic signature in foetal pathologies
Identification of news epigenetic signatures of exclusively pathologies associated with the HYLS1, TCTN3 and FLVCR2 genes
Time frame: 12 months

Study locations

1 of 1 sites recruiting

Department of Genomic Medicine for Rare Diseases and the Multidisciplinary Center for Prenatal Diagnosis of the Necker-Enfants malades Hospital
Paris, 75015, France
Recruiting
- Nicolas BOURGON, MD, PhD · Contact · nicolas.bourgon@aphp.fr · : +33 1 42 19 27 96
Recruiting

References and documents

Publications

Butcher DT, Cytrynbaum C, Turinsky AL, Siu MT, Inbar-Feigenberg M, Mendoza-Londono R, Chitayat D, Walker S, Machado J, Caluseriu O, Dupuis L, Grafodatskaya D, Reardon W, Gilbert-Dussardier B, Verloes A, Bilan F, Milunsky JM, Basran R, Papsin B, Stockley TL, Scherer SW, Choufani S, Brudno M, Weksberg R. CHARGE and Kabuki Syndromes: Gene-Specific DNA Methylation Signatures Identify Epigenetic Mechanisms Linking These Clinically Overlapping Conditions. Am J Hum Genet. 2017 May 4;100(5):773-788. doi: 10.1016/j.ajhg.2017.04.004. PubMed 28475860 ↗
Aref-Eshghi E, Kerkhof J, Pedro VP; Groupe DI France; Barat-Houari M, Ruiz-Pallares N, Andrau JC, Lacombe D, Van-Gils J, Fergelot P, Dubourg C, Cormier-Daire V, Rondeau S, Lecoquierre F, Saugier-Veber P, Nicolas G, Lesca G, Chatron N, Sanlaville D, Vitobello A, Faivre L, Thauvin-Robinet C, Laumonnier F, Raynaud M, Alders M, Mannens M, Henneman P, Hennekam RC, Velasco G, Francastel C, Ulveling D, Ciolfi A, Pizzi S, Tartaglia M, Heide S, Heron D, Mignot C, Keren B, Whalen S, Afenjar A, Bienvenu T, Campeau PM, Rousseau J, Levy MA, Brick L, Kozenko M, Balci TB, Siu VM, Stuart A, Kadour M, Masters J, Takano K, Kleefstra T, de Leeuw N, Field M, Shaw M, Gecz J, Ainsworth PJ, Lin H, Rodenhiser DI, Friez MJ, Tedder M, Lee JA, DuPont BR, Stevenson RE, Skinner SA, Schwartz CE, Genevieve D, Sadikovic B. Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders. Am J Hum Genet. 2020 Mar 5;106(3):356-370. doi: 10.1016/j.ajhg.2020.01.019. Epub 2020 Feb 27. PubMed 32109418 ↗

Individual participant data

Plan to share: No

Timeline

Tracking since Sep 25, 2026

ElapsedEstimatedEstimated, not yet reached

Started Feb 2026 (actual). Primary completion is estimated for Aug 2026, 6 months after the start.

How these figures are worked out, and which studies are left out of them.

Registered: Jun 20, 2024
First posted: Jun 26, 2024
StartActual: Feb 26, 2026
Primary completionEst.: Aug 26, 2026
CompletionEst.: Aug 26, 2026
Last update: Mar 27, 2026

What these dates mean

Start.: When the first participant enrolled; while estimated, when the study expects to open to recruitment.
Primary completion.: When the last participant was examined or treated to collect data for the study's main question, its primary outcome. A study that stopped early gives the date its data collection stopped.
Completion.: When the last participant's last visit took place, for every outcome, secondary ones and side effects included: the end of the study. Often later than primary completion, sometimes the same day.
Actual and Est.: Actual means the registry says the date has happened. Est. (estimated) is a date the sponsor plans or expects. It can still move, and the sponsor is expected to change it to actual once it has passed.

No changes since tracking began. The registry record was last updated on Mar 27, 2026, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT06475651
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Collaborators: URC-CIC Paris Descartes Necker Cochin
Responsible party: Sponsor
First posted: Jun 26, 2024
Start date: Feb 26, 2026
Primary completion: Aug 26, 2026 (estimated)
Completion: Aug 26, 2026 (estimated)
Last update: Mar 27, 2026

Study contacts

Nicolas BOURGON, MD, PhD

Contact

nicolas.bourgon@aphp.fr

+33 1 42 19 27 96

Nelly BRIAND, PhD

Contact

nelly.briand@aphp.fr

0144381862

Manon TESSIER, MD, PhD

study director · Assistance Publique - Hôpitaux de Paris

Oversight

Data monitoring committee: No
FDA-regulated drug: No
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

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