Rare Fetal Genetic DiseasesFOETEPISIGNNCT06475651
Characterization and Contribution of Genome-wide DNA Methylation (DNA Methylation Episignatures) in Rare Diseases With Prenatal Onset
An observational study of Rare Fetal Genetic Diseases and Congenital Malformation, run by Assistance Publique - Hôpitaux de Paris at 1 site in France.
Trial 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… Read more about this study
- Who is it for?
- Ages 0 to 18 yearsHealthy volunteers can take part
- Conditions the study is for
- Rare Fetal Genetic Diseases, Congenital Malformation
- What is being tested?
- Methylation analysis
- Type of treatment
- Injection or infusion
- How many people
- 63 participants
- Where
- 1 siteFrance
- Study dates
- 26 Feb 2026to 26 Aug 2026
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 0 to 18 years
- All sexes
- Healthy volunteers accepted
- Child, Adult
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.
Who may be able to join
- 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 :
Show all 15Show fewer
- 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
Who cannot join
- Refusal of postmortem examination in case of fetal loss
- Parents' refusal of molecular investigations
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
France1 site, 1 recruiting
- Recruiting
Department of Genomic Medicine for Rare Diseases and the Multidisciplinary Center for Prenatal Diagnosis of the Necker-Enfants malades Hospital
Paris, 75015
Nicolas BOURGON, MD, PhD, : +33 1 42 19 27 96, nicolas.bourgon@aphp.fr
About this study
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).
- Being tested
- Methylation analysis
- Keywords
- Congenital malformation, DNA methylation abnormalities, Episignature, CHD7 gene, KMT2D gene, HYLS1 gene, TCTN3 gene, FLVCR2 gene, CHARGE syndrome, KABUKI syndrome
- Medical subject headings
- Congenital Abnormalities, CHARGE Syndrome, Hydrolethalus Syndrome 1, Kabuki syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Methylation analysisGenetic
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.
| Study group | Role | What they receive |
|---|---|---|
| Workpackage 1, group 1 | Patients (children) with CHARGE syndrome Receives: Genetic: Methylation analysis | |
| Workpackage 1, group 2 | Healthy negative controls (children) matched for age and sex Receives: Genetic: Methylation analysis | |
| Workpackage 1, group 3 | Fetuses with CHARGE syndrome Receives: Genetic: Methylation analysis | |
| Workpackage 1, group 4 | Fetuses with no genetic pathology Receives: Genetic: Methylation analysis | |
| Workpackage 2, group 5 | Patients (children) with KABUKI syndrome Receives: Genetic: Methylation analysis | |
| Workpackage 2, group 6 | Fetuses with KABUKI syndrome Receives: Genetic: Methylation analysis | |
| Workpackage 3, group 7 | Fetuses with hydrolethalus syndrome Receives: Genetic: Methylation analysis | |
| Workpackage 3, group 8 | Fetuses with Meckel/OFD IV syndrome Receives: Genetic: Methylation analysis | |
| Workpackage 3, group 9 | Fetuses with Fowler syndrome Receives: Genetic: Methylation analysis |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 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
Measured: 12 months
Secondary outcomes (4)
Differential methylation between fetal and postnatal epigenetic signature
Evidence of differential methylation between fetal an postnatal epigenetic signature
Measured: 12 months
Differential methylation between tissue and amniotic fluid epigenetic signatures
Evidence of differential methylation between tissue and amniotic fluid epigenetic signatures
Measured: 12 months
Statistical prediction parameter for each epigenetic signature
Measurement of the statistical prediction parameter for each epigenetic signature
Measured: 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
Measured: 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Jun 2024
- Study start26 Feb 2026
- Primary completion26 Aug 2026 (estimated)
- Study completion26 Aug 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Rare Fetal Genetic DiseasesStudies of the same condition, open and under way.
- More trials run by Assistance Publique - Hôpitaux de ParisThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Other
- Time perspective
- Cross-sectional
- Enrolment
- 63 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Assistance Publique - Hôpitaux de Paris
- Sponsor type
- University, hospital or other
- Collaborators
- URC-CIC Paris Descartes Necker Cochin
- Responsible party
- Sponsor
- Investigators
- Manon TESSIER, MD, PhD, Study director, Assistance Publique - Hôpitaux de Paris
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06475651
- Sponsor's protocol ID
- APHP231311
- Acronym
- FOETEPISIGN
- Status last verified
- Mar 2026
- First submitted
- 20 Jun 2024
- Last updated
- 27 Mar 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
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 28475860Aref-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
Study at a glance
From the registry record, last updated by the sponsor on 27 Mar 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Characterization and Contribution of Genome-wide DNA Methylation (DNA Methylation Episignatures) in Rare Diseases With Prenatal Onset
- ClinicalTrials.gov ID
- NCT06475651
- Acronym / sponsor ID
- FOETEPISIGN / APHP231311
- Keywords
- Congenital malformation, DNA methylation abnormalities, Episignature, CHD7 gene, KMT2D gene, HYLS1 gene, TCTN3 gene, FLVCR2 gene
- Study type
- Observational
- Recruitment status
- Recruiting
- Enrolment
- 63 participants (estimated)
- Lead sponsor
- Assistance Publique - Hôpitaux de ParisUniversity, hospital or other
- Collaborators
- URC-CIC Paris Descartes Necker Cochin
- Study start
- 26 Feb 2026 (actual)
- Primary completion
- 26 Aug 2026 (estimated)
- Study completion
- 26 Aug 2026 (estimated)
- First posted
- 26 Jun 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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).
Study design
- Observational model
- Other
- Time perspective
- Cross-sectional
- Number of arms
- 9
| Arm | Type | Receives |
|---|---|---|
| Workpackage 1, group 1 | – | Genetic: Methylation analysisPatients (children) with CHARGE syndrome |
| Workpackage 1, group 2 | – | Genetic: Methylation analysisHealthy negative controls (children) matched for age and sex |
| Workpackage 1, group 3 | – | Genetic: Methylation analysisFetuses with CHARGE syndrome |
| Workpackage 1, group 4 | – | Genetic: Methylation analysisFetuses with no genetic pathology |
| Workpackage 2, group 5 | – | Genetic: Methylation analysisPatients (children) with KABUKI syndrome |
| Workpackage 2, group 6 | – | Genetic: Methylation analysisFetuses with KABUKI syndrome |
| Workpackage 3, group 7 | – | Genetic: Methylation analysisFetuses with hydrolethalus syndrome |
| Workpackage 3, group 8 | – | Genetic: Methylation analysisFetuses with Meckel/OFD IV syndrome |
| Workpackage 3, group 9 | – | Genetic: Methylation analysisFetuses with Fowler syndrome |
Who may qualify
- Ages
- 0 to 18 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult
- 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.
Key inclusion criteria (15 listed)
- Patient Inclusion Criteria:
- Negative Controls :
- For everyone:
- 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
Key exclusion criteria (2 listed)
- Refusal of postmortem examination in case of fetal loss
- Parents' refusal of molecular investigations
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Methylation analysisGenomic 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. | Genetic | Workpackage 1, group 1, Workpackage 1, group 2, Workpackage 1, group 3, Workpackage 1, group 4, Workpackage 2, group 5, Workpackage 2, group 6, Workpackage 3, group 7, Workpackage 3, group 8, Workpackage 3, group 9 |
Primary outcome
Epigenetic signature associated with pathogenic variations in the CHD7 gene (CHARGE Syndrome)
Time frame: 12 months
Evidence of epigenetic signature from fetal tissue DNA in fetuses with pathogenic or probably pathogenic variation
Epigenetic signature associated with pathogenic variations in the KMT2D gene (KABUKI syndrome)
Time frame: 12 months
Evidence of epigenetic signature from fetal tissue DNA in fetuses with pathogenic or probably pathogenic variation
4 secondary outcomes
Differential methylation between fetal and postnatal epigenetic signature
Time frame: 12 months
Differential methylation between tissue and amniotic fluid epigenetic signatures
Time frame: 12 months
Statistical prediction parameter for each epigenetic signature
Time frame: 12 months
Identification of a new epigenetic signature in foetal pathologies
Time frame: 12 months
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Mar 2026.
- Background: PubMed 28475860Butcher 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.
- Background: PubMed 32109418Aref-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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Manon TESSIER, MD, PhD study director
Assistance Publique - Hôpitaux de Paris
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Rare Fetal Genetic Diseases and Congenital Malformation, run by Assistance Publique - Hôpitaux de Paris at 1 site in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 15 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 27 Mar 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Nicolas BOURGON, MD, PhD (+33 1 42 19 27 96, nicolas.bourgon@aphp.fr), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Epigenetic signature associated with pathogenic variations in the CHD7 gene (CHARGE Syndrome) (time frame: 12 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06475651, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Mar 2026.