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

NCT06475651 | Recruiting

• 1 other identifier: APHP231311
• Study Type: observational
• Target: 63
• Locations: 1 country
• Sites: 1

Brief 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

Conditions

Rare Fetal Genetic Diseases; Congenital Malformation

Keywords

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

Outcome Measures

Primary Outcomes (2)

• 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

  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

  12 months

Secondary Outcomes (4)

• Differential methylation between fetal and postnatal epigenetic signature

  12 months

• Differential methylation between tissue and amniotic fluid epigenetic signatures

  12 months

• Statistical prediction parameter for each epigenetic signature

  12 months

• Identification of a new epigenetic signature in foetal pathologies

  12 months

Study Arms (9)

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

Methylation analysis GENETIC

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.

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

Eligibility Criteria

• Age: 0 Years - 18 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)
• 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.

You may qualify if:

• 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

You may not qualify if:

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

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead
• URC-CIC Paris Descartes Necker Cochin: collaborator

Study Sites (1)

Department of Genomic Medicine for Rare Diseases and the Multidisciplinary Center for Prenatal Diagnosis of the Necker-Enfants malades Hospital

Paris, 75015, France

RECRUITING

Related Publications (2)

• 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.

  PMID: 28475860 BACKGROUND

• 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.

  PMID: 32109418 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

All the biological tissues required to carry out this pilot study (lung, blood, amniotic fluid and extracted DNA) come from a biological collection already constituted and declared as part of the diagnosis

MeSH Terms

Conditions

Congenital Abnormalities; CHARGE Syndrome; Hydrolethalus Syndrome 1; Kabuki syndrome

Condition Hierarchy (Ancestors)

Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Deaf-Blind Disorders; Deafness; Hearing Loss; Hearing Disorders; Ear Diseases; Otorhinolaryngologic Diseases; Sensation Disorders; Neurologic Manifestations; Nervous System Diseases; Blindness; Vision Disorders; Coloboma; Eye Diseases, Hereditary; Eye Diseases; Abnormalities, Multiple; Genetic Diseases, Inborn; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Officials

• Manon TESSIER, MD, PhD

  Assistance Publique - Hôpitaux de Paris

  STUDY DIRECTOR

Central Study Contacts

Nicolas BOURGON, MD, PhD

CONTACT

+33 1 42 19 27 96; nicolas.bourgon@aphp.fr

Nelly BRIAND, PhD

CONTACT

0144381862; nelly.briand@aphp.fr

Study Design

• Study Type: observational
• Observational Model: OTHER
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 20, 2024
• First Posted: June 26, 2024
• Study Start: February 26, 2026
• Primary Completion (Estimated): August 26, 2026
• Study Completion (Estimated): August 26, 2026
• Last Updated: March 27, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)