A Study of Multilocus Methylation Abnormalities in Subjects With Imprinting Disorders (ImprintiNG)

Imprinting disorders may be caused by epimutations. Some subjects exhibit methylation abnormalities in several regions subject to imprinting, a condition known as multilocus imprinting disorder (MLID). The prevalence of MLID is unknown, due to variations in the methodologies used (including technique employed and number of regions studied). The phenotypic consequences of MLID are also poorly understood. Studying the methylation of all the imprinted regions would make it possible to determine the prevalence of MLID as well as its clinical consequences.

Study Overview

• Status: Not yet recruiting
• Conditions: Molecular Diagnosis; Imprinting Disorder; MLID; Multi-locus Imprinting Disturbance; Differentially Methylated Regions
• Intervention / Treatment: Other: Methylation study

Detailed Description

Imprinting disorders may be secondary to various molecular mechanisms, including "epimutations", i.e. aberrant methylation levels (gain or loss of methylation) at the level of the ICRs. The 11p15 region in humans contains two genes essential for controlling foetal growth: IGF2, expressed from the paternal allele, and whose expression is controlled by an imprinting centre called H19/IGF2: IG-DMR (or ICR1), methylated on the paternal allele; and CDKN1C, expressed from the maternal allele, and whose expression is controlled by a second imprinting centre called KCNQ1OT1:TSS-DMR (or ICR2), methylated on the maternal allele. (Eggermann et al, 2023) Among the diseases linked to parental imprinting, Beckwith Wiedemann syndrome (BWS, prevalence 1/13,500) is an overgrowth syndrome that, in particular, predisposes to the appearance of embryonic tumours during the first years of life. 80% of subjects with BWS have an alteration in the 11p15 region, which may be a loss of ICR2 methylation (around 50%) or a gain of ICR1 methylation (5 to 10%). (Brioude et al, 2018) Silver Russell syndrome (SRS, prevalence 1/50,000) is a syndrome of fetal and postnatal growth restriction, with preservation of head circumference, severe feeding difficulties and early metabolic complications. Approximately 50% of subjects with SRS have a loss of ICR1 methylation in the 11p15 region. (Wakeling et al, 2017). Temple syndrome (TS14) is a fetal and postnatal growth restriction syndrome similar to SRS with neonatal hypotonia, and associated with a risk of early puberty and obesity. This syndrome is usually caused by abnormalities of the 14q32 region at the MEG3/DLK1 locus which is also imprinted (maternal uniparental disomy, paternal deletion or loss of methylation of the MEG3/DLK1:IG-DMR). (Geoffron et al, 2017) For several years now, it has been shown that some subjects with a methylation anomaly at one locus may have methylation anomalies at other regions subject to parental imprinting. This condition is known as multilocus imprinting disorder (MLID). The prevalence of this multilocus disorder is not precisely known, because the methodologies used vary in terms of the technique used and the number of DMRs studied. In some subjects, symptoms of different diseases linked to these different regions may be present. However, little is currently known about the phenotypic consequences of these multilocus disorders. Finally, although most methylation anomalies occur sporadically, a few familial forms of methylation anomalies have been reported, with the common feature of recurrent miscarriages and the presence of multilocus disease in affected subjects. These familial forms have been associated with the presence in the mother of pathogenic variations in the genes encoding factors in the SCMC (subcortical maternal complex). Among other things, these factors are involved in oocyte maturation and the regulation of epigenetic marks after fertilisation and during the first cell divisions. (MacKay et al, 2024)

• Study Type: Interventional
• Enrollment (Estimated): 96
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Marie-Pierre LUTON, PhD; Phone Number: +33(0) 1 87 89 26 00; Email: mariepierre.luton@aphp.fr
• Study Contact Backup: Name: Frédéric BRIOUDE, MD, PhD; Phone Number: 00 33 1 44 73 66 31; Email: frederic.brioude@aphp.fr

Study Locations

• France
  • Paris, France, 75012
    • Molecular Endocrinology and Imprinting disorder department - Trousseau Hospital
    • Contact: Marie-Pierre LUTON, PhD; Phone Number: +33(0) 1 87 89 26 00; Email: mariepierre.luton@aphp.fr
    • Contact: Frédéric BRIOUDE, MD, PhD; Email: frederic.brioude@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. "Negative control" population: subjects who have undergone genetic exploration and:

   • Having had a study of normal methylation of the 11p15 region (H19/IGF2: IG-DMR and KCNQ1OT1:TSS-DMR) by the reference technique.
   • And having had a sequencing study of one or more genes involved in a growth pathology (Sanger sequencing and/or NGS analysis) and having concluded in the presence of a pathogenic variant responsible for the pathology.

   OR

   Study population:

   - subjects who had undergone a reference genetic investigation (ASMM-RTqPCR) and for whom the final diagnosis was: gain or loss of methylation at the H19/IGF2:IG-DMR locus (BWS,SRS), at the KCNQ1OT1:TSS-DMR locus (BWS) or at the DLK1/MEG3:IG-DMR locus (TS14).

2. Affiliation with a social security scheme or beneficiary (excluding AME).
3. Signature of the consent form by the subject's parents or guardians, or the subject if of age at the time of the study.

Exclusion Criteria:

• Inability of either the subject (if over 18) or the parents or holder of parental authority to receive informed information about the protocol.
• Subject (if over 18) or parent or holder of parental authority deprived of their liberty by judicial or administrative decision

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Negative control group; Control subjects from the DNA bank, subjects with normal methylation analysis using the reference technique, for whom the final diagnosis is a genetic rather than an epigenetic cause. This population will allow the establishment of normal reference values for the methylation index for each DMR studied using the newly developed technique.
Experimental: Study population; Subjects with a methylation anomaly in a previously identified imprinted region using the reference technique	Other: Methylation study; Methylation study by high-throughput sequencing technique after enzymatic DNA treatment and DMR capture

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To validate the ability of a new technique (ImprintCap) to detect abnormal methylation levels from a population for which a methylation anomaly has been detected at a region by the reference technique.	Methylation index reference values for each DMR will be established from the 24 negative control subjects.	30 month (end of the study)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To determine the proportion (%) of subjects with multilocus disease in the study population.	In the study population, the methylation indices of each DMR determined by the MethylCap technique will be compared with reference values: multilocus disease will be defined by the presence of a methylation index greater than +3 SDS (methylation gain) or less than -3 SDS (methylation loss) at least one other DMR compared with the established reference values.	30 month (end of the study)
To compare the phenotypic data (clinical and/or biological) collected during the usual follow-up consultations in the population of subjects with or without multilocus disease.	Association between the clinical and biological data of the study population according to the presence or absence of multilocus disease.	30 month (end of the study)

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Frédéric Brioude, MD, PhD, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2026
• Primary Completion (Estimated): October 1, 2028
• Study Completion (Estimated): October 1, 2028

Study Registration Dates

• First Submitted: March 23, 2026
• First Submitted That Met QC Criteria: March 23, 2026
• First Posted (Actual): March 27, 2026

Study Record Updates

• Last Update Posted (Actual): March 27, 2026
• Last Update Submitted That Met QC Criteria: March 23, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: DMR; Molecular diagnosis; Imprinting disorder; MLID; Multi-locus imprinting disturbance; Differentially methylated regions
• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Imprinting Disorders
• Other Study ID Numbers: APHP251316; IDRCB 2025-A01991-48 (Other Identifier: ANSM)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No