Contribution of Optical Genome Mapping (OGM) in the Diagnosis of Multiple Congenital Malformations With or Without Intellectual Disability Without Genetic Abnormality

NCT07370792 | Recruiting

• 1 other identifier: AOI 2024 PEBREL-RICHARD
• Study Type: interventional
• Target: 55
• Locations: 1 country
• Sites: 1

Brief Summary

Congenital malformations result from an embryonic or foetal developmental disorder (DD) affecting one or more systems (cardiac, skeletal, nervous, etc.). These are referred to as multiple congenital anomalies (MCAs). They may be associated with an intellectual disability (ID)1. Chromosomal analysis on Chromosomal Microarray Analysis (CMA) and gene panels or exome sequencing are the respective gold standard methods for chromosomal and molecular diagnosis of DD respectively2. In cases where no diagnosis is established after these first-line tests, short-read whole genome sequencing (WGS), via the Plan France Medicine Genomic 2020-2025 (AURAGEN), may be considered. This approach allows for diagnosis in nearly 40% of patients with DD3,4. However, many patients remain in diagnostic deadlock, likely due to the technical limitations of these methods, which potentially be overcome by emerging methodologies such as optical genome mapping (OGM)5,6,7,8,9. The investigators propose to systematically perform OGM in 30 patients presenting with MCA+/-ID who have inconclusive WGS result10. The main objective is to assess the contribution of OGM in identifying structural variants not detected or poorly characterised by WGS in this clinical context. This work will also contribute to the ongoing of OGM in routine diagnostics and determine its role in the overall genetic diagnosis of MCA+/-ID. Additionally it may lead to the identification of new candidate genes and/or mechanisms of pathogenicity. If the results are promising, further clinical could expand this preliminary work into a larger-scale project. Improving the genetic diagnosis of DD should enhance the medical management of patients, currently in diagnostic deadlock, and their families.

Conditions

Congenital Malformations

Keywords

multiple congenital anomalies; non-contributive whole-genome sequencing; optical genome mapping; structural variants; genetic diagnosis

Outcome Measures

Primary Outcomes (1)

• diagnostic yield of optical genome mapping (OGM) in multiple congenital anomalies with or without intellectual disability when whole-genome sequencing (WGS) is non-contributive

  Assessing the diagnostic yield of optical genome mapping (OGM) in multiple congenital anomalies with or without intellectual disability when whole-genome sequencing (WGS) is non-contributive (absence of causal genetic variation or detection of a variant of uncertain significance (VUS) or a single variant in a recessive disorder).

  day 1 (inclusion and blood collection)

Secondary Outcomes (7)

• Number of reclassified variants intially considered as VUS (Variants of Uncertain/Unknown Signification)

  day 1 (inclusion and blood collection)

• Number of patients in whom a new candidate gene/pathogenic mechanism is identified

  day 1 (inclusion and blood collection)

• Evaluation of the feasibility (duration) of the technique in current practice in 1st-line, 2nd-line (after routine tests such as chromosomal microarray, exome sequencing…), or 3rd-line in the case of non-contributive WGS based on several criteria

  day 1 (inclusion and blood collection)

• Evaluation of the feasibility of the technique (failure) in current practice in 1st-line, 2nd-line (after routine tests such as chromosomal microarray, exome sequencing…), or 3rd-line in the case of non-contributive WGS based on several criteria

  day 1 (inclusion and blood collection)

• Evaluation of the feasibility of the technique (reprocessing) in current practice in 1st-line, 2nd-line (after routine tests such as chromosomal microarray, exome sequencing…), or 3rd-line in the case of non-contributive WGS based on several criteria

  day 1 (inclusion and blood collection)

Study Arms (1)

single arm of patients with congenital malformations

EXPERIMENTAL

Genetic: blood sample

Interventions

blood sample GENETIC

A blood sample will be collected after obtaining consent from the patient and/or their legal guardians. The number of tubes required (1 to 3) will be determined according to the patient's weight, for the purpose of performing optical genome mapping and any necessary confirmatory analyses in the event that a structural variant is identified.

single arm of patients with congenital malformations

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients presenting with at least two congenital anomalies, with or without intellectual disability, and weighing more than 5 kg.
• Whole-genome sequencing performed by the AURAGEN laboratory deemed non-contributive (absence of class 4 or 5 variants, or identification of a VUS, or identification of only one variant in the context of a recessive disorder).
• Patient covered by a social security scheme.
• Patient able to understand and to oppose participation in the study.
• Written informed consent for genetic analyses, signed either by the patient or by their legal representatives (for minors), after clear and fair information about the study has been provided.
• Patients for whom a non-genetic cause (infectious, environmental, or toxic) has been previously identified.
• Inability to obtain a compliant sample.
• Patient or holder of parental authority under guardianship or legal protection, deprived of liberty, or placed under court-ordered protection.

Sponsors & Collaborators

• Céline PEBREL-RICHARD: lead

Study Sites (1)

CHU clermont-Ferrand

Clermont-Ferrand, France

RECRUITING

MeSH Terms

Conditions

Congenital Abnormalities; Abnormalities, Multiple

Interventions

Blood Specimen Collection

Condition Hierarchy (Ancestors)

Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques

Study Officials

• Lise LACLAUTRE

  University Hospital, Clermont-Ferrand

  STUDY CHAIR

Central Study Contacts

Lise Laclautre

CONTACT

+33473754963; promo_interne_drci@chu-clermontferrand.fr

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Masking Details: Each sample will be pseudonymized as follows: CARTOGEN\ N\[patient number\]-\[initial of last name\]-\[initial of first name\] Example: Pierre MARTIN, 15th enrolled patient → CARTOGEN\ N\[15\]-\[M\]-\[P\]
• Purpose: DIAGNOSTIC
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Dr

Study Record Dates

• First Submitted: December 9, 2025
• First Posted: January 27, 2026
• Study Start: November 18, 2025
• Primary Completion (Estimated): November 1, 2028
• Study Completion (Estimated): November 1, 2028
• Last Updated: January 27, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)