The Diagnostic Observatory: Combating Diagnostic Wandering and Impasse Within the AnDDI-Rares Network

Recruiting

• Conditions: Developmental Abnormality
• Interventions: Other: Questionnaire to assess expectations of a diagnosis; Biological: Blood sample +/- skin biopsy; Other: Questionnaire to assess understanding of previously reported results and expectations of a diagnosis

• Registration Number: NCT05448326
• Lead Sponsor: Centre Hospitalier Universitaire Dijon

Brief Summary

The Direction Générale de l'Organisation des Soins (DGOS) and the Banque Nationale de Données Maladies Rares (BNDMR) have launched a call for a letter of commitment for the implementation of a diagnostic observatory in order to fight against diagnostic wandering and impasse. In this context, the AnDDI-Rares network proposes 3 work packages (WP) to respond to the missions entrusted to it.

Work package 1 of the diagnostic observatory includes a retrospective and prospective study to evaluate how diagnostic wandering and impasse has evolved within the network, with regard to the integration of new technologies, and the expectations of patients and their families.

Work package 2 of the diagnostic observatory includes a reassessment of sporadic copy number variations (CNV) of unknown significance of more than 1 Mb obtained since the beginning of CGH array analyses in the territory.

Work package 3 of the diagnostic observatory aims to help put an end to diagnostic wandering for patients with certain emblematic syndromes by proposing genome and RNA analysis, which provides a certain diagnosis and negative targeted molecular study.

Detailed Description

Not available

Study Timeline

• Study Start: 2022-03-28
• Study First Submitted: 2022-06-01
• Study First Submitted QC: 2022-07-04
• Study First Posted: 2022-07-07
• Status Verified: 2025-04
• Last Update Submitted: 2025-04-04
• Last Update Posted: 2025-04-08
• Primary Completion: 2027-03
• Study Completion: 2027-03

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 1280

Inclusion Criteria

WP1:

• Children or adult patients who did not obtain a diagnosis after consulting for a developmental abnormality (that may include isolated or multiple, minor or major malformations, facial dysmorphia associated or not with learning disabilities and/or intellectual disability). These patients had a diagnostic evaluation over the 2 weeks randomly drawn from 2012 and 2022.

Patients agreeing to resume a diagnostic approach requiring new blood samples. For genome sequencing through the platforms of the France Genomic Medicine Plan, when they correspond to the criteria of existing preindications, the parents' sample will be proposed.

• Patients (adults or their parents) affiliated to national health insurance or beneficiaries of such a system

WP2:

For the identification of patients eligible for reanalysis (Part 1 Lab) :

• Patients, children or adults with developmental anomalies with or without neurodevelopmental disorders,
• Patients in whim a de novo CNV of unknown significance of more than 1 Mb has been detected since the implementation of the CGH array platforms
• The CNV remained of unknown significance or classified as (probably) benign after reanalysis* *reanalysis other than that performed in the context of the diagnostic observatory

For reanalysis, in addition to the previous inclusion criteria (Part 2 Clinical):

• CNV remained of unknown significance or classified as (probably) benign after reanalysis**
• Patients and/or their parents agreeing to resume diagnostic testing
• Patients (adults or their parents) affiliated to national health insurance or beneficiaries of such a system ** After reanalysis in the framework of the diagnostic observatory

WP3:

• Patients (children or adults) with a syndrome that corresponds to the study criteria:
• Established clinical diagnosis for one of the characteristic syndromes of the AnDDI-Rares pipeline (list may be revised in the future): Noonan syndrome, CHARGE syndrome, Kabuki syndrome, Cornelia de Lange syndrome, Rubinstein-Taybi syndrome ;
• Known gene(s) but patient's molecular diagnosis is negative.
• Patients and their parents agreeing to a new blood sample for genome ± RNA sequencing and/or skin biopsy for conditions where gene transcription is not satisfactory from RNA extracted from blood; or agreeing to perform these analyses from previously stored samples;
• Parents of legal age who are affiliated with national health insurance or who are beneficiaries of such a system;
• Signed informed consent from both biological parents and/or the index case if they are of legal age;
• Ability of both biological parents to understand correctly.

Exclusion Criteria

WP1:

• Patients without a developmental abnormality ;
• Patients with a previously identified diagnosis at the time of consultations on the weeks drawn randomly from 2012 and 2022.

WP3:

• Unlikely clinical diagnosis ;
• Family not wishing to pursue molecular investigations;
• Index case having already benefited from the investigations through another research project.
• The parents of the index case are under court protection ;
• Families where one of the 2 parental authority holders is not a biological parent

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Work package 1 (WP1)	Questionnaire to assess expectations of a diagnosis	Patients without a diagnosis who consulted for a developmental anomaly in 2012 and 2022 and agree to resume a diagnostic approach
Work package 3 (WP3)	Blood sample +/- skin biopsy	Patients with an established clinical diagnosis belonging to the characteristic syndromes of the AnDDI-Rares network (known gene(s) but negative molecular diagnosis)
Work package 2 (WP2)	Questionnaire to assess understanding of previously reported results and expectations of a diagnosis	Part 1 (Lab): Patients with developmental abnormalities with or without neurodevelopmental disorders who have had a CNV (Copy Number Variation) rendering that remained of unknown significance or classified as (probably) benign Part 2 (Clinical part): Patients who agree to resume the diagnostic process following a CNV report of unknown significance or classified as (probably) benign

Primary Outcome Measures

Name	Time	Method
CNVs reclassified as pathogenic/probably pathogenic or benign/probably benign.	through study completion, an average of 24 months
Molecular diagnosis identified by sequencing of the genome ± associated RNA.	through study completion, an average of 36 months
Consultations leading to a causal genetic diagnosis in 2012 and 2022	through study completion, an average of 24 months

Trial Locations

Locations (1)

Chu Dijon Bourogne; 🇫🇷 Dijon, France