Overview

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.

Eligibility

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