Genome Sequencing for Genetics Diagnosis of Patients With Intellectual Disability: The DEFIDIAG Study

Abstract

Introduction: Intellectual Disability (ID) is the most common cause of referral to pediatric genetic centers, as it affects around 1-3% of the general population and is characterized by a wide genetic heterogeneity. The Genome Sequencing (GS) approach is expected to achieve a higher diagnostic yield than exome sequencing given its wider and more homogenous coverage, and, since theoretically, it can more accurately detect variations in regions traditionally not well captured and identify structural variants, or intergenic/deep intronic putatively pathological events. The decreasing cost of sequencing, the progress in data-management and bioinformatics, prompted us to assess GS efficiency as the first line procedure to identify the molecular diagnosis in patients without obvious ID etiology. This work is being carried out in the framework of the national French initiative for genomic medicine (Plan France Médecine Génomique 2025). Methods and Analysis: This multidisciplinary, prospective diagnostic study will compare the diagnostic yield of GS trio analysis (index case, father, mother) with the French core minimal reference strategy (Fragile-X testing, chromosomal microarray analysis and Gene Panel Strategy of 44 selected ID genes). Both strategies are applied in a blinded fashion, in parallel, in the same population of 1275 ID index cases with no obvious diagnosis (50% not previously investigated). Among them, a subgroup of 196 patients are randomized to undergo GS proband analysis in addition to GS trio analysis plus the French core minimal reference strategy, in order to compare their efficiency. The study also aims to identify the most appropriate strategy according to the clinical presentation of the patients, to evaluate the impact of deployment of GS on the families' diagnostic odyssey and the modification of their care, and to identify the advantages/difficulties for the patients and their families. Ethics Statement: The protocol was approved by the Ethics Committee Sud Méditerranée I and the French data privacy commission (CNIL, authorization 919361). Trial Registration: ClinicalTrials.gov identifier NCT04154891 (07/11/2019).

Keywords: cost-effectiveness; diagnostic odyssey; genome sequencing; intellectual disability; minimal reference strategy.

FIGURE 1

Impact study procedures and schedule (DEFIDIAG study). The figure represents the key timepoints for patient visits in the inclusion centers (inclusion in the study, delivery of results, 12-months post-delivery visit), which also correspond to the time of the interviews between either a sociology or psychology researcher and the parents/patients who agreed to participate in the qualitative impact study. The figure also shows the three periods considered for cost estimation (period 1: before inclusion; period 2: waiting for results; period 3: during the 12 months following the results) and, for each of these periods, the different elements collected from the care teams and families in order to have the examinations carried out (for the three periods) and those envisaged with each of the strategies to confirm the diagnosis (period 2).

FIGURE 2

Sample flow description (DEFIDIAG study). C: Clinical centers; L: Reference laboratory (highlighted in light yellow) and Mirror Laboratory (highlighted in dark yellow); MDM: MultiDisciplinary meeting; CNRGH: Centre National de Recherche en Génomique Humaine (National Centre for Human Genomic Research). Each clinical center (C, numbered 1–12) is affiliated to one reference laboratory (numbered 1–6) in charge of the analysis of trio-genome sequencing—GST; each laboratory (L) is affiliated to 2 clinical recruitment centers as a reference laboratory (for example: L1 will be the reference laboratory for patients from C1 and C2) and will work in pairs with another laboratory (mirror laboratories), in charge of ID44 and of the analysis of solo-genome sequencing (GSS) for patients randomized in the appropriate sub-group. This mirror laboratory is itself affiliated with two other recruitment centers (for example: L1 will be the mirror laboratory for patients from C3 and C4). The 4 clinical centers organize the multidisciplinary meeting (MDM) together with their 2 official laboratories.