Genome sequencing for the diagnosis of intellectual disability as a paradigm for rare diseases in the French healthcare setting: the prospective DEFIDIAG study.
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El Chehadeh Salima, Heide Solveig, Quélin Chloé, Rio Marlène, Margot Henri, Geneviève David, Isidor Bertrand, Goldenberg Alice, Guégan Caroline, Lesca Gaëtan, Willems Marjolaine, Ormières Clothilde, Caumes Roseline, Busa Tiffany, Bonneau Dominique, Guerrot Anne-Marie, Marey Isabelle, Vera Gabriella, Marzin Pauline, Philippe Anaïs, Garde Aurore, Coubes Christine, Vincent Marie, Michaud Vincent, Mignot Cyril, Charles Perrine, Sigaudy Sabine, Edery Patrick, Lacombe Didier, Boland Anne, Nowak Frédérique, Bouctot Marion, Humbert-Asensio Marie-Laure, Simon Alban, Chennen Kirsley, Sabour Niki, Delmas Christelle, Nicolas Gaël, Saugier-Veber Pascale, Lecoquierre François, Cassinari Kévin, Keren Boris, Courtin Thomas, De Sainte Agathe Jean-Madeleine, Malan Valérie, Barcia Giulia, Tran Mau-Them Frédéric, Safraou Hana, Philippe Christophe, Thévenon Julien, Chatron Nicolas, Januel Louis, Piton Amélie, Haushalter Virginie, Gérard Bénédicte, Lejeune Catherine, Faivre Laurence, Sanlaville Damien, Héron Delphine, Odent Sylvie, Nitschké Patrick, Schluth-Bolard Caroline, Lyonnet Stanislas, Deleuze Jean-François, Binquet Christine, Dollfus Hélène, DEFIDIAG study group
Аннотация
METHODS: DEFIDIAG is a national, prospective pilot investigation, carried out in the framework of the French initiative for genomic medicine (Plan France Médecine Génomique 2025), aimed at comparing the diagnostic yield of WGS trio analysis (WGS-trio) (index case, father, mother) with the RefStrategy in real-life conditions of clinical and laboratory workflows. Both strategies were applied in a blinded fashion in 1239 ID probands (50% were already-tested, 50% were never-tested) with no definitive genetic diagnosis. Among them, a subgroup of 187 patients were randomized to undergo WGS-solo (proband only) in addition to WGS-trio and RefStrategy.
RESULTS: Four hundred forty two likely pathogenic/pathogenic single-nucleotide variants were identified (for 231 genes) as well as 171 variants of uncertain significance warranting clinical or functional reassessment for a potential reclassification (VUS +) (for 142 genes), 79 likely pathogenic/pathogenic copy number variants and 10 likely pathogenic/pathogenic structural variants. The diagnostic yield for likely pathogenic/pathogenic variants increased from 17.3% with the RefStrategy to 41.9% with WGS-trio in the never-tested patient cohort. An increase of 13.9% was observed in all categories by adding the VUS + , thus raising the yield to 56% for WGS-trio. Overall, WGS-solo enabled the identification of likely pathogenic/pathogenic variants in 29.9% of cases (increasing to 41.1% when including VUS +) compared to 21.9% with the RefStrategy. In addition, following recent reports of de novo variants in the non-coding spliceosomal RNU4-2 gene as a common cause of ID, this gene was subsequently analyzed, leading to the identification of pathogenic de novo variants in 7 patients.
CONCLUSIONS: As a first line test for ID diagnosis, WGS (including for solo situations) proved to be more effective than the reference strategy, in the context of real-life hospital settings in France.
TRIAL REGISTRATION: Prospectively registered with ClinicalTrials.gov under the identifier NCT04154891 (07/11/2019).