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Background <p>Intellectual disability (ID) is the leading cause of patient referral to medical genetic departments in French academic hospitals. Whole genome sequencing (WGS) as a first diagnostic approach is expected to achieve a higher diagnostic yield than the French national reference strategies (RefStrategy) (fragile X expansion testing, chromosomal microarray analysis, and 44 ID genes panel), given its broad and more homogeneous coverage, its ability to identify copy number, structural and intergenic/deep intronic events.</p> Methods <p>DEFIDIAG is a national, prospective pilot investigation, carried out in the framework of the French initiative for genomic medicine (<i>Plan France Médecine Génomique 2025</i>), 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.</p> Results <p>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 <i>RNU4-2</i> gene as a common cause of ID, this gene was subsequently analyzed, leading to the identification of pathogenic de novo variants in 7 patients.</p> Conclusions <p>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.</p> Trial registration <p>Prospectively registered with ClinicalTrials.gov under the identifier NCT04154891 (07/11/2019).</p>

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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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  • 发表日期：

    2025年10月3日

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  • Salima El Chehadeh,
  • Solveig Heide,
  • Chloé Quélin,
  • Marlène Rio,
  • Henri Margot,
  • David Geneviève,
  • Bertrand Isidor,
  • Alice Goldenberg,
  • Caroline Guégan,
  • Gaëtan Lesca,
  • Marjolaine Willems,
  • Clothilde Ormières,
  • Roseline Caumes,
  • Tiffany Busa,
  • Dominique Bonneau,
  • Anne-Marie Guerrot,
  • Isabelle Marey,
  • Gabriella Vera,
  • Pauline Marzin,
  • Anaïs Philippe,
  • Aurore Garde,
  • Christine Coubes,
  • Marie Vincent,
  • Vincent Michaud,
  • Cyril Mignot,
  • Perrine Charles,
  • Sabine Sigaudy,
  • Patrick Edery,
  • Didier Lacombe,
  • Anne Boland,
  • Frédérique Nowak,
  • Marion Bouctot,
  • Marie-Laure Humbert-Asensio,
  • Alban Simon,
  • Kirsley Chennen,
  • Niki Sabour,
  • Christelle Delmas,
  • Gaël Nicolas,
  • Pascale Saugier-Veber,
  • François Lecoquierre,
  • Kévin Cassinari,
  • Boris Keren,
  • Thomas Courtin,
  • Jean-Madeleine De Sainte Agathe,
  • Valérie Malan,
  • Giulia Barcia,
  • Frédéric Tran Mau-Them,
  • Hana Safraou,
  • Christophe Philippe,
  • Julien Thévenon,
  • Nicolas Chatron,
  • Louis Januel,
  • Amélie Piton,
  • Virginie Haushalter,
  • Bénédicte Gérard,
  • Catherine Lejeune,
  • Laurence Faivre,
  • Damien Sanlaville,
  • Delphine Héron,
  • Sylvie Odent,
  • Patrick Nitschké,
  • Caroline Schluth-Bolard,
  • Stanislas Lyonnet,
  • Jean-François Deleuze,
  • Christine Binquet,
  • Hélène Dollfus,
  • Magalie Barth,
  • Estelle Colin,
  • Yosra Halleb,
  • Clara Houdayer,
  • Clément Prouteau,
  • Marine Tessarech,
  • Alban Ziegler,
  • Chloé Angelini,
  • Marie-Pierre Baudier,
  • Meryem Britel,
  • Noémie Bronnec,
  • Clémence Deiber,
  • Virginie Dorian,
  • Juliette Gaudry,
  • Cyril Goizet,
  • Nawel Hairech,
  • Ouidad Hasnaoui,
  • Manon Laurent,
  • Marine Legendre,
  • Sophie Naudion,
  • Ndeye-Fatou Ngom,
  • Caroline Rooryck Thambo,
  • Julien Van Gils,
  • Cécile Zordan,
  • Myriam Borel,
  • Anne-Sophie Briffaut,
  • Charley Robert Viard,
  • Delphine Bacq-Daian,
  • Celine Besse,
  • Bertrand Fin,
  • Vincent Meyer,
  • Marie-Laure Moutet,
  • Robert Olaso,
  • Florian Sandron,
  • Violette Turon,
  • Celine Bernard,
  • Marie Bournez,
  • Ange-Line Bruel,
  • Eleonore Viora-Dupont,
  • Julian Delanne,
  • Anne-Sophie Denommé-Pichon,
  • Yannis Duffourd,
  • Romain Duquet,
  • Aurelie Espitalier,
  • Clemence Fauconnier-Fatus,
  • Sophie Nambot,
  • Aurore Petiot,
  • Victor Pillay,
  • Charlotte Poe,
  • Melodie Soto,
  • Christel Thauvin,
  • Mylene Tharreau,
  • Antonio Vitobello,
  • Marjolaine Gauthier,
  • Marie-Ange Nguyen Morel,
  • Frederique Nugues,
  • Antoine Wyrebski,
  • Klaus Dieterich,
  • Pauline Le Tanno,
  • Laurence Bellengier,
  • Odile Boute,
  • Cindy Colson,
  • Anne Dieux,
  • Jamal Ghoumid,
  • Luisa Marsili,
  • Florence Petit,
  • Coralie Rubeck,
  • Clemence Vanlerberghe,
  • Catherine Vincent-Delorme,
  • Christelle Rougeot-Jung,
  • Aurore Curie,
  • Vincent des Portes,
  • Sylvie Goutte,
  • Damien Haye,
  • Audrey Labalme,
  • Pauline Monin,
  • Marianne Till,
  • Thibaud Armand,
  • Julie Reversat,
  • Françoise Robert,
  • Amelie Berthiot,
  • Marion Colard,
  • Lamia El Amrani-El Idrissi,
  • Tiphaine Francois,
  • Haymanot George,
  • Manel Saidi,
  • Karima Rendja,
  • Iracema Triguel,
  • Claire Bardel,
  • Pierre Antoine Rollat-Farnier,
  • Audrey Putoux,
  • Massimiliano Rossi,
  • Linda Pons,
  • Emilie Consolino,
  • Olga Glazunova,
  • Audrey Mallet,
  • Nicole Philip-Sarles,
  • Florence Riccardi,
  • Valerie Seror,
  • Severine Beltram,
  • Florent Cerret,
  • Laura Crantelle,
  • Mirna Khalil,
  • Patricia Blanchet,
  • Caroline Deiller,
  • Emmanuelle Haquet,
  • Lucile Pinson,
  • Constance Wells,
  • Francis Guillemin,
  • Solene Conrad,
  • Laura Guyon,
  • Sandra Mercier,
  • Mathilde Nizon,
  • Annastasia Voisine,
  • Kahina Abdallah,
  • Jeanne Amiel,
  • Genevieve Baujat,
  • Wiam Bhia,
  • Jean-Paul Bonnefont,
  • Valerie Cormier-Daire,
  • Narimene De Nadai,
  • Valeria Florentino,
  • Kelly Gouvenot,
  • Anne Guimier,
  • Hamza Hadj Abdallah,
  • Jerome Jeannette,
  • Sandrine Marlin,
  • Cecile Masson,
  • Caroline Michot,
  • Lea Peroni,
  • Serge Romana,
  • Alexandra Afenjar,
  • Lydie Burglen,
  • Sandra Whalen,
  • Julien Buratti,
  • Eric Leguern,
  • Anne Faudet,
  • Anna Gerasimenko,
  • Caroline Moukossi-Mouelle,
  • Linda Mouthon,
  • Anne-Sophie Pellen,
  • Stephanie Staraci,
  • Daphne Lehalle,
  • Helene Esperou,
  • Soizic Le Mestre,
  • Claire Levy-Marchal,
  • Wilfrid Carre,
  • Marie De Tayrac,
  • Christele Dubourg,
  • Chloé Fournier,
  • Linda Akloul,
  • Melanie Fradin,
  • Nolwenn Jean-Marcais,
  • Alinoë Lavillaureix,
  • Godelieve Morel,
  • Laurent Pasquier,
  • Elisabeth Poirel,
  • Audrey Riou,
  • Paul Rollier,
  • Anne-Claire Brehin,
  • Pascal Chambon,
  • Delphine Gonde,
  • Geraldine Joly-Helas,
  • Nadege Calmels,
  • Celine Cuny,
  • Claire Feger,
  • Benjamin Durand,
  • Nathalie Goetz,
  • Pierre-Yves Maillard,
  • Sophie Monduc,
  • Elise Schaefer,
  • Sophie Scheidecker,
  • Jean Muller,
  • Amelie Piton

摘要

Background

Intellectual disability (ID) is the leading cause of patient referral to medical genetic departments in French academic hospitals. Whole genome sequencing (WGS) as a first diagnostic approach is expected to achieve a higher diagnostic yield than the French national reference strategies (RefStrategy) (fragile X expansion testing, chromosomal microarray analysis, and 44 ID genes panel), given its broad and more homogeneous coverage, its ability to identify copy number, structural and intergenic/deep intronic events.

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).