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  • Multiple molecular diagnoses in the field of intellectual disability and congenital anomalies: 3.5% of all positive cases

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Diagnostics
Original research
Multiple molecular diagnoses in the field of intellectual disability and congenital anomalies: 3.5% of all positive cases
  1. Caroline Racine1,2,
  2. Anne-Sophie Denommé-Pichon2,3,
  3. Camille Engel2,
  4. Frederic Tran Mau-them2,3,
  5. Ange-Line Bruel2,3,
  6. Antonio Vitobello2,3,
  7. Hana Safraou2,3,
  8. Arthur Sorlin1,2,
  9. Sophie Nambot1,3,
  10. Julian Delanne1,
  11. Aurore Garde1,
  12. Estelle Colin1,2,
  13. Sébastien Moutton1,
  14. Julien Thevenon1,
  15. Nolwenn Jean-Marçais1,
  16. Marjolaine Willems4,
  17. David Geneviève4,5,
  18. Lucile Pinson4,
  19. Laurence Perrin6,
  20. Fanny Laffargue7,
  21. James Lespinasse8,
  22. Elodie Lacaze9,
  23. Arnaud Molin10,
  24. Marion Gerard10,
  25. Laetitia Lambert11,
  26. Charlotte Benigni11,
  27. Olivier Patat12,
  28. Orphanomix Physician's Group,
  29. Valentin Bourgeois2,3,
  30. Charlotte Poe2,3,
  31. Martin Chevarin2,3,
  32. Victor Couturier2,3,
  33. Philippine Garret2,3,
  34. Christophe Philippe2,3,
  35. Yannis Duffourd2,3,
  36. Laurence Faivre1,3,
  37. Christel Thauvin-Robinet1,3
    1. 1 Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l’interrégion Est et FHU TRANSLAD, Centre Hospitalier Universitaire de Dijon Centre de Genetique, Dijon, France
    2. 2 Functional Unity of Innovative Diagnosis for Rare Diseases, University of Burgundy, Dijon, France
    3. 3 Inserm UMR1231 team GAD, University of Burgundy, Dijon, France
    4. 4 Centre de Référence "Anomalies du Développement syndromes malformatifs" Occitanie, Service de Génétique Médicale, Hôpital Arnaud de Villeneuve, Montpellier, France
    5. 5 INSERM U1183, Université de Montpellier, Montpellier, France
    6. 6 Genetic Department, Robert-Debré Hospital Department of Genetics, Paris, France
    7. 7 Service de Génétique médicale, CHU Clermont-Ferrand, Clermont-Ferrand, France
    8. 8 Unité de Génétique médicale, Centre Hospitalier Métropole Savoie, Chambery, France
    9. 9 Department of Medical Genetics, Hospital Group Le Havre, Le Havre, France
    10. 10 Service de Génétique, University Hospital Centre Caen, Caen, France
    11. 11 Service de Génétique Clinique, CHRU de Nancy, Nancy, France
    12. 12 Department of Medical Genetics, University Hospital Centre Toulouse, Toulouse, France
    1. Correspondence to Dr Caroline Racine, Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l’interrégion Est et FHU TRANSLAD, Centre Hospitalier Universitaire de Dijon Centre de Genetique, Dijon, France; caroline.racine{at}chu-dijon.fr

    Abstract

    Purpose Wide access to clinical exome/genome sequencing (ES/GS) enables the identification of multiple molecular diagnoses (MMDs), being a long-standing but underestimated concept, defined by two or more causal loci implicated in the phenotype of an individual with a rare disease. Only few series report MMDs rates (1.8% to 7.1%). This study highlights the increasing role of MMDs in a large cohort of individuals addressed for congenital anomalies/intellectual disability (CA/ID).

    Methods From 2014 to 2021, our diagnostic laboratory rendered 880/2658 positive ES diagnoses for CA/ID aetiology. Exhaustive search on MMDs from ES data was performed prospectively (January 2019 to December 2021) and retrospectively (March 2014 to December 2018).

    Results MMDs were identified in 31/880 individuals (3.5%), responsible for distinct (9/31) or overlapping (22/31) phenotypes, and potential MMDs in 39/880 additional individuals (4.4%).

    Conclusion MMDs are frequent in CA/ID and remain a strong challenge. Reanalysis of positive ES data appears essential when phenotypes are partially explained by the initial diagnosis or atypically enriched overtime. Up-to-date clinical data, clinical expertise from the referring physician, strong interactions between clinicians and biologists, and increasing gene discoveries and improved ES bioinformatics tools appear all the more fundamental to enhance chances of identifying MMDs. It is essential to provide appropriate patient care and genetic counselling.

    • Genetics
    • Genetic Variation

    Data availability statement

    Data are available upon reasonable request. Data that support the findings of this study, both clinical and molecular, are available from the corresponding author upon reasonable request.

    https://doi.org/10.1136/jmg-2023-109170

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      Data availability statement

      Data are available upon reasonable request. Data that support the findings of this study, both clinical and molecular, are available from the corresponding author upon reasonable request.

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      Footnotes

      • Collaborators Orphanomix Physician’s Group: Alain Verloes, Alice Goldenberg, Alice Masurel, Aline Vincent, Anne-Marie Frances-Guidet, Aude Tessier, Audrey Putoux, Béatrice Laudier, Bénédicte Demeer, Benoit Funalot, Bérénice Doray, Brigitte Gilbert-Dussardier, Bruno Leheup, Céline Poirsier, Charlotte Dubucs, Christine Chiaverini, Christine Coubes, Christine Francannet, Cindy Colson, Claire Bansept, Constance Wells, Cyril Goizet, Cyril Mignot, Daniel Amram, Daniel Amsallem, Didier Lacombe, Dominique Martin-Coignard, Elise Schaefer, Fabienne Guiliano, Fabienne Prieur, Florence Petit, Florence Riccardi, Francesca Meloni, François Feillet, Gwenael Le Guyader, Hubert Journel, Isabelle Coupier, Isabelle Maystadt, Jean-Luc Alessandri, Lyse Ruaud, Marie-Line Jacquemont, Marie Noëlle Bonnet-Dupeyron, Marine Lebrun, Marta Spodenkiewicz, Martine Doco-Fenzy, Mathilde Renaud, Maude Grelet, Nicolas Chassaing, Nicole Philip, Odile Boute, Pascal Pujol, Patricia Blanchet, Philippe Khau Van Kien, Philippe Parent, Pierre Vabres, Renaud Touraine, Rodolphe Dard, Roseline Caumes, Sabine Sigaudy, Sandra Whalen, Sandrine Passemard, Sarah Grotto, Séverine Audebert Bellanger, Sophie Julia, Thierry Lavabre Bertrand, Tiffany Busa, Valérie Layet, Varoona Bizaoui, Yaumara Perdomo Trujillo, Yline Capri.

      • Contributors Conceptualisation: CR, LF, CT-R; data curation: all authors; formal analysis: CR, A-SD-P, YD; methodology: CR, LF, CT-R; visualisation: CR, A-SD-P, LF, CT-R; writing-original draft: CR, CT-R; writing-review and editing: all authors except OPG; guarantor: CT-R.

      • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

      • Competing interests None declared.

      • Provenance and peer review Not commissioned; externally peer reviewed.

      • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.