Topological data analysis reveals genotype-phenotype relationships in primary ciliary dyskinesia

Autor: Matthew S. Edwards, Deborah J. Morris-Rosendahl, Robert Wilson, Guillaume Thouvenin, Siobhán B. Carr, Claire Hogg, Amelia Shoemark, Mary P. Carroll, Bruna Rubbo, Eric G. Haarman, Bernard Maitre, Estelle Escudier, Gregory Jouvion, Mahmood R. Fassad, Marie Legendre, Michel R. Loebinger, Gunnar E. Carlsson, Camille Parsons, Irma C.M. Bon, Pierre-Régis Burgel, Sunayna Best, Joost Brandsma, Isabelle Honoré, David Hunt, Jean-François Papon, Woolf T. Walker, Hannah M. Mitchison, Jane S. Lucas, Simon N. Thomas, Mitali P. Patel
Přispěvatelé: Pediatric surgery, Amsterdam Reproduction & Development (AR&D), Royal Brompton and Harefield NHS Foundation Trust, University of Dundee, University of Southampton, Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), UF de Génétique moléculaire [CHU Trousseau], CHU Trousseau [APHP], Great Ormond Street Institute of Child Health (UCL), University College of London [London] (UCL), Université Senghor [Alexandria], Amsterdam UMC - Amsterdam University Medical Center, University of Leeds, Service de pneumologie [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Department of Mathematics [Stanford], Stanford University, National Heart and Lung Institute [London] (NHLI), Imperial College London-Royal Brompton and Harefield NHS Foundation Trust, Service de Pneumologie [CHI Créteil], CHI Créteil, Molecular virology and immunology – Physiopathology and therapeutic of chronic viral hepatitis (Team 18) (Inserm U955), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d’ORL et de chirurgie cervico-faciale [CHU Le Kremlin-Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Faculté de Médecine Paris-Saclay, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Université Paris-Saclay, Biomécanique cellulaire et respiratoire (BCR), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), IMRB - 'Biomechanics and Respiratory Apparatus' [Créteil] (U955 Inserm - UPEC), Service de Pneumologie pédiatrique [CHU Trousseau], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), NIHR Biomedical Research Centre [London], Guy's and St Thomas' NHS Foundation Trust-King‘s College London, University Hospital Southampton NHS Foundation Trust, Couvet, Sandrine
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: The European respiratory journal, 58(2):2002359. European Respiratory Society
European Respiratory Journal
European Respiratory Journal, 2021, 58 (2), pp.2002359. ⟨10.1183/13993003.02359-2020⟩
Shoemark, A, Rubbo, B, Legendre, M, Fassad, M R, Haarman, E G, Best, S, Bon, I C M, Brandsma, J, Burgel, P-R, Carlsson, G, Carr, S B, Carroll, M, Edwards, M, Escudier, E, Honoré, I, Hunt, D, Jouvion, G, Loebinger, M R, Maitre, B, Morris-Rosendahl, D, Papon, J-F, Parsons, C M, Patel, M P, Thomas, N S, Thouvenin, G, Walker, W T, Wilson, R, Hogg, C, Mitchison, H M & Lucas, J S 2021, ' Topological data analysis reveals genotype-phenotype relationships in primary ciliary dyskinesia ', The European respiratory journal, vol. 58, no. 2, 2002359 . https://doi.org/10.1183/13993003.02359-2020
European Respiratory Journal, European Respiratory Society, 2021, 58 (2), pp.2002359. ⟨10.1183/13993003.02359-2020⟩
ISSN: 0903-1936
1399-3003
Popis: BackgroundPrimary ciliary dyskinesia (PCD) is a heterogeneous inherited disorder caused by mutations in approximately 50 cilia-related genes. PCD genotype–phenotype relationships have mostly arisen from small case series because existing statistical approaches to investigating relationships have been unsuitable for rare diseases.MethodsWe applied a topological data analysis (TDA) approach to investigate genotype–phenotype relationships in PCD. Data from separate training and validation cohorts included 396 genetically defined individuals carrying pathogenic variants in PCD genes. To develop the TDA models, 12 clinical and diagnostic variables were included. TDA-driven hypotheses were subsequently tested using traditional statistics.ResultsDisease severity at diagnosis, measured by forced expiratory volume in 1 s (FEV1) z-score, was significantly worse in individuals with CCDC39 mutations (compared to other gene mutations) and better in those with DNAH11 mutations; the latter also reported less neonatal respiratory distress. Patients without neonatal respiratory distress had better preserved FEV1 at diagnosis. Individuals with DNAH5 mutations were phenotypically diverse. Cilia ultrastructure and beat pattern defects correlated closely to specific causative gene groups, confirming these tests can be used to support a genetic diagnosis.ConclusionsThis large scale, multi-national study presents PCD as a syndrome with overlapping symptoms and variations in phenotype according to genotype. TDA modelling confirmed genotype–phenotype relationships reported by smaller studies (e.g. FEV1 worse with CCDC39 mutation) and identified new relationships, including FEV1 preservation with DNAH11 mutations and diversity of severity with DNAH5 mutations.
Databáze: OpenAIRE
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