Amelia Shoemark1,2,3, Bruna Rubbo4,5,3, Marie Legendre6,7, Mahmoud R Fassad8,9, Eric G Haarman10, Sunayna Best8,11, Irma C M Bon10, Joost Brandsma5, Pierre-Regis Burgel12,13, Gunnar Carlsson14, Siobhan B Carr1, Mary Carroll4,5, Matt Edwards15, Estelle Escudier6,7, Isabelle Honoré12, David Hunt16, Gregory Jouvion6,7, Michel R Loebinger17,18, Bernard Maitre19,20, Deborah Morris-Rosendahl15, Jean-Francois Papon21,22,23,24, Camille M Parsons25, Mitali P Patel8, N Simon Thomas26,27, Guillaume Thouvenin5,28,29, Woolf T Walker4,5, Robert Wilson17, Claire Hogg1, Hannah M Mitchison8,30,31, Jane S Lucas32,5,31. 1. PCD Diagnostic Centre and Dept of Paediatric Respiratory Medicine, Royal Brompton and Harefield NHS Trust, London, UK. 2. Division of Molecular and Clinical Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK. 3. Equal first author contribution. 4. Primary Ciliary Dyskinesia Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK. 5. School of Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, UK. 6. Département de Génétique Médicale, Hôpital Trousseau, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France. 7. Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM) U933, Hôpital Trousseau, Paris, France. 8. Genetics and Genomic Medicine Dept, University College London, UCL Great Ormond Street Institute of Child Health, London, UK. 9. Dept of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt. 10. Dept of Pediatric Pulmonology, Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. 11. Leeds Institute of Medical Research, Faculty of Medicine and Health, University of Leeds, Leeds, UK. 12. Service de Pneumologie, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France. 13. Université de Paris, Institut National de la Santé et de la Recherche Médicale (INSERM) U1016, Institut Cochin, Paris, France. 14. Dept of Mathematics, Stanford University, Stanford, CA, USA. 15. Clinical Genetics and Genomics, Royal Brompton and Harefield NHS Foundation Trust, London, UK. 16. Wessex Clinical Genetics Service, University Hospitals Southampton, Princess Anne Hospital, Southampton, UK. 17. Host Defence Unit, Dept of Respiratory Medicine, Royal Brompton and Harefield NHS Foundation Trust, London, UK. 18. National Heart and Lung Institute (NHLI), Imperial College, London, UK. 19. Service de Pneumologie, DHU A-TVB, Centre Hospitalier Intercommunal de Créteil, Université Paris Est, Créteil, France. 20. Université Paris Est, Institut National de la Santé et de la Recherche Médicale (INSERM) U955, Institut Mondor de Recherche Biomédicale (IMRB), Créteil, France. 21. Service d'ORL et Chirurgie Cervico-Faciale, Hôpital Kremlin-Bicêtre, Assistance Publique-Hôpitaux de Paris (AP-HP), Le Kremlin-Bicêtre, France. 22. Faculté de Médecine, Université Paris-Saclay, Le Kremlin-Bicêtre, France. 23. Centre national de la recherche scientifique (CNRS) ERL 7240, Créteil, France. 24. Institut National de la Santé et de la Recherche Médicale (INSERM) U955, Créteil, France. 25. Medical Research Council (MRC) Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK. 26. Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury, UK. 27. Human Genetics and Genomic Medicine, University of Southampton Faculty of Medicine, Southampton, UK. 28. Service de Pneumologie Pédiatrique, Hôpital Trousseau, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France. 29. Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM) U938, Centre de Recherche Saint-Antoine, Paris, France. 30. National Institute for Health Research (NIHR) Great Ormond Street Hospital Biomedical Research Centre, London, UK. 31. H.M. Mitchison and J.S. Lucas contributed equally to this article as lead authors and supervised the work. 32. Primary Ciliary Dyskinesia Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK jlucas1@soton.ac.uk.
Abstract
BACKGROUND: Primary 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. METHODS: We 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. RESULTS: Disease 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. CONCLUSIONS: This 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.
BACKGROUND: Primary 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. METHODS: We 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. RESULTS: Disease 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. CONCLUSIONS: This 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.
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