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

Amelia Shoemark^{1

2

3}, Bruna Rubbo^{4

5

3}, Marie Legendre^{6

7}, Mahmoud R Fassad^{8

9}, Eric G Haarman¹⁰, Sunayna Best^{8

11}, Irma C M Bon¹⁰, Joost Brandsma⁵, Pierre-Regis Burgel^{12

13}, Gunnar Carlsson¹⁴, Siobhan B Carr¹, Mary Carroll^{4

5}, Matt Edwards¹⁵, Estelle Escudier^{6

7}, Isabelle Honoré¹², David Hunt¹⁶, Gregory Jouvion^{6

7}, Michel R Loebinger^{17

18}, Bernard Maitre^{19

20}, Deborah Morris-Rosendahl¹⁵, Jean-Francois Papon^{21

22

23

24}, Camille M Parsons²⁵, Mitali P Patel⁸, N Simon Thomas^{26

27}, Guillaume Thouvenin^{5

28

29}, Woolf T Walker^{4

5}, Robert Wilson¹⁷, Claire Hogg¹, Hannah M Mitchison^{8

30

31}, Jane S Lucas^{32

5

31}

Affiliations

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.

PMID: 33479112
DOI: 10.1183/13993003.02359-2020

Free article

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

Amelia Shoemark et al. Eur Respir J. 2021.

Free article

. 2021 Aug 5;58(2):2002359.

doi: 10.1183/13993003.02359-2020. Print 2021 Aug.

Authors

Affiliations

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.

PMID: 33479112
DOI: 10.1183/13993003.02359-2020

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.

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Conflict of interest statement

Conflict of interest: B. Rubbo has nothing to disclose. Conflict of interest: M. Legendre has nothing to disclose. Conflict of interest: M.R. Fassad has nothing to disclose. Conflict of interest: E.G. Haarman has nothing to disclose. Conflict of interest: S. Best has nothing to disclose. Conflict of interest: I.C.M. Bon has nothing to disclose. Conflict of interest: J. Brandsma has nothing to disclose. Conflict of interest: P-R. Burgel reports personal fees for lectures and advisory board work from AstraZeneca, Boehringer Ingelheim, Chiesi, Novartis, Teva and Vertex, as well as personal fees for lectures from GSK, Pfizer and Zambon, outside the submitted work. Conflict of interest: G. Carlsson has nothing to disclose. Conflict of interest: S.B. Carr reports non-financial support and other (advisory board, lecture fee, travel, steering committee) from Vertex Pharmaceuticals, other (advisory board) from Profile Pharmaceuticals and other (lectures) from Teva Pharmaceuticals, as well as non-financial support and other (advisory board, travel, accommodation) from Chiesi Pharmaceuticals, outside the submitted work. Conflict of interest: M. Carroll has nothing to disclose. Conflict of interest: M. Edwards has nothing to disclose. Conflict of interest: E. Escudier has nothing to disclose. Conflict of interest: I. Honoré has nothing to disclose. Conflict of interest: D. Hunt has nothing to disclose. Conflict of interest: G. Jouvion has nothing to disclose. Conflict of interest: M.R. Loebinger reports personal fees for advisory board work and consultancy from AstraZeneca, Insmed, Polyphor, Bayer and Griffols, outside the submitted work. Conflict of interest: B. Maitre has nothing to disclose. Conflict of interest: D. Morris-Rosendahl has nothing to disclose. Conflict of interest: J-F. Papon has nothing to disclose. Conflict of interest: C.M. Parsons has nothing to disclose. Conflict of interest: M.P. Patel has nothing to disclose. Conflict of interest: N.S. Thomas has nothing to disclose. Conflict of interest: G. Thouvenin has nothing to disclose. Conflict of interest: W.T. Walker has nothing to disclose. Conflict of interest: R. Wilson has nothing to disclose. Conflict of interest: C. Hogg has nothing to disclose. Conflict of interest: H.M. Mitchison has nothing to disclose. Conflict of interest: J.S. Lucas has nothing to disclose. Conflict of interest: A. Shoemark has nothing to disclose.

Comment in

Phenotype-genotype associations in primary ciliary dyskinesia: where do we stand?
Goutaki M, Pedersen ESL. Goutaki M, et al. Eur Respir J. 2021 Aug 5;58(2):2100392. doi: 10.1183/13993003.00392-2021. Print 2021 Aug. Eur Respir J. 2021. PMID: 34353866 No abstract available.

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Comment in

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MeSH terms

Grants and funding

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