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.
Abstract
Topological data analysis of 396 primary ciliary dyskinesia patients shows genetic mutations of worse (CCDC39), variable (DNAH5) and milder (DNAH11) effects on lung function, offering the potential for more accurately targeted disease management https://bit.ly/3oL5r64
Footnotes
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This article has an editorial commentary: https://doi.org/10.1183/13993003.00392-2021
Author contributions: Concept and design of the study: J.S. Lucas, C. Hogg, H.M. Mitchison, A. Shoemark and B. Rubbo. Genotyping: H.M. Mitchison, M.R. Fassad, M.P. Patel, N.S. Thomas, D. Hunt, M. Edwards, D. Morris-Rosendahl and M. Legendre. Clinical characterisation: J.S. Lucas, C. Hogg, W.T. Walker, M. Carroll, S.B. Carr, M.R. Loebinger, R. Wilson, E.G. Haarman, J-F. Papon, B. Maitre, G. Thouvenin, P-R. Burgel and I. Honoré. TDA models: B. Rubbo, J. Brandsma and G. Carlsson. Data collection: B. Rubbo, A. Shoemark, S. Best, W.T. Walker, C. Hogg, J-F. Papon, B. Maitre, G. Thouvenin, P-R. Burgel, I. Honoré, E.G. Haarman, I.C.M. Bon, E. Escudier, G. Jouvion and M. Legendre. Planned and performed the statistical analyses: B. Rubbo, A. Shoemark, C.M. Parsons and J.S. Lucas. Laboratory analyses and data collection: E. Escudier, G. Jouvion, A. Shoemark, M. Legendre, S. Best, H.M. Mitchison and M.R. Fassad. Interpretation of data analyses: B. Rubbo, A. Shoemark, J.S. Lucas, H.M. Mitchison and C. Hogg. Drafted the manuscript: A. Shoemark, B. Rubbo, J.S. Lucas, H.M. Mitchison and C. Hogg. Revised the manuscript: J.S. Lucas, C. Hogg, H.M. Mitchison, A. Shoemark, B. Rubbo, N.S. Thomas, M. Legendre, M.R. Fassad, W.T. Walker, S.B. Carr, I. Honoré and E. Escudier. All authors read and approved the final manuscript. H.M. Michison (h.mitchison@ucl.ac.uk) was principal investigator for the genetics aspect of the work, and J.S. Lucas (jlucas1@soton.ac.uk) was clinical and epidemiological principal investigator. H.M. Mitchison and J.S. Lucas had full access to all data and take final responsibility for the decision to submit for publication.
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.
Support statement: The PCD Centres in Southampton and London, the Wessex Regional Genetics Laboratory and Wessex Clinical Genetics Service are funded by the National Health Service for England (NHSE). Clinical research in Southampton was supported by the National Institute for Health Research (NIHR) Southampton Respiratory Biomedical Research Centre (BRC) and NIHR Southampton Wellcome Trust Clinical Research Facility. H.M. Mitchison acknowledges support from Action Medical Research, the Great Ormond Street Children's Charity and the NIHR Great Ormond Street Hospital (GOSH) BRC. M.R. Fassad was also supported by the NIHR GOSH BRC and a PhD studentship from the British Council Newton–Mosharafa Fund and the Ministry of Higher Education in Egypt. In France, this work was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), the RaDiCo funded by the French National Research Agency under the specific programme “Investments for the Future” (cohort grant agreement ANR-10-COHO-0003) and the legs Poix grant from La Chancellerie des Universités of the Sorbonne Universités de Paris. The funders had no role in the writing of the manuscript or the decision to submit it for publication. No payment was received to write this article.
- Received June 16, 2020.
- Accepted December 24, 2020.
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