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 investigate 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, twelve clinical and diagnostic variables were included. TDA-driven hypotheses were subsequently tested using traditional statistics.
Results Disease severity at diagnosis measured by FEV1 z-score was (i) significantly worse in individuals with CCDC39 mutations compared to other gene mutations and (ii) 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 variation in phenotype, according to genotype. TDA modelling confirmed genotype-phenotype relationships reported by smaller studies (e.g. FEV1 worse with CCDC39 mutations), and identified new relationships, including FEV1 preservation with DNAH11 mutations and diversity of severity with DNAH5 mutations.
Footnotes
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Conflict of interest: Dr. Shoemark has nothing to disclose.
Conflict of interest: Dr. Rubbo has nothing to disclose.
Conflict of interest: Dr. Legendre has nothing to disclose.
Conflict of interest: Dr. Fassad has nothing to disclose.
Conflict of interest: Dr. Haarman has nothing to disclose.
Conflict of interest: Dr. Best has nothing to disclose.
Conflict of interest: Dr. Bon has nothing to disclose.
Conflict of interest: Dr. Brandsma has nothing to disclose.
Conflict of interest: Dr. Burgel reports personal fees from Astra-Zeneca, personal fees from Boehringer Ingelheim, personal fees from Chiesi, personal fees from GSK, personal fees from Novartis, personal fees from Pfizer, personal fees from Teva, personal fees from Vertex, personal fees from Zambon, outside the submitted work;.
Conflict of interest: Dr. Carr reports non-financial support and other from Vertex Pharmaceuticals, other from Profile Pharmaceuticals, other from Teva Pharmaceuticals, non-financial support and other from Chiesi Pharmaceuticals, outside the submitted work;.
Conflict of interest: Dr. Carroll has nothing to disclose.
Conflict of interest: Dr. Edwards has nothing to disclose.
Conflict of interest: Dr. Escudier has nothing to disclose.
Conflict of interest: Dr. HONORE has nothing to disclose.
Conflict of interest: Dr. Hunt has nothing to disclose.
Conflict of interest: Dr. Jouvion has nothing to disclose.
Conflict of interest: Dr. Loebinger reports personal fees from Astra Zeneca, personal fees from Insmed, personal fees from Polyphor, personal fees from Bayer, personal fees from Griffols, outside the submitted work;.
Conflict of interest: Dr. MAITRE has nothing to disclose.
Conflict of interest: Dr. Morris-Rosendahl has no disclosures to make.
Conflict of interest: Dr. Papon has nothing to disclose.
Conflict of interest: Dr. Parsons has nothing to disclose.
Conflict of interest: Dr. Patel has nothing to disclose.
Conflict of interest: Dr. Thomas has nothing to disclose.
Conflict of interest: Dr. Thouvenin has nothing to disclose.
Conflict of interest: Dr. Walker has nothing to disclose.
Conflict of interest: Dr. Wilson has nothing to disclose.
Conflict of interest: Dr. Hogg has nothing to disclose.
Conflict of interest: Dr. Mitchison has nothing to disclose.
Conflict of interest: Dr. Lucas has nothing to disclose.
- Received June 16, 2020.
- Accepted December 24, 2020.
- ©The authors 2021. For reproduction rights and permissions contact permissions{at}ersnet.org
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