TY - JOUR
T1 - Topological data analysis reveals genotype-phenotype relationships in primary ciliary dyskinesia
AU - Shoemark, Amelia
AU - Rubbo, Bruna
AU - Legendre, Marie
AU - Fassad, Mahmood R.
AU - Haarman, Eric G.
AU - Best, Sunayna
AU - Bon, Irma C. M.
AU - Brandsma, Joost
AU - Burgel, Pierre-Regis
AU - Carlsson, Gunnar
AU - Carr, Siobhan B.
AU - Carroll, Mary
AU - Edwards, Matt
AU - Escudier, Estelle
AU - Honoré, Isabelle
AU - Hunt, David
AU - Jouvion, Gregory
AU - Loebinger, Michel R.
AU - Maitre, Bernard
AU - Morris-Rosendahl, Deborah
AU - Papon, Jean-Francois
AU - Parsons, Camille M.
AU - Patel, Mitali P.
AU - Thomas, Simon N.
AU - Thouvenin, Guillaume
AU - Walker, Woolf T.
AU - Wilson, Robert
AU - Hogg, Claire
AU - Mitchison, Hannah M.
AU - Lucas, Jane S.
N1 - Funding Information:
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.
Publisher Copyright:
© 2021 European Respiratory Society. All rights reserved.
PY - 2021/8/1
Y1 - 2021/8/1
N2 - 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 (FEV 1) 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 FEV 1 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. FEV 1 worse with CCDC39 mutation) and identified new relationships, including FEV 1 preservation with DNAH11 mutations and diversity of severity with DNAH5 mutations.
AB - 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 (FEV 1) 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 FEV 1 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. FEV 1 worse with CCDC39 mutation) and identified new relationships, including FEV 1 preservation with DNAH11 mutations and diversity of severity with DNAH5 mutations.
UR - http://www.scopus.com/inward/record.url?scp=85105402921&partnerID=8YFLogxK
U2 - 10.1183/13993003.02359-2020
DO - 10.1183/13993003.02359-2020
M3 - Article
C2 - 33479112
SN - 0903-1936
VL - 58
JO - European Respiratory Journal
JF - European Respiratory Journal
IS - 2
M1 - 2002359
ER -