Topological data analysis reveals genotype–phenotype relationships in primary ciliary dyskinesia
Amelia Shoemark
(1, 2)
,
Bruna Rubbo
(3)
,
Marie Legendre
(4, 5)
,
Mahmoud Fassad
(6, 7)
,
Eric Haarman
(8)
,
Sunayna Best
(6, 9)
,
Irma C.M. Bon
(8)
,
Joost Brandsma
(3)
,
Pierre-Regis Burgel
(10, 11)
,
Gunnar Carlsson
(12)
,
Siobhan Carr
(1)
,
Mary Carroll
(3)
,
Matt Edwards
(1)
,
Estelle Escudier
(4, 5)
,
Isabelle Honoré
(10)
,
David Hunt
(3)
,
Gregory Jouvion
(4, 5)
,
Michel Loebinger
(13, 1)
,
Bernard Maitre
(14, 15)
,
Deborah Morris-Rosendahl
(1)
,
Jean-Francois Papon
(16, 17, 18, 19)
,
Camille Parsons
(3)
,
Mitali Patel
(6)
,
N. Simon Thomas
(3)
,
Guillaume Thouvenin
(3, 5, 20)
,
Woolf Walker
(3)
,
Robert Wilson
(1)
,
Claire Hogg
(1, 21)
,
Hannah Mitchison
(6)
,
Jane Lucas
(22, 3)
1
Royal Brompton and Harefield NHS Foundation Trust
2 University of Dundee
3 University of Southampton
4 U933 - Maladies génétiques d'expression pédiatrique
5 CHU Trousseau [APHP]
6 UCL - Great Ormond Street Institute of Child Health
7 Université Senghor [Alexandria]
8 Amsterdam UMC - Amsterdam University Medical Center
9 University of Leeds
10 Service de pneumologie [CHU Cochin]
11 IC UM3 (UMR 8104 / U1016) - Institut Cochin
12 Department of Mathematics [Stanford]
13 NHLI - National Heart and Lung Institute [London]
14 Service de Pneumologie [CHI Créteil]
15 Inserm U955 - Molecular virology and immunology – Physiopathology and therapeutic of chronic viral hepatitis (Team 18)
16 Service d’ORL et de chirurgie cervico-faciale [CHU Le Kremlin-Bicêtre]
17 Faculté de Médecine Paris-Saclay
18 BCR - Biomécanique cellulaire et respiratoire
19 U955 Inserm - UPEC - IMRB - "Biomechanics and Respiratory Apparatus" [Créteil]
20 CRSA - Centre de Recherche Saint-Antoine
21 NIHR Biomedical Research Centre [London]
22 University Hospital Southampton NHS Foundation Trust
2 University of Dundee
3 University of Southampton
4 U933 - Maladies génétiques d'expression pédiatrique
5 CHU Trousseau [APHP]
6 UCL - Great Ormond Street Institute of Child Health
7 Université Senghor [Alexandria]
8 Amsterdam UMC - Amsterdam University Medical Center
9 University of Leeds
10 Service de pneumologie [CHU Cochin]
11 IC UM3 (UMR 8104 / U1016) - Institut Cochin
12 Department of Mathematics [Stanford]
13 NHLI - National Heart and Lung Institute [London]
14 Service de Pneumologie [CHI Créteil]
15 Inserm U955 - Molecular virology and immunology – Physiopathology and therapeutic of chronic viral hepatitis (Team 18)
16 Service d’ORL et de chirurgie cervico-faciale [CHU Le Kremlin-Bicêtre]
17 Faculté de Médecine Paris-Saclay
18 BCR - Biomécanique cellulaire et respiratoire
19 U955 Inserm - UPEC - IMRB - "Biomechanics and Respiratory Apparatus" [Créteil]
20 CRSA - Centre de Recherche Saint-Antoine
21 NIHR Biomedical Research Centre [London]
22 University Hospital Southampton NHS Foundation Trust
Amelia Shoemark
- Fonction : Auteur
- PersonId : 1168550
- ORCID : 0000-0001-7360-6060
Bruna Rubbo
- Fonction : Auteur
- PersonId : 817484
- ORCID : 0000-0002-1629-8601
Marie Legendre
- Fonction : Auteur
- PersonId : 1147534
- IdHAL : marie-legendre
- ORCID : 0000-0003-2178-0846
Pierre-Regis Burgel
- Fonction : Auteur
- PersonId : 756824
- ORCID : 0000-0003-0903-9828
- IdRef : 097685003
Siobhan Carr
- Fonction : Auteur
- PersonId : 1168629
- ORCID : 0000-0003-0580-2478
Estelle Escudier
- Fonction : Auteur
- PersonId : 1213534
- IdHAL : estelle-escudier
- ORCID : 0000-0002-1569-8072
- IdRef : 033701997
Gregory Jouvion
- Fonction : Auteur
- PersonId : 951348
- ORCID : 0000-0003-0188-2554
- IdRef : 076698416
Guillaume Thouvenin
- Fonction : Auteur
- PersonId : 763642
- ORCID : 0000-0003-0528-5458
Jane Lucas
- Fonction : Auteur
- PersonId : 1168631
- ORCID : 0000-0001-8701-9975
Résumé
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.
Domaines
Génétique humaine
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