Ty-jour t1 - 拓扑数据分析显示在原发性睫状体缺陷症jf中的基因型 - 表型关系 - 欧洲呼吸杂志jo - 欧元jo - eur reshir J do - 10.1183/13993003.02359-2020 vl - 58是 - 2 sp - 2002359 Au - Shoemark，Amelia Au -Rubbo, Bruna AU - Legendre, Marie AU - Fassad, Mahmoud 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, N. Simon AU - Thouvenin, Guillaume AU - Walker, Woolf T. AU - Wilson, Robert AU - Hogg, Claire AU - Mitchison, Hannah M. AU - Lucas, Jane S. Y1 - 2021/08/01 UR - //www.qdcxjkg.com/content/58/2/2002359.abstract 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 (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.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 ER -