TY - JOUR
T1 - Primary ciliary dyskinesia
T2 - Longitudinal study of lung disease by ultrastructure defect and genotype
AU - and the Genetic Disorders of Mucociliary Clearance Consortium
AU - Davis, Stephanie D.
AU - Rosenfeld, Margaret
AU - Lee, Hye Seung
AU - Ferkol, Thomas W.
AU - Sagel, Scott D.
AU - Dell, Sharon D.
AU - Milla, Carlos
AU - Pittman, Jessica E.
AU - Shapiro, Adam J.
AU - Sullivan, Kelli M.
AU - Nykamp, Keith R.
AU - Krischer, Jeffrey P.
AU - Zariwala, Maimoona A.
AU - Knowles, Michael R.
AU - Leigh, Margaret W.
N1 - Funding Information:
The Genetic Disorders of Mucociliary Clearance (U54HL096458) is a part of the National Center for Advancing Translational Sciences (NCATS) Rare Diseases Clinical Research Network. Rare Diseases Clinical Research Network is an initiative of the Office of Rare Diseases Research, NCATS, funded through a collaboration between NCATS and NHLBI; Clinical and Translational Science Awards NIH/NCATS UNC ULTR000083; R01HL071798; NIH/NCATS Colorado Clinical and Translational Science Awards grant number UL1 TR001082; and Intramural Research Program of NIH/National Institute of Allergy and Infectious Diseases.
Funding Information:
The Genetic Disorders of Mucociliary Clearance (U54HL096458) is a part of the National Center for Advancing Translational Sciences (NCATS) Rare Diseases Clinical Research Network. Rare Diseases Clinical Research Network is an initiative of the Office of Rare Diseases Research, NCATS, funded through a collaboration between NCATS and NHLBI; Clinical and Translational Science Awards NIH/NCATS UNC ULTR000083; R01HL071798; NIH/NCATS Colorado Clinical and Translational Science Awards grant number UL1 TR001082; and Intramural Research Program of NIH/National Institute of Allergy and Infectious Diseases. Acknowledgment: The authors thank the children and families that participated in this study. They acknowledge Susan Minnix, Caroline LaFave, and Kathy Thurlow (research coodinators); Whitney Wolf (research technician) for performing DNA extractions, processing, and sequencing; Kimberly Burns (research technician) for processing the ciliary biopsies for ultrastructural analysis; and Robin Johnson (respiratory therapist), all from the University of North Carolina at Chapel Hill. Charles Clem (respiratory therapist, Indiana University) assisted in overreading lung function test results. They also appreciate the effort and skills provided by Jane Quante (research coordinator, Washington University); Carol Kopecky and Shelley Mann (research coordinators, University of Colorado); Melody Miki (research coordinator, The Hospital for Sick Children, Toronto); Liz Cochrane, Molly Elliott, Sharon McNamara, and Robert Johnson (research coordinators, Children’s Hospital and Regional Medical Center, Seattle); Jackie Zirbes (research coordinator, Stanford University); and Lou Ann Epperson (research coordinator, Indiana University). They also acknowledge Shrikant Mane, Francesc Lopez-Giraldez, and Weilai Dong (Yale Center for Mendelian Genomics; [UM1 HG006504]) for providing whole-exome sequencing and bioinformatics support; and Jay Shendure, Deborah Nickerson, and Michael Bamshad (University of Washington School of Medicine, Seattle [NIH/NHGRI grant U54HG0006493] and Seattle GO Sequencing project [HL-102926]) and the family studies project team for providing whole-exome sequencing and bioinformatics support. Finally, they thank all participants and families who were part of this study.
Publisher Copyright:
Copyright © 2019 by the American Thoracic Society.
PY - 2019/1/15
Y1 - 2019/1/15
N2 - Rationale: In primary ciliary dyskinesia, factors leading to disease heterogeneity are poorly understood. Objectives: To describe early lung disease progression in primary ciliary dyskinesia and identify associations between ultrastructural defects and genotypes with clinical phenotype. Methods: This was a prospective, longitudinal (5 yr), multicenter, observational study. Inclusion criteria were less than 19 years at enrollment and greater than or equal to two annual study visits. Linear mixed effects models including random slope and random intercept were used to evaluate longitudinal associations between the ciliary defect group (or genotype group) and clinical features (percent predicted FEV 1 and weight and height z-scores). Measurements and Main Results: A total of 137 participants completed 732 visits. The group with absent inner dynein arm, central apparatus defects, and microtubular disorganization (IDA/CA/MTD) (n = 41) were significantly younger at diagnosis and in mixed effects models had significantly lower percent predicted FEV 1 and weight and height z-scores than the isolated outer dynein arm defect (n = 55) group. Participants with CCDC39 or CCDC40 mutations (n = 34) had lower percent predicted FEV 1 and weight and height z-scores than those with DNAH5 mutations (n = 36). For the entire cohort, percent predicted FEV 1 decline was heterogeneous with a mean (SE) decline of 0.57 (0.25) percent predicted/yr. Rate of decline was different from zero only in the IDA/MTD/CA group (mean [SE], 21.11 [0.48] percent predicted/yr; P = 0.02). Conclusions: Participants with IDA/MTD/CA defects, which included individuals with CCDC39 or CCDC40 mutations, had worse lung function and growth indices compared with those with outer dynein arm defects and DNAH5 mutations, respectively. The only group with a significant lung function decline over time were participants with IDA/MTD/CA defects.
AB - Rationale: In primary ciliary dyskinesia, factors leading to disease heterogeneity are poorly understood. Objectives: To describe early lung disease progression in primary ciliary dyskinesia and identify associations between ultrastructural defects and genotypes with clinical phenotype. Methods: This was a prospective, longitudinal (5 yr), multicenter, observational study. Inclusion criteria were less than 19 years at enrollment and greater than or equal to two annual study visits. Linear mixed effects models including random slope and random intercept were used to evaluate longitudinal associations between the ciliary defect group (or genotype group) and clinical features (percent predicted FEV 1 and weight and height z-scores). Measurements and Main Results: A total of 137 participants completed 732 visits. The group with absent inner dynein arm, central apparatus defects, and microtubular disorganization (IDA/CA/MTD) (n = 41) were significantly younger at diagnosis and in mixed effects models had significantly lower percent predicted FEV 1 and weight and height z-scores than the isolated outer dynein arm defect (n = 55) group. Participants with CCDC39 or CCDC40 mutations (n = 34) had lower percent predicted FEV 1 and weight and height z-scores than those with DNAH5 mutations (n = 36). For the entire cohort, percent predicted FEV 1 decline was heterogeneous with a mean (SE) decline of 0.57 (0.25) percent predicted/yr. Rate of decline was different from zero only in the IDA/MTD/CA group (mean [SE], 21.11 [0.48] percent predicted/yr; P = 0.02). Conclusions: Participants with IDA/MTD/CA defects, which included individuals with CCDC39 or CCDC40 mutations, had worse lung function and growth indices compared with those with outer dynein arm defects and DNAH5 mutations, respectively. The only group with a significant lung function decline over time were participants with IDA/MTD/CA defects.
KW - Cilia
KW - Kartagener syndrome
KW - Respiratory function tests
UR - http://www.scopus.com/inward/record.url?scp=85060021116&partnerID=8YFLogxK
U2 - 10.1164/rccm.201803-0548OC
DO - 10.1164/rccm.201803-0548OC
M3 - Article
C2 - 30067075
AN - SCOPUS:85060021116
SN - 1073-449X
VL - 199
SP - 190
EP - 198
JO - American journal of respiratory and critical care medicine
JF - American journal of respiratory and critical care medicine
IS - 2
ER -