Non-coding DNA variants increase the genetic diagnostic yield in primary ciliary dyskinesia
Author(s)
Type
Journal Article
Abstract
Rationale
Primary ciliary dyskinesia (PCD) is a rare respiratory disorder of motile cilia caused by pathogenic variants in >50 known genes. Genetic testing routinely examines the coding regions of these genes, and biallelic pathogenic variants are reported in as many as 70% of patients. Many patients remain with an incomplete or no genetic diagnosis.
Objectives
To retrospectively analyze the diagnostic yield in 496 patients referred for genetic testing and the increase in yield by investigating pathogenic DNA variants in the noncoding regions of PCD genes in 42 patients with an incomplete genetic diagnosis.
Methods
End-to-end next-generation gene sequencing including coding and noncoding regions of 17 PCD genes was performed, following routine genetic diagnosis of a panel of more than 46 genes. Intronic variants were prioritized for pathogenicity using in silico tools to predict splice effects that were subsequently confirmed in RNA extracted from nasal epithelium.
Measurements and Main Results
232 of 496 patients (46.8%) had a complete genetic diagnosis of PCD after stringent variant assessment during routine genetic testing. Eighty-six patients (17.3%) had an incomplete genetic diagnosis, 42 of whom had end-to-end gene sequencing. Novel, potentially pathogenic, noncoding variants were identified in 16 of 42 patients (38.1%). Three recurrent deep-intronic variants were found.
Conclusions
Diagnostic yield for PCD is increased by end-to-end gene sequencing. Noncoding variants that affect splicing are recurrent and are an important source of pathogenic genomic variation in patients with PCD. This work illustrates the potential clinical utility of end-to-end gene or genome sequencing for PCD.
Primary ciliary dyskinesia (PCD) is a rare respiratory disorder of motile cilia caused by pathogenic variants in >50 known genes. Genetic testing routinely examines the coding regions of these genes, and biallelic pathogenic variants are reported in as many as 70% of patients. Many patients remain with an incomplete or no genetic diagnosis.
Objectives
To retrospectively analyze the diagnostic yield in 496 patients referred for genetic testing and the increase in yield by investigating pathogenic DNA variants in the noncoding regions of PCD genes in 42 patients with an incomplete genetic diagnosis.
Methods
End-to-end next-generation gene sequencing including coding and noncoding regions of 17 PCD genes was performed, following routine genetic diagnosis of a panel of more than 46 genes. Intronic variants were prioritized for pathogenicity using in silico tools to predict splice effects that were subsequently confirmed in RNA extracted from nasal epithelium.
Measurements and Main Results
232 of 496 patients (46.8%) had a complete genetic diagnosis of PCD after stringent variant assessment during routine genetic testing. Eighty-six patients (17.3%) had an incomplete genetic diagnosis, 42 of whom had end-to-end gene sequencing. Novel, potentially pathogenic, noncoding variants were identified in 16 of 42 patients (38.1%). Three recurrent deep-intronic variants were found.
Conclusions
Diagnostic yield for PCD is increased by end-to-end gene sequencing. Noncoding variants that affect splicing are recurrent and are an important source of pathogenic genomic variation in patients with PCD. This work illustrates the potential clinical utility of end-to-end gene or genome sequencing for PCD.
Date Issued
2025-11-01
Date Acceptance
2025-07-30
Citation
American Journal of Respiratory and Critical Care Medicine, 2025, 211 (11), pp.2043-2052
ISSN
1073-449X
Publisher
American Thoracic Society
Start Page
2043
End Page
2052
Journal / Book Title
American Journal of Respiratory and Critical Care Medicine
Volume
211
Issue
11
Copyright Statement
Copyright © YYYY Copyright Owner. This is the author’s accepted manuscript made available under a CC-BY licence in accordance with Imperial’s Research Publications Open Access policy (www.imperial.ac.uk/oa-policy)
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/40758541
Subjects
Ciliopathy
Genetic testing
Non-coding genome
Primary Ciliary Dyskinesia
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2025-11-01