Noncoding DNA Variants Increase the Genetic Diagnostic Yield in Primary Ciliary Dyskinesia

TY - JOUR

T1 - Noncoding DNA Variants Increase the Genetic Diagnostic Yield in Primary Ciliary Dyskinesia

AU - Briggs, Lizi

AU - Brandão, Cátia

AU - Fleming, Andrew

AU - Edwards, Matthew

AU - Mueller, Steven

AU - Wilkinson, Sam

AU - Rogers, Andrew

AU - Quinn, Ellie

AU - Rai, Ranjit

AU - Hogg, Claire

AU - Bottier, Matthieu

AU - Burgoyne, Tom

AU - Carr, Siobhan

AU - Gardner, Laura

AU - Jones, Andrew

AU - Loebinger, Michael

AU - Mitchison, Hannah M.

AU - Jose, Ricardo

AU - Shah, Anand

AU - Shoemark, Amelia

AU - Slater, Amy

AU - John, Shibu

AU - Morris-Rosendahl, Deborah J.

N1 - Publisher Copyright: Copyright © 2025 by the American Thoracic Society

PY - 2025/11

Y1 - 2025/11

N2 - 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.

AB - 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.

KW - ciliopathy

KW - genetic testing

KW - noncoding genome

KW - primary ciliary dyskinesia

UR - https://www.scopus.com/pages/publications/105028944817

U2 - 10.1164/rccm.202501-0186OC

DO - 10.1164/rccm.202501-0186OC

M3 - Article

C2 - 40758541

AN - SCOPUS:105028944817

SN - 1073-449X

VL - 211

SP - 2043

EP - 2052

JO - American Journal of Respiratory and Critical Care Medicine

JF - American Journal of Respiratory and Critical Care Medicine

IS - 11

ER -