Systematic Reanalysis of Whole-Exome Sequencing in Genetically Unsolved Pediatric Primary Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder, and despite advances in next-generation sequencing, a substantial proportion of clinically suspected pediatric cases remain without a molecular diagnosis. This persistent diagnostic gap reflects limitations of earlier analysis pipelines and incomplete knowledge of PCD-related genes. Reanalysis of existing whole-exome sequencing (WES) data using updated resources has become a practical strategy to improve diagnostic yield in pediatric populations.

We retrospectively reanalyzed WES data from 34 Turkish pediatric patients with clinical suspicion of PCD evaluated at a tertiary center between 2019 and 2023, all of whom had previously nondiagnostic genetic results. Reanalysis incorporated updated population and disease databases, curated ciliary gene resources, phenotype-driven variant interpretation, and copy number variant (CNV) assessment.

Molecular diagnoses were established in 3 of 34 patients (8.8%) through variants in known PCD genes, demonstrating the incremental value of systematic reanalysis enabled by detection of previously missed CNVs and updated literature evidence. In addition, rare variants in biologically plausible candidate genes were prioritized in 8 cases (23.5%), including genes involved in ciliary structure (RIBC1, NINL, DNAH14, SPMIP2), host defense pathways (USHBP1, CRYBG1, TRIM34), and laterality determination (WDR90).

Systematic WES reanalysis can identify missed molecular diagnoses and prioritize biologically relevant candidate genes in unresolved pediatric PCD cases, supporting future gene discovery and refinement of the genetic architecture of PCD, particularly in populations with high rates of consanguinity.