Integrative Transcriptomic Analysis Reveals Molecular Signatures and Candidate Therapeutic Targets for Primary Ciliary Dyskinesia

Abstract Primary ciliary dyskinesia (PCD) is a rare genetic disorder arising from motile cilia dysfunction, causing chronic respiratory infections, bronchiectasis, and progressive lung damage. We analysed the GSE25186 microarray dataset (6 PCD vs. 9 controls, Illumina HumanHT-12 V3.0, GPL6947) using an empirical-Bayes moderated t-test with sex-covariate correction. After Benjamini-Hochberg adjustment, 176 genes were differentially expressed (nominal p < 0.01, |log2FC| > 1; no gene reached FDR < 0.05 after multiple-testing correction), with a broader set of 1,014 genes at nominal p < 0.05. After sex correction, biologically coherent PCD-relevant genes (MED13L, DDX58, HLA-C, CLN8, TP53BP2, SLC18A1) emerged at the top of the ranked list. MED13L is a mediator complex subunit that is involved in FOXJ1-driven ciliogenesis. MED13L emerged as the top network hub gene. The WGCNA was unstable at n = 15 (standard requirement >= 20 samples). Therefore, module-trait correlations did not reach significance after permutation testing (all permutation p > 0.05). A fully nested leave-one-out cross-validation pipeline yielded AUC = 0.750 (95% CI 0.43-1.00, permutation p = 0.062). LINCS L1000 connectivity analysis identified curcumin and resveratrol as top repurposing candidates; NAC was not significant (p = 0.37). Molecular docking against MED13L (AlphaFold, CDK8-interaction domain) ranked dexamethasone (−6.2 kcal/mol) and resveratrol (−5.9 kcal/mol) above NAC (−3.7 kcal/mol). The results demonstrate the critical importance of sex-covariate correction, nested cross-validation, and cross-cohort replication in small-cohort rare-disease transcriptomics.