Two Distinct Clinical Presentations of Primary Ciliary Dyskinesia (PCD): Diagnostic Utility of Whole-Exome Sequencing in a Genetically Heterogeneous Disorder

Abstract: Primary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous disorder with variable clinical presentation. In cases where traditional diagnostic tools such as transmission electron microscopy (TEM) or nasal nitric oxide (nNO) measurement are inconclusive/unavailable, molecular diagnostics via whole-exome sequencing (WES) may provide essential insights. In this case report, we present two male infants with diverse phenotypes and genotypes. 1st patient was ultimately diagnosed with PCD thanks to WES, while 2nd patient was strongly suggestive of PCD. The 1st patient portrayed in his clinical history symptoms such as perinatal respiratory distress, situs inversus, and recurrent otitis media. He was found to carry a known pathogenic homozygous variant c.461A>C (p.His154Pro), in the CCDC103 gene. The second patient exhibited more complex phenotype, including diaphragmatic hernia, absence of the pericardium, significant delay in the motor development. WES identified two variants in both DNAH5 and DNAH9 . Parental testing identified the maternal origin for the c.10243-6C>T (p.?) and c.308del (p.Phe103Serfs*31) variants in the DNAH9 gene and a paternal origin for the c.1206T>A (p.Asn402Lys) variant in the DNAH5 gene. The second variant c.5124G>T (p.Glu1708Asp) in the DNAH5 gene in the proband arose de novo. At the time of analysis, these variants were classified as variants of uncertain significance (VUS) or likely benign, with limited segregation data and no definitive functional validation. Although the genetic findings were not diagnostic on their own, the clinical picture (situs inversus, neonatal respiratory distress, recurrent infections) was strongly suggestive of PCD. Both cases illustrate the crucial role of WES in establishing a molecular diagnosis of PCD, particularly when the use of traditional diagnostic methods is inconclusive. Moreover, they demonstrate the value of genomic testing in guiding the clinical management and informing about prognosis in diseases like PCD. Keywords: DNAH5, DNAH9, CCD103, WES, pediatric