Discovery of novel alleles in Kartagener's syndrome

Kartagener's syndrome (KS) is a rare, typically autosomal recessive ciliopathy and a subtype of primary ciliary dyskinesia (PCD), characterized by situs inversus, bronchiectasis, and chronic sinusitis. KS accounts for approximately 50% of PCD cases and results from impaired motile cilia function. Defective embryonic nodal ciliary beating leads to stochastic left-right axis determination and situs abnormalities. Although numerous genes have been implicated in PCD, up to 30% of cases remain genetically unresolved, and studies specifically focused on KS cohorts remain limited. Here, we performed whole exome sequencing in 17 adult patients from a Turkish KS cohort to identify pathogenic variants and novel candidate genes. Variants were prioritised based on sequencing quality, population allele frequency, and predicted functional impact, and included single-nucleotide variants, small insertions/deletions, and copy-number variations. The restriction of the cohort to individuals with situs inversus provided a phenotype-specific context for variant interpretation, as genes not typically associated with left-right axis determination were less likely to account for disease in this study population. Pathogenic or potentially disease-associated variants were identified in multiple established PCD genes, including DNAH5, DNAI1, DNAI2, DNAAF1, DNAAF3, CFAP300, and ODAD1, with several novel alleles detected. In one patient lacking biallelic variants in known PCD genes, expanded analysis identified heterozygous variants in the cilia-associated genes DLEC1 and DNAAF9 together with a hemizygous copy number loss in EZR, a gene known to affect motile cilia function. The possible relevance of these concurrent findings warrants further investigation in genetically unresolved cases. Overall, analysis of this KS-specific cohort demonstrated a high diagnostic yield, expanded the variant spectrum associated with Kartagener's syndrome, and further supported the utility of phenotype-driven genomic analysis in genetically heterogeneous ciliopathies.