Long-Read Sequencing as a Diagnostic Tool for Primary Ciliary Dyskinesia

Primary ciliary dyskinesia (PCD) is a rare, inherited disease resulting from abnormal structure and/or function of cilia. To date, pathogenic variants in over 50 genes have been reported as causes of PCD. One of the genes, HYDIN, presents a diagnostic challenge due to the existence of HYDIN2, a highly homologous pseudogene that significantly complicates accurate molecular diagnosis. Here, we present a 43-year-old female with a clinical diagnosis of PCD seeking molecular diagnosis underlying her disease. Short-read genome sequencing detected two potentially pathogenic HYDIN variants (c.5416C > T and c.3786-1G > T), but clinical validation was hindered due to the pseudogene overlap. Using clinical long-read genome sequencing (lrGS), we confirmed the presence of both HYDIN pathogenic variants and a trans configuration, establishing the molecular diagnosis for this patient. This case highlights the promise of lrGS in diagnosing HYDIN-related PCD and demonstrates that offering lrGS to PCD patients, especially those with suspected HYDIN variants, could enhance diagnostics, disease management, and genetic counseling.