Clinical application of prospective whole‐exome sequencing in the diagnosis of genetic disease: Experience of a regional disease center in South Korea

Abstract Introduction Next‐generation sequencing helps clinicians diagnose patients with suspected genetic disorders. The current study aimed to investigate the diagnostic yield and clinical utility of prospective whole‐exome sequencing (WES) in rare diseases. Methods WES was performed in 92 patients who presented with clinical symptoms suggestive of genetic disorders. The WES data were analyzed using an in‐house developed software. The patients’ phenotypic characteristics were classified according to the human phenotype ontology. Results WES detected 64 variants, 13 were classified as pathogenic, 26 as likely pathogenic, and 25 as variants of uncertain significance. In 57 patients with these variants, 30 were identified as causal variants. The diagnostic yield was higher in patients with abnormalities in joint mobility and skin morphology than in those with cerebellar hypoplasia/atrophy, epilepsy, global developmental delay, dysmorphic features/facial dysmorphisms, and chronic kidney disease/abnormal renal morphology. Conclusion In this study, a WES‐based variant interpretation system was employed to provide a definitive diagnosis for 28.3% of the patients suspected of having genetic disorders. WES is particularly useful for diagnosing rare diseases with symptoms that affect more than one system, when targeted genetic panels are difficult to employ.