Prospective evaluation of the clinical utility of whole-exome sequencing using buccal swabbing for undiagnosed rare diseases

ABSTRACT

Purpose@#Whole-exome sequencing (WES) has been a useful tool for novel gene discovery of various disease categories, further increasing the diagnostic yield. This study aimed to investigate the clinical utility of WES prospectively in undiagnosed genetic diseases. @*Materials and Methods@#WES tests were performed on 110 patients (age range, 0-28 years) with suspected rare genetic diseases. WES tests were performed at a single reference laboratory and the variants reported were reviewed by clinical geneticists, pediatricians, neurologists, and laboratory physicians. @*Results@#The patients’ symptoms varied with abnormalities in the head or neck, including facial dysmorphism, being the most common, identified in 85.4% of patients, followed by abnormalities in the nervous system (83.6%). The average number of systems manifesting phenotypic abnormalities per patient was 3.9±1.7. The age at presentation was 2.1±2.7 years old (range, 0-15 years), and the age at WES testing was 6.7±5.3 years (range, 0-28 years). In total, WES test reported 100 pathogenic/likely pathogenic variants or variants of uncertain significance for 79 out of 110 probands (71.8%). Of the 79 patients with positive or inconclusive calls, 55 (50.0%) patients were determined to have good genotype-phenotype correlations after careful review. Further clinical reassessment and family member testing determined 45 (40.9%) patients to have been identified with a molecular diagnosis. @*Conclusion@#This study showed a 40.9% diagnostic yield for WES test for a heterogeneous patient cohort with suspected rare genetic diseases. WES could be the feasible genetic test modality to overcome the diversity and complexity of rare disease diagnostics.