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

  • Chong Kun Cheon (Department of Pediatrics, Pusan National University Children's Hospital, Pusan National University School of Medicine) ;
  • Yong Beom Shin (Department of Rehabilitation, Pusan National University Hospital) ;
  • Soo-Yeon Kim (Department of Rehabilitation Medicine, Pusan National University Yangsan Hospital, Pusan National University School of Medicine) ;
  • Go Hun Seo (3billion Inc.) ;
  • Hane Lee (3billion Inc.) ;
  • Changwon Keum (3billion Inc.) ;
  • Seung Hwan Oh (Department of Laboratory Medicine, Pusan National University Yangsan Hospital)
  • Received : 2022.11.21
  • Accepted : 2022.12.20
  • Published : 2022.12.31

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.

Keywords

Acknowledgement

This work was supported by a 2-Year Research Grant of Pusan National University.

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