DOI QR코드

DOI QR Code

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)
  • 투고 : 2022.11.21
  • 심사 : 2022.12.20
  • 발행 : 2022.12.31

초록

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.

키워드

과제정보

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

참고문헌

  1. Haendel M, Vasilevsky N, Unni D, Bologa C, Harris N, Rehm H, et al. How many rare diseases are there? Nat Rev Drug Discov 2020;19:77-8.  https://doi.org/10.1038/d41573-019-00180-y
  2. Moon D, Park HW, Surl D, Won D, Lee ST, Shin S, et al. Precision medicine through next-generation sequencing in inherited eye diseases in a Korean cohort. Genes (Basel) 2021;13:27. 
  3. Ghaoui R, Cooper ST, Lek M, Jones K, Corbett A, Reddel SW, et al. Use of whole-exome sequencing for diagnosis of limb-girdle muscular dystrophy: outcomes and lessons learned. JAMA Neurol 2015;72:1424-32.  https://doi.org/10.1001/jamaneurol.2015.2274
  4. Tan TY, Dillon OJ, Stark Z, Schofield D, Alam K, Shrestha R, et al. Diagnostic impact and cost-effectiveness of whole-exome sequencing for ambulant children with suspected monogenic conditions. JAMA Pediatr 2017;171:855-62.  https://doi.org/10.1001/jamapediatrics.2017.1755
  5. Retterer K, Juusola J, Cho MT, Vitazka P, Millan F, Gibellini F, et al. Clinical application of whole-exome sequencing across clinical indications. Genet Med 2016;18:696-704.  https://doi.org/10.1038/gim.2015.148
  6. Nolan D, Carlson M. Whole exome sequencing in pediatric neurology patients: clinical implications and estimated cost analysis. J Child Neurol 2016;31:887-94.  https://doi.org/10.1177/0883073815627880
  7. Srivastava S, Love-Nichols JA, Dies KA, Ledbetter DH, Martin CL, Chung WK, et al.; NDD Exome Scoping Review Work Group. Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders. Genet Med 2019;21:2413-21. Erratum in: Genet Med 2020;22:1731-2. 
  8. Wang F, Zhu L, Liu B, Zhu X, Wang N, Deng T, et al. Noninvasive and accurate detection of hereditary hearing loss mutations with buccal swab based on droplet digital PCR. Anal Chem 2018;90:8919-26.  https://doi.org/10.1021/acs.analchem.8b01096
  9. Harari S. Why we should care about ultra-rare disease. Eur Respir Rev 2016;25:101-3.  https://doi.org/10.1183/16000617.0017-2016
  10. Monroe GR, Frederix GW, Savelberg SM, de Vries TI, Duran KJ, van der Smagt JJ, et al. Effectiveness of whole-exome sequencing and costs of the traditional diagnostic trajectory in children with intellectual disability. Genet Med 2016;18:949-56.  https://doi.org/10.1038/gim.2015.200
  11. Said M, Cappiello C, Devaney JM, Podini D, Beres AL, Vukmanovic S, et al. Genomics in premature infants: a non-invasive strategy to obtain high-quality DNA. Sci Rep 2014;4:4286. 
  12. Huang Z, Sun Y, Fan Y, Wang L, Liu H, Gong Z, et al. Genetic evaluation of 114 Chinese short stature children in the next generation era: a single center study. Cell Physiol Biochem 2018;49:295-305.  https://doi.org/10.1159/000492879
  13. Retterer K, Juusola J, Cho MT, Vitazka P, Millan F, Gibellini F, et al. Clinical application of whole-exome sequencing across clinical indications. Genet Med 2016;18:696-704.  https://doi.org/10.1038/gim.2015.148
  14. Zamani M, Sedighzadeh S, Seifi T, Negahdari S, Zeighami J, Sedaghat A, et al. Whole-exome sequencing deciphers the genetic profile of visual impairments in patients from Southwest Iran. Mol Genet Genomics 2022;297:1289-300. https://doi.org/10.1007/s00438-022-01917-y